The structure and function of the kidney are described in detail in Chapter 2 . A brief summary is provided here to serve as the context for understanding kidney metabolism. The structure and function of the kidney are highly compartmentalized. The primary functional unit of the kidney is the nephron. The number of nephrons averages approximately 1 million in a human kidney. Each nephron consists of a glomerulus and a Bowman capsule connected serially to a proximal tubule, a loop of Henle, and a distal tubule. Several nephrons drain into a shared collecting duct. Tubular segments have distinct transport characteristics. The glomerulus filters the plasma in bulk, and 98% of the filtered water and sodium is reabsorbed by the tubule. The afferent arteriole feeds blood to the capillary tuft in the glomerulus, while the efferent arteriole drains the glomerulus and then forms a second capillary network that surrounds the tubule before returning blood to the veins. Juxtamedullary nephrons, of which the glomeruli are in the deeper region of the renal cortex close to the renal medulla, have long loops of Henle that extend to the renal inner medulla. Special capillaries called vasa recta run along these long loops of Henle, an anatomic arrangement that is essential for urinary concentration.

Substrates enter the kidney by renal blood flow (RBF) and glomerular filtration and enter renal epithelial cells by substrate transporters, often facilitated by the inward-directed Na ⁺ gradient created by the sodium pump, as discussed thoroughly in Chapter 8 . Oxygen is likewise delivered by RBF to the epithelial cells. Once in the cell, substrates face one of three fates: 1. transport across the epithelium back into the blood (reabsorption); 2. conversion into another substrate (e.g., lactate to pyruvate); or 3. oxidization to CO ₂ in the process of cellular ATP production.

A detailed description of the biochemistry of fuel metabolism can be found in biochemistry textbooks. The aspects of fuel metabolism that are relevant to the kidney are summarized here to provide a foundation for detailed discussions of kidney metabolism in later parts of the chapter. A variety of substrates may be used as fuel in the kidney ( Fig. 5.2 ). Long-chain free fatty acids are modified to form acyl-coenzyme A (CoA) in the cytosol, transported into mitochondria via the carnitine shuttle, and converted to acetyl-CoA via β oxidation. Fatty acids with shorter chains, including those produced from very long chains by peroxisomes, may diffuse into mitochondria without using the carnitine shuttle. Acetyl-CoA reacts with 4-carbon oxaloacetate to form 6-carbon citrate. Citrate is converted to a series of metabolic intermediates in the tricarboxylic acid (TCA) cycle, during which reduced nicotinamide adenine dinucleotide (NADH) and reduced flavin adenine dinucleotide (FADH2) are produced. Fatty acid metabolism produces ketone bodies, especially β-hydroxybutyrate, which may also be used to generate acetyl-CoA and enter the TCA cycle in the kidney. Glucose is metabolized to pyruvate through glycolysis, which produces two net ATP and two NADH. Pyruvate may be converted to lactate or enter the TCA cycle in the form of acetyl-CoA. Lactate may be converted back to pyruvate, which may either feed the TCA cycle or generate glucose via the gluconeogenesis pathway. The latter may form part of the Cori cycle. Glutamine contributes to ATP production when it is converted to glutamate and subsequently the TCA cycle intermediate α-ketoglutarate. Other amino acids may be catabolized to produce acetyl-CoA and other metabolites and enter the TCA cycle. Some circulating TCA cycle intermediates also may be taken up by the kidneys and used as fuel.

Major substrate metabolic pathways in the kidney.

To make the figure legible, only rate-limiting or key enzymes are shown, and arrows that contain multiple enzymatic steps are shown as dashed arrows. The box surrounded by the dashed line indicates mitochondria. α-KGDH, α-Ketoglutarate dehydrogenase; CPT1, carnitine palmitoyltransferase I; CS, citrate synthase; FBP, fructose 1,6-bisphosphatase; GLS, glutaminase; HK, hexokinase; HMGCS2, mitochondrial HMG-CoA synthetase; IDH, isocitrate dehydrogenase; PEPCK-C, cytosolic phosphoenolpyruvate carboxykinase; PFK-1, phosphofructokinase-1; PK, pyruvate kinase; SCOT, succinyl-CoA:3-ketoacid-CoA transferase.

From Tian Z, Liang M. Renal metabolism and hypertension. Nat Commun. 2021;12:963.

Renal epithelia, except in the descending and thin ascending limbs of the loop of Henle, are packed with mitochondria (see Chapter 2 ). All the pathways of fuel oxidation take place in the mitochondrial matrix, except for glycolysis, which occurs in the cytosol. Substrates in the cytosol can freely cross the outer mitochondrial membrane through integral membrane porins. These substrates, as well as adenosine diphosphate (ADP) and phosphate (the building blocks of ATP), cross the inner mitochondrial membrane into the mitochondrial matrix via specific substrate transporters driven by their respective concentration gradients or by the H ⁺ gradient created by the electron transport chain (ETC; Fig. 5.3 ).

Whittam model.

Coupling of adenosine triphosphate (ATP) utilization by Na ⁺ -K ⁺ -ATPase to ATP production by mitochondrial oxygen consumption (Q o ₂ ). Hydrolysis of ATP produces ADP plus inorganic phosphate (Pi), which lowers the ATP/ADP ratio, a signal to increase ADP uptake into the mitochondria and increase ATP synthesis.

As illustrated in Fig. 5.4 , amino acids, fatty acids, and pyruvate are metabolized to acetyl-CoA and enter the TCA cycle. With each turn of the cycle, three molecules of NADH, one molecule of FADH2, one molecule of guanosine triphosphate (GTP) or ATP, and two molecules of CO ₂ are released in oxidative decarboxylation reactions ( Table 5.1 ). Electrons carried by NADH and FADH2 are transferred into the mitochondrial ETC, a series of integral membrane complexes located within the inner mitochondrial membrane, where the electrons are sequentially transferred, ultimately to oxygen, which is reduced to H ₂ O. NADH and FADH2 oxidization provoke the transport of H ⁺ from the matrix to the inner mitochondrial space.

Catabolism of proteins, fats, and carbohydrates in three stages of cellular respiration.

Stage 1: oxidation of fatty acids, glucose, and some amino acids yields acetyl–coenzyme A ( CoA ). Stage 2: oxidation of acetyl groups in the citric acid cycle includes four steps in which electrons are abstracted. Stage 3: electrons carried by reduced nicotinamide adenine dinucleotide ( NADH ) and reduced flavin adenine dinucleotide ( FADH ₂ ) are funneled into a chain of mitochondrial (or, in bacteria, plasma membrane–bound) electron carriers (the respiratory chain) that ultimately reduces O ₂ to H ₂ O. This electron flow drives the production of ATP. Also indicated are two proximal tubule pathways: 1. oxidation of lactate through pyruvate and acetyl-CoA and 2. glutamine conversion to glutamate and α-ketoglutarate in the mitochondria with the production of two molecules of NH ₃ , which is the main source of NH ₃ secreted during acidosis.

Modified from Nelson DL, Cox MM. Lehninger Principles of Biochemistry . 5th ed. New York: WH Freeman; 2008.

The release of the potential energy stored in the H ⁺ gradient across the inner mitochondrial membrane provides the driving force for ATP synthesis from ADP by the ATP synthase: H ⁺ is transported into the matrix coupled to the production of ATP from ADP and inorganic phosphate (Pi) (see Fig. 5.3 ). The newly synthesized ATP is extruded from the matrix into the intermembrane space via the ADP–ATP countertransporter known as adenine nucleotide translocase and then exits the mitochondria across the permeable outer membrane. In the cytosol, ATP is available to bind to ATPases such as plasma membrane Na ⁺ -K ⁺ -ATPase. Complete oxidation of palmitate, a 16-carbon fatty acid, produces up to 129 ATP, and a molecule of glucose produces up to 38 ATP if it is metabolized completely through the TCA cycle. The actual number of ATP molecules produced is lower because of several reasons.

The oxidation of substrates is coupled to ATP synthesis by an electrochemical proton gradient. This coupling can be influenced by uncoupling protein isoforms (UCPs) located in the mitochondrial inner membrane and expressed in a tissue-specific manner. UCPs create a proton leak that dissipates the proton gradient available to drive oxidative phosphorylation (see Fig. 5.3 ). It has been reported that UCP-2 is expressed in the renal proximal tubule and thick ascending limb (TAL) (not in glomerulus or the distal nephron) and that its expression is elevated in kidneys of diabetic rats.

In addition to a high specific metabolic rate, kidney metabolism is unique in that most, possibly 80% or more, of the oxygen consumed by the kidney is used to support active transport, primarily by fueling Na ⁺ -K ⁺ -ATPase. Another prominent feature of kidney metabolism is that blood flow and tissue oxygenation vary substantially between kidney regions. The high blood flow in the renal cortex exceeds the tissue’s metabolic needs but is necessary for the bulk filtration at glomeruli that is essential for removing whole-body metabolic wastes. The partial pressure of oxygen (PO ₂ ) is about 50 mm Hg in the renal cortex. Tissue PO ₂ decreases gradually into the renal medulla, reaching 10 to 15 mm Hg in the renal inner medulla. These features are important for understanding kidney metabolism and its relation with kidney function and disease as detailed later in this chapter.

Sampling of arterial blood, renal venous blood, and urine, coupled with unbiased metabolomic analysis, is a powerful approach for understanding the whole kidney handling of metabolites. The difference in the level of a metabolite in the renal venous blood compared with arterial blood is equal to the kidney production minus consumption and excretion of the metabolite.

In overnight-fasted and briefly anesthetized adult pigs (∼50 kg), quantitative analysis of several hundred metabolites in arterial and renal venous serum and urine reveals that a large number of metabolites are cleared by the kidneys. However, except for typical metabolic waste products such as uric acid and creatinine, a strong correlation was observed between the reabsorption efficiency of water-soluble metabolites and these metabolites’ concentrations in the blood. In other words, more abundant metabolites are more effectively reabsorbed, which may contribute to preserving circulating metabolite levels. In these overnight-fasted and briefly anesthetized pigs, kidneys have a net production of glucose, likely because of the gluconeogenic capability of kidneys. Kidneys also produce glycocyamine, guanosine, allantoate, and phenylacetate. Kidneys release significant amounts of several amino acids.

Kidneys take up a significant amount of the TCA cycle intermediate citrate. The amount of citrate taken up by kidneys is less only than lactate, uric acid, and glutamine. Tracing the fate of intravenously infused ¹³ C-labeled substrates reveals that citrate contributes up to 20% of the kidney TCA cycle, making citrate one of the largest contributors to the kidney TCA cycle. This is unique to kidneys as citrate does not contribute significantly to the TCA cycle in other organs. Other intravenously infused TCA cycle intermediates such as malate and succinate do not contribute significantly to the kidney TCA cycle.

Kidneys also consume medium and long-chain acylcarnitine and exhibit significant uptake of C5:0, C6:0, C8:0, C10:0, C10:1, C12:0, C12:1, C14:0, C14:1, C14:2, and C16:1 without release into urine. In addition, kidneys use the short-chain fatty acid acetate, which may be produced by the gut microbiota and other organs, as fuel for TCA metabolism and a substrate for ketone body synthesis.

In a study of conscious, freely moving Sprague-Dawley rats, Shimada and colleagues analyzed the metabolome in the arterial and renal venous blood and urine and calculated metabolite balance to identify metabolites that had net production or net consumption or loss by the kidney. They found that glucose was being net produced in the kidney in rats fed a normal-salt diet but not after the rats had been switched to a high-salt diet. The net production of lactate became significant at days 14 and 21 of the high-salt diet. A net consumption of citrate was found with the low-salt diet, which was sustained at most time points analyzed on the high-salt diet. There was a net consumption or loss of α-ketoglutarate in the low-salt–fed rats.

Few studies have simultaneously analyzed the metabolomes in arterial and renal venous blood in humans. Rhee and colleagues collected arterial and renal venous plasma from nine individuals. The patients were referred for heart catheterization as part of their routine clinical care and were fasting at the time of their procedure. Plasma samples were obtained from a renal vein and the abdominal aorta before coronary artery catheterization. More than 200 metabolites were identified in these samples. Creatinine levels showed a renal venous-to-arterial (rV/A) ratio of 0.84. Several dozen metabolites showed rV/A ratios less than 1 consistently across subjects, indicating net loss of these metabolites as they pass through the kidney. Among them, hippuric acid, malate, xanthosine, and β-aminoisobutyric acid had rV/A ratios <0.50. Arginine (rV/A ratio 1.20) and serine (rV/A ratio 1.53) were among the metabolites that showed rV/A ratios >1 consistently across subjects, indicating net release of these metabolites from the kidney into the renal vein. Lipid metabolite levels were largely unchanged as they passed from the artery to the renal vein.

The metabolism of a specific substance and the activities of the metabolic pathways involved can be assessed by tracing the metabolic products of the substance. The tracing can be achieved by approaches of fluxomics. In vivo fluxomics involves injecting a substance with stable isotope labeling into an organism, followed by analyzing the levels of isotope-labeled metabolites in the tissue of interest.

Hui and colleagues ^, performed fluxomic studies in mice for 15 ¹³ C-labeled circulating metabolites or groups of metabolites. Each of the isotope-labeled metabolites was infused at a rate that resulted in 10% to 15% final enrichment of tracer in serum. They measured tissue succinate and malate labeling to assess the direct contribution of each of the circulating metabolites to the TCA cycle in a given tissue, taking into account the circulating level of the metabolite and interconversion of circulating nutrients.

In the kidneys of fed mice on a carbohydrate diet, lactate accounts for 44% of the TCA cycle labeling, followed by approximately 20% from fatty acids and 10% each from glutamine and citrate. Short-chain fatty acid acetate, ketone body 3-hydroxybutyrate (3-HB), and a group of nonglutamine amino acids each contributes about 5%. Glycerol and glucose make small but appreciable contributions. The distribution of sources of tissue TCA metabolites in fasted mice on a carbohydrate diet is similar with fed mice, except for modest shifts to greater contributions of fatty acids, acetate, and 3-HB and fewer contributions of lactate and glucose. The glucose infusion resulted in strong labeling of lactate in the kidney, while the lactate infusion resulted in more labeling of TCA intermediates. This is consistent with the presence of glycolytic cells in the kidney that metabolize glucose to lactate and oxidative cells that use lactate to feed the TCA cycle.

It is important to note that the TCA contributions do not always correspond to tissue energy sources. In addition, fluxomic data are sensitive to experimental conditions including the amount of the tracer injected and the timing of tissue collection relative to the tracer injection. Finally, metabolic characteristics of mice may differ in some respects from larger mammals including humans. For example, mice devote a large fraction of energy to maintaining body heat.

Spatial metabolomics refers to the study of the metabolome in the spatial context of the tissue, which is enabled by advances in imaging mass spectrometry. Several lipids and other metabolites have been detected in kidneys using spatial metabolomic approaches. Spatial metabolomics may be combined with fluxomics to reveal metabolic pathway activities in specific regions or tissues in the kidney.

Wang and colleagues infused ¹³ C- or ¹⁵ N-labeled nutrients into fasted mice and analyzed cryosections of the kidney using matrix-assisted laser desorption/ionization mass spectrometry imaging. Histologic or immunohistochemical analyses were performed in adjacent tissue sections to obtain anatomic information, and liquid chromatography (LC)–MS analysis was performed to validate mass spectrometry imaging signal assignments. Infusion of [U- ¹³ C]glucose resulted in the production of ¹³ C6-UDP-glucose, an indication of glycolytic activities, primarily in the renal medulla. Infusion of [U- ¹³ C]glycerol resulted in the production of ¹³ C3-UDP-glucose, an indication of gluconeogenesis, predominantly in the renal cortex. With malate as the readout, it was determined that lactate and citrate were the largest direct contributors to the TCA cycle carbon in the cortex. Lactate and free fatty acids were the largest direct contributors to the TCA cycle carbon in the medulla. In each kidney region, glucose contributes to TCA cycle intermediates primarily indirectly via circulating lactate. Glycerol and glutamine labeled the cortex more than the medulla. However, the detected labeling differences across kidney regions were modest for most substrates tested, which may be in part due to technical limitations.

The spatial labeling of the infused substrate and its downstream metabolites can be explained by the tissue distribution of transporters and enzymes in some cases. For example, following the [U- ¹³ C]glutamine infusion, glutamine itself was most intensely labeled in the medulla, while malate was most intensely labeled in the cortex. The medulla has low levels of protein expression of glutamine synthetase and glutaminase. Therefore the infused glutamine is not diluted or metabolized substantially in the medulla. The cortex has high levels of glutaminase and glutamate dehydrogenase expression, which explains the high degree of conversion of glutamine to downstream metabolites. These findings support the value of using gene expression or enzymatic activity analysis to predict in vivo metabolic activities in specific cell types or tissue regions in the kidney as detailed in later parts of this chapter.

Applying the combination of fluxomics and spatial metabolomics to study 350-μm-thick vibratome slices of fresh mouse kidney, Wang and colleagues were able to measure several endogenous and ¹³ C-labeled metabolites from glycolysis and the TCA cycle, as well as branching metabolites. They found significant differences between the S1/S2 and S3 segments of the proximal tubule. The S3 segment, which is in kidney regions with lower oxygen levels, showed higher glycolytic activities and lower TCA cycle activities, compared to the S1/S2 segments. In addition, they found greater glycolytic activities and lower TCA cycle activities in proximal tubules in sections of kidneys from mice subjected to ischemia-reperfusion injury. Such metabolic disturbances were observed even in proximal tubules that appeared normal, which is reminiscent of the substantial molecular alterations observed in histologically normal glomeruli and tubulointerstitial regions in patients with focal segmental glomerulosclerosis.

Spatial metabolomics, alone or in combination with fluxomics, holds great promise for revealing metabolic activities in specific cell types in vivo, which will be especially informative for histologically and metabolically complex organs such as the kidney. This approach will benefit from technologic advances that improve spatial resolution of the metabolite analysis, as well as detection and accurate quantification of a larger number of metabolites.

Kidney metabolism is closely linked with kidney tissue oxygenation. Determinants of renal oxygenation and tissue oxygen tension (PO ₂ ) include 1. RBF and oxygen content of arterial blood; 2. the oxygen consumed by the cells, which is largely determined by tubular transport activities; and 3. arterial-to-venous (AV) oxygen shunting, which entails the diffusion of oxygen from preglomerular arteries to postglomerular veins without being available to the cell for consumption.

The kidney receives a high blood flow, nearly 25% of the cardiac output, which is needed to sustain glomerular filtration rate (GFR). Compared with other major body organs, renal QO ₂ (product of RBF and renal oxygen extraction) per gram of tissue is high, second only to the heart (2.7 mmol/kg/min vs. 4.3 mmol/kg/min for the heart). The phenomenon of O ₂ shunting from descending to ascending vasa recta in the medulla has been accepted, ^, yet little else is known regarding the location of shunting in the cortex or its impact on oxygenation.

Countercurrent flow in “hairpin loops” formed by the vasa recta facilitates the recycling of solutes to the inner medulla, where a high osmolarity is essential to the formation of concentrated urine (see Chapter 10 ). As an inherent consequence of this countercurrent mechanism for maintaining a medullary osmotic gradient, there arises a negative oxygen gradient from cortex to inner medulla, where PO ₂ falls to 10 mm Hg. This results from the combination of slow blood flow through the vasa recta, O ₂ consumption by active transport in the outer medullary TAL, and diffusion of O ₂ from descending to ascending vasa recta. This leaves the medullary tissue at the brink of hypoxia, especially the stripe of outer medulla where the S3 segment of the proximal tubule and medullary TAL lie, making these segments most vulnerable to ischemic injury as they reabsorb significant fractions of filtered Na ⁺ .

In most organs, tissue oxygen can be stabilized by metabolic regulation of blood flow. In such an arrangement, vasoactive end products of metabolism due to increased metabolic activity and oxygen utilization produce a signal that results in more blood flow to that organ. A unique feature of renal oxygenation is that the kidney cannot rely on this mode of metabolic autoregulation because, unlike other organs that receive blood solely to supply the metabolic needs of the organ, the kidney also receives blood to perform the functions of glomerular filtration and tubule transport.

RBF creates its own demand because it determines GFR, which in turn determines the rate of sodium reabsorption, which is the main determinant of QO ₂ . ^, If the kidneys were to modulate RBF as a means of stabilizing renal O ₂ content, this would create a vicious cycle of positive feedback in which increased O ₂ delivery would increase O ₂ consumption, which would call for more O ₂ delivery. Positive feedback is inherently destabilizing, so this arrangement alone could not work to stabilize either RBF or renal O ₂ content. Hence the kidney is compelled to invoke mechanisms that are more complex. There are two generic routes for the kidney to stabilize its O ₂ content. One is to dissociate RBF from GFR. The other is to alter the metabolic efficiency of Na ⁺ transport.

The rate at which the kidney consumes oxygen is linked to GFR. This is because the main use of oxygen is to support the reabsorption of the filtered sodium, which is linked to GFR by glomerulotubular balance (GTB). GTB describes the direct effect of the filtered load on tubular reabsorption, and it operates in all nephron segments, although the mechanism differs between segments. In the proximal tubule, shear strain tied to increased tubular flow exerts torque on the apical microvilli, which leads to upregulation of apical sodium transporters. ^, In cases in which filtration fraction increases, the parallel increase in peritubular capillary oncotic pressure will increase the Starling force driving fluid reabsorption. In the TAL, flux through NKCC2 is limited by chloride concentration, which declines more slowly along the TAL at high flow rates. On the other hand, increased flow rate in the tubule also shortens the time that a given sodium ion is exposed to the reabsorptive machinery. This leads to the prediction that GTB will just maintain constant fractional reabsorption.

Renal regional tissue oxygenation levels in humans may be measured by blood oxygenation level–dependent magnetic resonance imaging (BOLD-MRI). A BOLD-MRI analysis in 10 male normotensive humans and 8 untreated hypertensive patients found that a low-salt diet increased renal medullary tissue oxygenation levels in both groups when compared with a high-salt diet. Renal cortical tissue oxygenation did not change in either group. In the normotensive group only, renal medullary oxygenation correlated positively with proximal tubular reabsorption of sodium estimated from measurements of the fractional excretion of lithium and negatively with distal sodium reabsorption. These data indicate that low sodium intake increases renal medullary oxygenation, which might involve greater proximal reabsorption and less reabsorption and possibly lower metabolic activities and oxygen consumption in the distal nephron in some humans.

Renal medullary tissue oxygenation levels were significantly lower in a group of 20 African Americans compared with 29 Whites. The participants of this study had hypertension and were treated with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. Daily sodium intake and urinary sodium excretion were the same between the two groups, while RBF, GFR, and the filtered sodium load were higher in the African American group, which would suggest greater tubular reabsorption of sodium in the African Americans. Renal cortical tissue oxygenation was similar between the two groups, but renal medullary tissue oxygenation levels were lower in the African Americans. Furosemide, which inhibits sodium reabsorption in the thick ascending limb, increased medullary tissue oxygenation to similar levels in the two groups, suggesting that the thick ascending limb in African Americans might have greater reabsorptive activities and consume more oxygen than in Whites. Blood pressure in African Americans is more likely to be salt sensitive than in Whites.

The proximal tubule reabsorbs approximately 65% of the filtered NaCl and water and nearly all filtered glucose and amino acids. Part of this reabsorption may occur passively through the paracellular space because of the presence of leaky tight junctions in the proximal tubule and the preferential reabsorption of bicarbonate in the early proximal tubule that leads to a chloride gradient favoring passive reabsorption. The reabsorption in the proximal tubule therefore may be energetically less expensive than other nephron segments that rely more on transcellular transport. Na ⁺ -K ⁺ -ATPase activity per unit length of the tubule segment is modest in the proximal tubule: lower than the thick ascending limb of the loop of Henle and the distal tubule but higher than other nephron segments ( Fig. 5.8 ).

Distribution of Na ⁺ -K ⁺ ATPase and mitochondrial density along the nephron.

(A) Relative levels of Na ⁺ -K ⁺ ATPase activity measured in individual segments of the rat nephron. (Data are normalized to that of the distal convoluted tubule and expressed per unit length of tubule segment.) (B) Detection of Na ⁺ -K ⁺ -ATPase α ₁ – and β ₁ -subunits along the nephron. Tubule segments 40 mm long were resolved by sodium dodecyl sulfate–polyacrylamide gel electrophoresis and subjected to immunoblotting with subunit-specific antisera. Blots placed below corresponding tubule label indicated in (A). (C) Morphologic analysis of mitochondrial density relative to a unit of cytoplasm. CCD, Cortical collecting duct; CTAL, cortical thick ascending limb of the loop of Henle; DCT, distal convoluted tubule; MCD, outer medullary collecting duct; MTAL, medullary thick ascending limb of the loop of Henle; PCT, proximal convoluted tubule; PR, pars recta (proximal straight tubule); TAL, thin ascending limb of the loop of Henle; TDL, thin descending limb of the loop of Henle.

[A] redrawn from Katz AI, Doucet A, Morel F. Na+-K+-ATPase activity along the rabbit, rat, and mouse nephron. Am J Physiol . 1979;237:F114–F120; [B] based on data from McDonough AA, Magyar CE, Komatsu Y. Expression of Na[+]-K[+]-ATPase alpha- and beta-subunits along rat nephron: isoform specificity and response to hypokalemia. Am J Physiol . 1994;267:C901–C908; [C] based on data from Pfaller W, Rittinger M. Quantitative morphology of the rat kidney. Int J Biochem . 1980;12[1-2]:17–22.

Mitochondrial volume relative to cytosolic volume and normalized surface area of mitochondrial inner membrane in the proximal tubule are similar to or slightly lower than the thick ascending limb of the loop of Henle and the distal tubule and higher than other nephron segments (see Fig. 5.8 ). Distribution of mitochondrial enzymes, normalized to dry tissue weight or total protein, follows a similar pattern.

Free fatty acids appear to be a significant fuel for the proximal tubule. Other substances that the proximal tubule may use as fuel include glutamine, lactate, and ketone bodies. Glutamine catabolism in the proximal tubule generates ammonium ions, which plays a vital role in the renal excretion of excess acids. Glucose does not appear to be a major fuel in the proximal tubule. Instead, the proximal tubule has a significant gluconeogenetic capability, which may generate glucose from lactate and other substances including metabolites of amino acids and free fatty acids. The gluconeogenetic capability is unique to the proximal tubule and mostly absent in other nephron segments.

Studies carried out in a number of laboratories provide evidence that sodium transport and gluconeogenesis compete for ATP in the proximal convoluted tubule. Friedrichs and Schoner studied both processes in rat renal tubules and slices and found that ouabain inhibition of Na ⁺ -K ⁺ -ATPase increased renal gluconeogenesis by 10% to 40% depending on the substrate, and that stimulating Na ⁺ -K ⁺ -ATPase activity with high extracellular K ⁺ inhibited gluconeogenesis. The authors concluded that inhibition of the sodium pump induced a higher energy state of the cell, which would favor energy-requiring synthetic processes.

Nagami and Lee used an isolated perfused mouse proximal tubule preparation to address this issue. When tubules were perfused at higher rates, delivering more sodium to the proximal tubule, the glucose production rate was decreased by 50%, whereas when tubules were incubated with ouabain in the bath or perfused with amiloride (to inhibit apical transport), the glucose production rate increased above that seen in nonperfused tubules. These authors also verified that the reduction in glucose production seen at elevated perfusion rates does not result from increased glucose utilization and is not dependent on the presence of specific substrates. Related to the topic of proximal tubule gluconeogenesis, two studies suggest that the blood glucose–lowering effects of sodium-glucose cotransporter isoform 2 (SGLT2) inhibitors are due, in part, to reduced proximal gluconeogenesis: Inhibiting SGLT2-mediated glucose uptake in diabetic mice reduced gluconeogenic gene expression, including PEPCK, a principal regulator of gluconeogenesis. ^,

The thick ascending limb (TAL) of the loop of Henle reabsorbs approximately 20% to 25% of the filtered NaCl without reabsorbing water. The thin descending and ascending limbs of the loop of Henle do not have significant active transport. The TAL has a high rate of Na ⁺ transport against a steep concentration gradient, high levels of Na ⁺ -K ⁺ -ATPase activity and expression, and 40% of its cytosolic volume occupied by mitochondria (see Fig. 5.8 ). Although the TALs have a far greater capacity for anaerobic metabolism than the proximal tubules, this region still requires oxidative metabolism to maintain cellular ATP levels and active Na ⁺ reabsorption. ^, Glucose appears to be a significant fuel in the TAL. Lactate, fatty acids, and ketone bodies may also contribute. Glucose may be used to produce ATP via both glycolysis and oxidative phosphorylation in the TAL. Glycolytic capabilities are present in the TAL and subsequent nephron segments and largely absent in the proximal tubule.

The distal tubule and the collecting duct reabsorb 5% to 10% of the filtered sodium and are the final segments that may control sodium excretion and urine flow rate. Substrate utilization in the cortical collecting duct is qualitatively similar to the TAL. The importance of glucose as the fuel appears to increase, and that of fatty acids decreases, as the collecting duct progresses to the renal inner medulla region.

CCD metabolism is particularly interesting because it is made up of distinctly different cell types: principal cells that reabsorb sodium and intercalated cells that can secrete bicarbonate (HCO ₃ ^– ). Hering-Smith and Hamm microperfused rabbit CCD and measured Na ⁺ reabsorption (with ²² Na ⁺ ) from lumen to bath and HCO ₃ ^– transport by microcalorimetry in the presence of substrates with or without inhibitors. Both Na ⁺ reabsorption and HCO ₃ ^– secretion were inhibited by antimycin A, which provides evidence for dependence on oxidative phosphorylation. However, neither was dependent on either glycolysis or the hexose–monophosphate shunt pathways. A small component of Na ⁺ transport was supported by endogenous substrates. Na ⁺ reabsorption was supported best by a mixture of basolateral glucose and acetate, whereas HCO ₃ ^– secretion was fully supported by either glucose or acetate. HCO ₃ ^– secretion (but not Na ⁺ transport) was supported to some extent by luminal glucose. In sum, this study indicates that principal cells and intercalated cells may have distinct metabolic phenotypes.

Medullary collecting ducts contribute to final urinary acidification. Comparing the outer medullary collecting duct (OMCD) with the CCD, Hering-Smith and Hamm found that bicarbonate secretion in the OMCD could be fully supported by endogenous substrates. This region has far less sodium transport and few mitochondria (see Fig. 5.8 ). Stokes and colleagues isolated IMCDs and examined their metabolic characteristics. In the absence of exogenous substrate, IMCD can maintain cellular ATP and respire normally, which is evidence for the presence of significant endogenous substrate. In the presence of rotenone, an inhibitor of oxidative phosphorylation, glycolysis increased 56%, which provides evidence for anaerobic metabolism, as supported by enzymatic profiles. Inhibition of sodium pump activity reduced QO ₂ by 25% to 35%, which provides evidence for a linkage between sodium pump activity and oxidative metabolism.

In studies that examined the metabolic determinants of K ⁺ transport in isolated IMCD, glucose increased both oxygen consumption and cell K ⁺ content by more than 10%, whereas an inhibitor of glycolysis promoted a release of cell K ⁺ . Nor could cell K ⁺ content be maintained during inhibition of mitochondrial oxidative phosphorylation. Thus in the IMCD, both glycolysis and oxidative phosphorylation are required to maintain optimal Na ⁺ -K ⁺ -ATPase activity to preserve cellular K ⁺ gradients. Given the low PO ₂ and low density of mitochondria in this region, the collecting ducts have a higher reliance on anaerobic metabolism but still take advantage of oxidative metabolism to fully support transport.

In a review of renal gluconeogenesis, Gerich and colleagues comment that the kidney can be considered two separate organs, because the proximal tubule makes and releases glucose from noncarbohydrate precursors, whereas glucose utilization occurs primarily in the medulla. Because the kidney is both a consumer and a producer of glucose and glucose consumption in the medulla can mask glucose release by the cortex, net arteriovenous glucose differences across the kidney can be uninformative.

Gerich and colleagues also make the case that the kidney is a significant gluconeogenic organ in normal humans based on the following: 1. In humans fasted overnight, proximal tubule gluconeogenesis can be as much as 40% of whole-body gluconeogenesis; 2. during liver transplantation, endogenous glucose release falls to only 50% of control levels by 1 hour after liver removal; and 3. pathologically in type 2 diabetes, renal glucose release is increased by about the same fraction as hepatic glucose release.

Lactate can reach the nephron by filtration or blood flow and can also be produced along the nephron. Within the kidney, lactate can be 1. oxidized to produce energy with generation of CO ₂ , a process that consumes oxygen but generates ATP; or 2. converted to glucose via gluconeogenesis in the proximal tubule, a process that consumes oxygen and ATP. This is shown in Fig. 5.9 . Studies by Cohen in an isolated whole kidney perfused with just lactate as substrate demonstrated a change in ¹⁴ C–lactate utilization as a function of its concentration in the perfusate: At low concentrations, all the lactate was oxidized (detected as CO ₂ ) in order to fuel transport and basal metabolism; when lactate in perfusate was raised above 2 mmol/L, some of the lactate was used for synthesis of glucose (gluconeogenesis); and at high lactate in perfusate, the metabolic and synthetic rates approach maximum and some lactate is conserved (reabsorbed). However, it is not the normal circumstance that lactate is the sole substrate, and it is now appreciated that the metabolism of lactate is affected by the presence of other substrates—for example, lactate uptake and oxidation are inhibited in the presence of fatty acids. ^,

Fate of lactate and oxygen in renal metabolism.

Oxygen can be used to generate ATP via oxidative phosphorylation or heat if mitochondrial uncoupling occurs. Lactate can act as a substrate for gluconeogenesis, which consumes energy, or can enter into the citric acid cycle to generate energy. ATP is either used for Na transport ( T _Na ) or consumed in the process of gluconeogenesis.

The kidney’s ability to convert lactate to glucose provides evidence that it can participate in cell–cell lactate shuttle, also known as the Cori cycle. This cycle is important when oxidative phosphorylation is inhibited in vigorously exercising muscle, which becomes hypoxic. In the muscle, pyruvate is reduced to lactate to regenerate NAD+ from NADH, which is necessary for ATP production by glycolysis to continue. Lactate is released into the blood and can be taken up by tissues capable of gluconeogenesis, such as the liver and kidney. In the proximal tubule, the lactate that is not oxidized can be converted to glucose, and because this substrate is not used by the proximal tubule, glucose will be reabsorbed back into the blood, where it will be available for metabolism by the exercising muscle. Overall, this cycle is metabolically costly: Glycolysis produces 2 ATP molecules at a cost of 6 ATP molecules consumed in the gluconeogenesis. Thus the Cori cycle is an energy-requiring process that shifts the metabolic burden away from the exercising muscle during hypoxia. This cell–cell lactate shuttle could also operate within the kidney between nephron segments that produce lactate anaerobically and the proximal tubule.

Renal medullary lactate concentration was explored in a 1965 study in rats by Scaglione and colleagues to test the idea that the medulla used glycolysis in the low-oxygen environment. Medullary lactate concentration is a function of delivery via the blood flow, production in the medulla, and removal by the blood flow because there is no gluconeogenesis in this region to consume lactate. Because of the countercurrent arrangement of the vasa recta, lactate would be expected to concentrate in the medulla somewhat. The study results indicated that lactate concentration was twice as high in the inner medulla as in the cortex and that during osmotic diuresis the medullary lactate doubled, whereas cortical lactate remained unchanged. The authors postulated that increased medullary lactate was evidence for increased glycolysis during osmotic diuresis because the diuresis and increased flow through the vasa recta would be expected to decrease medullary lactate if synthesis rates were unchanged. Sodium delivery to the distal nephron would also increase during osmotic diuresis, and the accompanying increased Na ⁺ reabsorption could drive the increased glycolysis.

Bagnasco and colleagues studied lactate production along the nephron in dissected rat nephron segments incubated in vitro with glucose with or without an inhibitor of oxidative metabolism, antimycin A. The only pathway for lactate production in the kidney is from pyruvate via lactate dehydrogenase. Proximal tubules produced no lactate with or without antimycin A. The distal segments all produced lactate, and the production was significantly increased (approximately 10-fold in TAL) during antimycin A incubation ( Fig. 5.10 ), which led the authors to conclude that significant amounts of lactate can be produced by anaerobic glycolysis during anoxia in the distal segments. The IMCD, a region with low oxygen tension under control conditions, had high levels of lactate production even without antimycin A, which indicates that it is primed for anaerobic glycolysis.

Lactate production by rat nephron segments under control conditions and in the presence of antimycin A.

CAL, Cortical ascending limb; CCT, cortical collecting tubule; DCT, distal convoluted tubule; IMCD, inner medullary collecting duct; MAL, medullary thick ascending limb; OMCD, outer medullary collecting duct; PROX, proximal tubule.

From Bagnasco S, Good D, Balaban R, et al. Lactate production in isolated segments of the rat nephron. Am J Physiol . 1985;248:F522–F526.

Results from global analysis of isolated nephron segments using techniques like RNA-seq or proteomics confirmed many of the findings from previous, targeted analyses of metabolic activity and enzyme abundance and provided additional insights into metabolism in nephron segments. An RNA-seq analysis of 14 renal tubule segments isolated from rat kidneys confirmed that the proximal tubule lacked key glycolytic enzymes (hexokinase, phosphofructokinases, and pyruvate kinase) and strongly expressed mRNAs for enzymes that are critical for gluconeogenesis. The study indicates that hexokinase 1 and phosphofructokinases are expressed in all segments beyond the proximal tubule, including the thin limbs of the loop of Henle, suggesting that glycolysis may be important for ATP production in the thin limbs. The proximal tubule also strongly expresses the key enzymes for fructolysis (fructokinase and dihydroxyacetone kinase 2) and is the main segment that expresses argininosuccinate synthase that is necessary for arginine synthesis. The kidney is a major producer of arginine in the body. The TAL and distal convoluted tubule (DCT) show particularly high mRNA abundance of carnitine palmitoyl transferases, key enzymes for fatty acid metabolism.

A proteomic analysis, again, confirmed many of the known metabolic characteristics of rat nephron segments. The study shows selective expression of the osmoprotective enzyme aldose reductase in inner medullary segments and rate-limiting enzymes for ammoniagenesis in proximal tubule cells and maximum abundance of creatine kinase in segments with the highest rates of sodium reabsorption (mTAL, cTAL, DCT) or transport against a large Na gradient (CNT, CCD).

For a cell in a steady state, the pumping of ions by the Na ⁺ -K ⁺ -ATPase must be offset by an equal and opposite diffusion of those ions back across the cell membrane. Because cell membranes are generally more permeable to potassium than sodium, potassium diffusion contributes more to the cell voltage than sodium diffusion, even though three sodium ions leak into the cell for every two potassium ions that leak out. Thus diffusion of potassium out of the cell dominates the cell voltage, making it negative. The net outcome of this pump-leak process is that electrochemical potential, which originates with ATP hydrolysis, becomes concentrated in the transmembrane sodium gradient, whereas potassium resides near electrochemical equilibrium.

The difference in electrochemical potential for sodium across the cell membrane is available to drive the unfavorable passage of other solutes across the membrane by a variety of exchangers and cotransporters. Examples include the proximal tubule Na ⁺ /H ⁺ exchanger (NHE), sodium-glucose cotransporters (SGLTs), the basolateral Na/α-ketoglutarate (α-KG) cotransporter, the furosemide-sensitive Na-K-2Cl cotransporter (NKCC2), and the thiazide-sensitive Na-Cl cotransporter (NCC). Generically, transport that directly uses free energy from the sodium gradient to drive uphill flux of another solute is referred to as secondary active transport. Tertiary active transport refers to the net flux of a solute against its electrochemical potential gradient coupled indirectly to the Na+ gradient (three transport processes working in parallel). An example of tertiary active transport is the uptake of various organic anions from the peritubular blood into the proximal tubular cell by the so-called organic anion transporters (OATs). Energy from the sodium gradient is converted into a gradient for α-KG to diffuse into the cell by Na/α-KG cotransport. OATs use this potential difference to exchange α-KG for another organic anion.

For tubular cells that actively reabsorb chloride, free energy is transferred from the Na potential to drive apical chloride entry and raise cell chloride above equilibrium. In the proximal tubule, the energy for apical chloride entry is derived circuitously via sodium-hydrogen exchange that is coupled to oxalate, formate, or hydroxyl ion transport (see Chapter 6 ). In the thick ascending loop of Henle and DCT, the energy transfer occurs by direct cotransport with Na via NKCC2 or NCC. In each case, raising cell chloride above equilibrium provides a driving force for chloride to diffuse out of the cell across the basolateral membrane, which is permeable to chloride. Raising cell chloride also makes the basolateral membrane voltage less negative, as is apparent from the Goldman equation. Because luminal voltage is the sum of voltage steps across the basolateral and apical membranes, raising cell chloride in a cell with basolateral chloride conductance will raise the lumen voltage (make it more positive), thus providing free energy that can either be dissipated by the intercellular back-leak of chloride, which would increase entropy, or be applied to do the useful work of cation reabsorption, which would decrease entropy. The kidney uses the latter mechanism of energy transfer to augment Na reabsorption in the proximal tubule, as well as calcium and magnesium reabsorption in the thick ascending loop of Henle.

For cells that express epithelial Na channel (ENaC), opening these channels will depolarize the apical membrane, as can be seen from the Goldman equation. K ions, which enter the cell via the basolateral Na pump, can leave the cell by K conductance in either basolateral or apical membranes. Depolarizing the apical membrane will increase the fraction of K ions leaving by way of the apical membrane conductance. This represents the transfer of free energy from the Na ⁺ -K ⁺ -ATPase and the apical Na potential to the useful work of K secretion.

The polar arrangement of transporters in renal cells is essential for vectorial transport. Wherever it is expressed along the nephron, the sodium pump, which removes sodium from the cell, is restricted to the basolateral membrane. Meanwhile, the variety of exchangers, cotransporters, and sodium channels through which sodium enters the tubular cell are restricted to the apical membrane. These include the principal Na+/H+ exchanger NHE3 and SGLTs in the proximal tubule, the NKCC2 in the TAL of the loop of Henle, the NCC in the DCT, and epithelial sodium channels in the connecting tubule and collecting duct (see Chapter 6 ). These apical sodium transporters affect secondary active transport coupled to the primary active transporter, Na ⁺ -K ⁺ -ATPase.

Close coordination of sodium uptake across the apical membrane with sodium extrusion across the basolateral membrane is required to avoid osmotic swelling and shrinking of the cell. Assuming ATP is not limiting for basolateral exit, the magnitude of transepithelial transport is a function of 1. the number of transporters in the plasma membrane, which can be varied by changes in synthesis or degradation rates and/or trafficking between intracellular and plasma membranes, and 2. the activity per transporter, which can be varied by covalent modification (e.g., phosphorylation or proteolysis) or protein–protein interaction (e.g., Na ⁺ -K ⁺ -ATPase kinetics are influenced by FXYD subunit association). The rate of apical sodium entry is also subject to influence by the availability of substrates for cotransport. For example, the amount of sodium-glucose cotransport depends on the availability of glucose in proximal tubular fluid, and the sodium entry at a given point along the TAL is subject to variations in the local chloride concentration because NKCC2 has a relatively low affinity for chloride.

Many factors and hormones known to regulate renal sodium reabsorption (including angiotensin II, aldosterone, dopamine, parathyroid hormone, and blood pressure) act in parallel to affect the activity, distribution, or abundance of apical transporters and basolateral sodium pumps. ^, The molecular basis of this apical–basolateral crosstalk is not clearly understood, especially in the light of close cell volume control; however, there is evidence for the role of elevated cellular calcium level in response to depressed sodium transport. There is also evidence for a salt-inducible kinase that responds to slight elevations in cell Na and Ca, as well as evidence for coupling of Na ⁺ -K ⁺ -ATPase to apical channel activity.

In the early 1960s, the coupling between active transport, respiration, and Na ⁺ -K ⁺ -ATPase activity was recognized by Whittam and Blond, ^, who tested the idea that inhibition of active ion transport at the plasma membrane would cause a fall in oxygen consumption (QO ₂ ) in the mitochondria. Using brain or kidney samples studied in vitro, they demonstrated that inhibition of Na ⁺ -K ⁺ -ATPase activity by removal of sodium or addition of the sodium pump–specific inhibitor ouabain (neither of which directly inhibits mitochondrial respiration) markedly reduced QO ₂ , which led the investigators to conclude that an extramitochondrial ATPase, sensitive to Na ⁺ and ouabain, as well as to K ⁺ and Ca ²⁺ , is one of the pacemakers of respiration of the kidney cortex. ^,

A study by Balaban and colleagues 2 decades later used a suspension of renal cortical tubules to reexamine this Whittam model (see Fig. 5.3 ) in more detail by measuring the redox state of mitochondrial nicotinamide adenine dinucleotide (NAD), cellular ATP and ADP concentrations, ATP/ADP ratio, and QO ₂ in the same samples. If transport and respiration are assumed to be coupled, inhibition of transport is predicted to provoke a mitochondrial transition to a resting state accompanied by an increase in NADH/NAD ⁺ (reduced to oxidized NAD), increase in [ATP], decrease in [ADP] and [Pi], increase in ATP/ADP ratio, and decrease in QO ₂ . Stimulation of active transport would provoke the opposite pattern: decreased NADH, ATP, and ATP/ADP ratio and increased QO ₂ . Predictably, incubating the renal cortical tubule suspension with the Na ⁺ -K ⁺ -ATPase inhibitor ouabain caused a 50% decline in QO ₂ , reduction of NAD to NADH, and a 30% increase in the ATP/ADP ratio, all evidence for coupling of mitochondrial ATP production to ATP consumption via Na ⁺ -K ⁺ -ATPase. Similarly, in tubules deprived of K ⁺ (which is required for Na ⁺ -K ⁺ -ATPase turnover), adding 5 mmol/L K ⁺ increased QO ₂ by more than 50%, oxidized NADH to NAD ⁺ , and decreased the cellular ATP/ADP ratio by 50%. These results provide evidence for the coupling of both Na ⁺ -K ⁺ -ATPase and ATP production via ATP synthase to the cellular ATP/ADP ratio (see Fig. 5.3 ).

Despite consistent distribution and function, the relative abundance of Na ⁺ -K ⁺ -ATPase as a function of tubular location along the nephron is highly variable. Na ⁺ -K ⁺ -ATPase activity, ouabain binding, and Na ⁺ -K ⁺ -ATPase subunit abundance have been studied in dissected tubules and with imaging techniques. Na, K-ATPase expression patterns and ouabain binding patterns along the nephron are similar. ^, The pronounced differences in activity can largely be accounted for by differences in sodium pump number measured either by ouabain binding or by immunoblot of subunits in dissected nephron segments (see Fig. 5.8 ).

The patterns of Na ⁺ -K ⁺ -ATPase protein expression and activity as a function of tubule length are what is to be expected from what is understood of the physiology of the nephron segments: Moderate levels are expressed in the proximal tubule, where two-thirds of the sodium is reabsorbed across a leaky epithelium, and lower levels are expressed in the straight than in the convoluted segments, reflecting the amount of sodium transported in these two regions. Low levels are detected in the thin limbs of the loop of Henle, whereas high levels are expressed in the medullary and cortical TAL that reabsorbs a significant fraction of NaCl without water against an increasingly steep transepithelial gradient. The Na ⁺ -K ⁺ -ATPase activity and expression in the DCT, which is responsible for reabsorbing another 5% to 7% of the filtered load against a steep transepithelial gradient, is high. In the collecting duct, which reabsorbs a smaller fraction of Na ⁺ via channels electrically coupled to the secretion of K ⁺ or H ⁺ and has variable H ₂ O permeability, the Na ⁺ -K ⁺ -ATPase is quite low, albeit sufficient to drive sodium reabsorption in this region. The distribution of the ATP-producing mitochondria along the nephron, reported as percent of cytoplasmic volume, parallels the distribution of the ATP-consuming sodium pumps but is somewhat less variable, ranging from 10% or less of the cell volume in the thin loop of Henle and medullary collecting duct to 20% in the cortical collecting duct (CCD) and proximal straight tubule to 30% to 40% of cell volume in the proximal convoluted tubule and TAL (see Fig. 5.8 ).

For 30 years, sex differences in renal hemodynamics including lower GFR and higher RVR in females and similar blood pressures between sexes have been recognized in experimental rodents. Immunoblots coupled with physiologic assays in rats indicate that females, versus males, exhibit a distinct transporter profile of lower proximal transporters’ abundance and HCO ₃ ^– reabsorption coupled to higher distal NCC and ENaC activation ( Fig. 5.11 ). This shift in T _Na from the energetically efficient PT to the costlier distal nephron is predicted to decrease sodium transport energy efficiency (T _Na /Q o ₂ ) in females. A rationale for this downstream shift in T _Na can be found in female biology. Pregnancy, and even more so lactation, represent major challenges to fluid homeostasis in females. The proximal tubule, which is shorter at baseline in females versus males, lengthens during lactation, driving a proportional increase in T _Na in a region where transport efficiency is high due to paracellular T _Na . ^, These significant sex- and reproduction-dependent differences in renal transport function likely necessitate differences in nephron region–specific metabolism that warrant serious future consideration.

Profile of renal sodium transporter protein abundance in female C57BL/6 mice expressed relative to abundance in male mice (defined as 1.0).

Cortical and medullary ( -m ) samples were detected by immunoblot: Na ⁺ /H ⁺ exchanger isoform 3 ( NHE3 ), Na ⁺ -phosphate cotransporter isoform 2 (NaPi2), Na ⁺ -glucose cotransporter ( SGLT2 ), claudin 2, Na ⁺ -K ⁺ -2Cl ^– cotransporter isoform 2 ( NKCC2 and activated phosphorylated form NKCC2p ), Na,K-ATPase α catalytic isoform, Na ⁺ -Cl ^– cotransporter ( NCC and activated phosphorylated form NCCp), claudin 7, epithelial Na ⁺ channel α,β,γ subunits full length (fl), and activated cleaved (cl) forms.

Adapted from Veiras LC, Girardi ACC, Curry J, et al. Sexual dimorphic pattern of renal transporters and electrolyte homeostasis. J Am Soc Nephrol . 2017;28:3504–3517 and Pastor-Soler NM, Hallows KR. AMP-activated protein kinase regulation of kidney tubular transport. Curr Opin Nephrol Hypertens . 2012;21:523–533.

The cost of renal sodium transport can be estimated from the sodium pump stoichiometry and amount of oxygen required to produce ATP. Sodium pump stoichiometry dictates that hydrolysis of one ATP molecule is coupled with the transport of 3 Na ⁺ ions out of the cell and 2 K ⁺ ions into the cell, and oxidative metabolism generates approximately 6 ATP molecules per O ₂ molecule consumed (see Table 5.1 and Fig. 5.4 ). In the 1960s, several investigators undertook measuring the metabolic cost of tubular reabsorption in various species of mammals. There is fair consensus among four oft-cited studies published between 1961 and 1966 that the relationship between Q o ₂ and T _Na is linear and that the kidney reabsorbs 25 to 29 Na ⁺ ions per molecule of O ₂ consumed in the process.

If one assumes that kidney mitochondria make 6 molecules of ATP per molecule of O ₂ , the kidney must then reabsorb 4 to 5 Na ⁺ per ATP molecule. This exceeds the 3:1 stoichiometry of the Na ⁺ -K ⁺ -ATPase, which was known at the time (reviewed in Burg and Good). In fact, one might expect a ratio lower than 3 because of the metabolic needs of the kidney that are independent of sodium transport (i.e., insensitive to the Na ⁺ -K ⁺ -ATPase inhibitor ouabain) ( Fig. 5.12 ) and because of tubular backleak. Because there are thermodynamic difficulties with the idea of an undiscovered basolateral sodium pump capable of forcing 5 Na ⁺ from a tubular cell with energy from a single ATP molecule, it was surmised that a considerable fraction of overall sodium reabsorption must be passive and paracellular, as is now accepted.

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