Role of Receptor Protein Tyrosine Phosphatase γ in Sensing Extracellular CO2 and HCO3 −

Abstract

Regulation of blood pH-critical for virtually every facet of life-requires that the renal proximal tubule (PT) adjust its rate of H(+) secretion (nearly the same as the rate of HCO3 (-) reabsorption, JHCO3 ) in response to changes in blood [CO2] and [HCO3 (-)]. Yet CO2/HCO3 (-) sensing mechanisms remain poorly characterized. Because receptor tyrosine kinase inhibitors render JHCO3 in the PT insensitive to changes in CO2 concentration, we hypothesized that the structural features of receptor protein tyrosine phosphatase-γ (RPTPγ) that are consistent with binding of extracellular CO2 or HCO3 (-) facilitate monitoring of blood CO2/HCO3 (-) concentrations. We now report that PTs express RPTPγ on blood-facing membranes. Moreover, RPTPγ deletion in mice eliminated the CO2 and HCO3 (-) sensitivities of JHCO3 as well as the normal defense of blood pH during whole-body acidosis. Thus, RPTPγ appears to be a novel extracellular CO2/HCO3 (-) sensor critical for pH homeostasis.

Receptor Protein Tyrosine Phosphatase γ, CO2 Sensing in Proximal Tubule and Acid Base Homeostasis

“…15 Indeed, blood HCO 3 2 and pH in RPTPg-KO mice were significantly lower versus baseline conditions after exposure to ammonium chloride acid load, and in comparison to wild-type mice, which completely recovered from systemic acidosis after 7 days of acid load. 15 Intriguingly, RPTPg -KO mice displayed significant downregulation of apical Na 1 /H 1 exchanger NHE-3 expression under baseline conditions. 15 This raises the possibility that RPTPg can function both as a CO 2 sensor and as a regulator of NHE-3, the main HCO 3 2 -absorbing transporter in the kidney proximal tubule.…”

“…15 Intriguingly, RPTPg -KO mice displayed significant downregulation of apical Na 1 /H 1 exchanger NHE-3 expression under baseline conditions. 15 This raises the possibility that RPTPg can function both as a CO 2 sensor and as a regulator of NHE-3, the main HCO 3 2 -absorbing transporter in the kidney proximal tubule. Taken together, these results may suggest that RPTPg has two distinct functions.…”

“…15 The authors concluded that RPTPg appears to be a novel extracellular CO 2 /HCO 3 2 sensor in proximal tubule cells and may be critical for regulating HCO 3 2 absorption and pH homeostasis. 15 In addition to the impaired ability to sense basolateral CO 2 alteration in proximal tubule cells, RPTPg-KO mice displayed an inability to recover from ammonium chloride-induced metabolic acidosis. 15 Indeed, blood HCO 3 2 and pH in RPTPg-KO mice were significantly lower versus baseline conditions after exposure to ammonium chloride acid load, and in comparison to wild-type mice, which completely recovered from systemic acidosis after 7 days of acid load.…”

“…15 In isolated proximal tubules from RPTPg-knockout (KO) mice, the authors found that the dependence of JHCO 3 2 on basolateral CO 2 concentration was abolished; however, the effect of basolateral HCO 3 2 on JHCO 3 2 remained comparable in wild-type and mutant mice. 15 The authors concluded that RPTPg appears to be a novel extracellular CO 2 /HCO 3 2 sensor in proximal tubule cells and may be critical for regulating HCO 3 2 absorption and pH homeostasis. 15 In addition to the impaired ability to sense basolateral CO 2 alteration in proximal tubule cells, RPTPg-KO mice displayed an inability to recover from ammonium chloride-induced metabolic acidosis.…”

“…15 In addition to the impaired ability to sense basolateral CO 2 alteration in proximal tubule cells, RPTPg-KO mice displayed an inability to recover from ammonium chloride-induced metabolic acidosis. 15 Indeed, blood HCO 3 2 and pH in RPTPg-KO mice were significantly lower versus baseline conditions after exposure to ammonium chloride acid load, and in comparison to wild-type mice, which completely recovered from systemic acidosis after 7 days of acid load. 15 Intriguingly, RPTPg -KO mice displayed significant downregulation of apical Na 1 /H 1 exchanger NHE-3 expression under baseline conditions.…”