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Renal Physiology Renal Physiology Proximal Tubule Function and Response to Acidosis Norman P. Curthoys* and Orson W. Moe† Summary The human kidneys produce approximately 160–170 L of ultrafiltrate per day. The proximal tubule contributes to fluid, electrolyte, and nutrient homeostasis by reabsorbing approximately 60%–70% of the water and NaCl, a greater proportion of the NaHCO , and nearly all of the nutrients in the ultrafiltrate. The proximal tubule is also *Department of 3 Biochemistry and the site of active solute secretion, hormone production, and many of the metabolic functions of the kidney. This Molecular Biology, review discusses the transport of NaCl, NaHCO3, glucose, amino acids, and two clinically important anions, Colorado State citrate and phosphate. NaCl and the accompanying water are reabsorbed in an isotonic fashion. The energy University, Fort 1 1 that drives this process is generated largely by the basolateral Na /K -ATPase, which creates an inward nega- Collins, Colorado; and 1 1 † tive membrane potential and Na -gradient. Various Na -dependent countertransporters and cotransporters use Departments of 2 1 Internal Medicine and the energy of this gradient to promote the uptake of HCO3 and various solutes, respectively. A Na -dependent 2 1 Physiology, University cotransporter mediates the movement of HCO3 across the basolateral membrane, whereas various Na - of Texas Southwestern independent passive transporters accomplish the export of various other solutes. To illustrate its homeostatic feat, Medical Center, the proximal tubule alters its metabolism and transport properties in response to metabolic acidosis. The uptake and Dallas, Texas catabolism of glutamine and citrate are increased during acidosis, whereas the recovery of phosphate from the ultrafiltrate is decreased. The increased catabolism of glutamine results in increased ammoniagenesis and gluco- Correspondence: Dr. Norman neogenesis. Excretion of the resulting ammonium ions facilitates the excretion of acid, whereas the combined 2 P. Curthoys, pathways accomplish the net production of HCO3 ions that are added to the plasma to partially restore acid-base Department of balance. Biochemistry and Clin J Am Soc Nephrol 9: 1627–1638, 2014. doi: 10.2215/CJN.10391012 Molecular Biology, Colorado State University, Campus Delivery 1870, Fort Introduction In addition to solute reabsorption and secretion, the Collins, CO 80523- The extracellular fluid (ECF) space provides a constant proximal tubule is also a metabolic organ. For exam- 1870; or Dr. Orson W. Moe, Department environment for the cells of a multicellular organism ple, within the proximal tubule, 25-hydroxy-vitamin of Internal Medicine, and prevents wide fluctuations in the ambient environ- D is converted to 1,25-dihydroxy-vitamin D, a hor- University of Texas 1 ment. This enables the cells to devote their gene pro- mone that increases blood Ca2 levels. The proximal Southwestern Medical ducts to more productive functions. The kidney is the tubule is also the site of the 24-hydroxylase reac- Center, 5323 Harry Hines Boulevard, principal organ that maintains the amount and com- tion that converts 25-hydroxy-vitamin D and 1,25- Dallas, TX 75390. position of the ECF by executing functions of excretion, dihydroxy-vitamin D to their inactive forms (1). In Email: Norman. metabolism, and provision of endocrine substances. addition, the proximal tubule is an important site of Curthoys@Colostate. Most of these kidney functions occur in the proximal gluconeogenesis that parallels the liver (2). As an en- edu or orson.moe@ utsouthwestern.edu tubule, which is an ancient segment in mammalian docrine organ, the kidney also releases erythropoie- nephron evolution. tin, renin, and Klotho into the systemic circulation In terms of excretion, the proximal tubule maintains and produces a plethora of locally active paracrine/ an array of secretory mechanisms inherited from the autocrine and intracrine hormones, such as dopamine, more archaic secretory nephrons, which are ancestors endothelin, PGs, renin, angiotensin II, and so forth of mammalian nephrons. The proximal tubule is also a (1,3–5). tour de force of reabsorption of the glomerular filtrate. Space constraints do not permit a comprehensive The filtration-reabsorption scheme is critical because, account of proximal tubule function in this article. as metabolic rates escalated during mammalian evo- Thus, we will highlight NaCl and NaHCO3 handling lution, GFR had to increase accordingly. The high as examples of reclamation of filtrate that are critical GFR mandates a corresponding increase in reabsorp- in preventing shock and fatal acidosis and where the tion to prevent loss of valuable solutes and water. The proximal tubule accomplishes the bulk uptake, leav- proximal tubule fulfills most of the reabsorptive role ing the completion to the distal nephron. We will also fi fl for NaCl and NaHCO3, leaving the ne-tuning to the brie y cover the reabsorption of glucose, amino distal nephron. The proximal tubule also completes acids, phosphate, and one organic anion, citrate, the reabsorption of glucose, amino acids, and impor- where the entire regulatory and absorptive func- tant anions, including phosphate and citrate, because tion is confined to the proximal tubule. Whereas it is the sole site of transport of these filtered solutes. glucose and phosphate are primarily returned to the www.cjasn.org Vol 9 ▪▪▪,2014 Copyright © 2014 by the American Society of Nephrology 1627 1628 Clinical Journal of the American Society of Nephrology circulation, citrate represents one substrate that is par- with disastrous consequences. The proximal tubule is the tially metabolized in the proximal tubule. Another organic first nephron segment after the glomerulus where reab- substrate that is absorbed and metabolized is the amino sorption commences. It is important to note that proximal acid glutamine. This process provides the nitrogen and solute and water reabsorption proceeds primarily in an carbon skeleton necessary to support renal gluconeogen- isotonic fashion with very small changes in luminal osmo- esis and ammoniagenesis. Finally, the proximal tubule larity. Figure 1A shows the profile of changes in selected constantly adjusts its functions in response to needs, solutes along the length of the proximal tubule. Figure 1B which is the hallmark of a stringent homeostatic system shows a generic cell model of how transepithelial trans- (6). Metabolic acidosis represents a state where there is con- port is achieved. Transporters can broadly be viewed certed adaptations in multiple proximal tubule transport from a thermodynamic standpoint as being driven primar- and metabolic functions aimed at minimization of the ef- ily by changes in enthalpy or entropy. Enthalpy-based or fect of the excess acid on the organism and rectification of active transporters are directly coupled to ATP hydrolysis. the disturbance. They use energy released from the hydrolysis of phos- phoanhydride bonds to move solutes uphill; hence, such transporters are by nature ATPases. Entropy-based or sec- NaCl and NaHCO Transport ondary active transporters dissipate existing electrochem- 1 3 Na is the primary cation that maintains the ECF vol- ical gradients to move a solute against a concentration 2 ume (ECFV). Because Cl is four times more abundant gradient. Thus, they use the downhill free energy change 2 than HCO3 as an ECFV anion, NaCl balance has become of one solute to energize the uphill movement of another synonymous with ECFV regulation. NaHCO3 is also a ma- solute. jor ECFV solute, second only to NaCl, but it is the princi- Transepithelial transport can occur via the paracellular 1 pal intracellular and extracellular buffer for H . Thus, or transcellular route, both of which are driven by electro- NaHCO3 is better known for its role in acid-base balance chemical forces. The energy for solute movement is de- than ECFV maintenance. There is limited regulation of rived ultimately from high energy bonds in organic 1 2 2 gastrointestinal Na ,Cl ,orHCO3 absorption so the kid- substrates taken up from the blood whose catabolism con- ney is the primary organ that regulates external electrolyte verts the energy into ATP (Figure 1B). Although there are balance. The high GFR in humans (160–170 L/d) mandates multiple active transport systems directly coupled to ATP 1 1 reabsorption of the valuable filtered solutes. Otherwise, hydrolysis, the basolateral Na -K -ATPase is the principal 1 approximately 24,000 mmol of filtered Na and approxi- consumer of ATP in the proximal tubule. It creates a low fi 2 1 mately 4000 mmol of ltered HCO3 would be lost per day cellular [Na ] and negative voltage, which provides the Figure 1. | General considerations of proximal tubule transport. (A) Profile of the tubular fluid to plasma ultrafiltrate ratio (TF/PUF). Selected solutes are shown along the length of the proximal tubule. PUF is a surrogate for the proto-urine in Bowman’s space. Inulin represents a filtered molecule that is neither secreted nor reabsorbed and the rise in its TF/PUF solely reflects reabsorption of water, which concentrates luminal inulin. Sodium reabsorption is near isotonic with water, which results in a very small increase in TF/PUF by the end of the proximal tubule. 2 2 HCO3 absorption in the early proximal convoluted tubule is particularly avid leading to rapid fall in TF/PUF. The fall in luminal [HCO3]is 2 accompanied by a reciprocal rise in luminal [Cl ] as reabsorption remains by-and-large isotonic. Inorganic phosphate (Pi) reabsorption is more avid in the earlier parts of the proximal tubule. (B) Generic scheme of the proximal tubule cell. The primary energy currency is organic metabolic substrates that enter the proximal tubule and are catabolized to produce ATP, which serves as the secondary energy currency. Some 1 1 1 transporters are directly coupled to ATP hydrolysis (enthalpic transport), such as the H -ATPase and Na /K -ATPase. The latter represents the 1 1 main workhorse of the proximal tubule responsible for the majority of the cellular ATP consumption. The Na /K -ATPase converts the energy 1 1 1 1 stored in ATP into low cellular [Na ] and high cellular [K ].
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