The kidney adjusts net acid excretion to match production with exquisite precision, despite little or no change in the plasma bicarbonate concentration. The acid-sensing pathway that signals the kidney to increase acid secretion involves activation of the proto-oncogene c-Src. A new study in this issue shows that proline-rich tyrosine kinase 2 (Pyk2) is responsible for acid-induced activation of c-Src and is essential for acid sensing in renal epithelial cells. The findings implicate a broader role for Pyk2 in acid-base homeostasis in bone and other tissues beyond the kidney.
[Show abstract][Hide abstract] ABSTRACT: The Canadian physiologist PA Stewart advanced the theory that the proton concentration, and hence pH, in any compartment is dependent on the charges of fully ionized and partly ionized species, and on the prevailing CO2 tension, all of which he dubbed independent variables. Because the kidneys regulate the concentrations of the most important fully ionized species ([K+], [Na+], and [Cl-]) but neither CO2 nor weak acids, the implication is that it should be possible to ascertain the renal contribution to acid-base homeostasis based on the excretion of these ions. One further corollary of Stewart's theory is that, because pH is solely dependent on the named independent variables, transport of protons to and from a compartment by itself will not influence pH. This is apparently in great contrast to models of proton pumps and bicarbonate transporters currently being examined in great molecular detail. Failure of these pumps and cotransporters is at the root of disorders called renal tubular acidoses. The unquestionable relation between malfunction of proton transporters and renal tubular acidosis represents a problem for Stewart theory. This review shows that the dilemma for Stewart theory is only apparent because transport of acid-base equivalents is accompanied by electrolytes. We suggest that Stewart theory may lead to new questions that must be investigated experimentally. Also, recent evidence from physiology that pH may not regulate acid-base transport is in accordance with the concepts presented by Stewart.
[Show abstract][Hide abstract] ABSTRACT: Chronic metabolic acidosis results in renal Ca2+ and Mg2+ wasting, whereas chronic metabolic alkalosis is known to exert the reverse effects. It was hypothesized that these adaptations are mediated at least in part by the renal Ca2+ and Mg2+ transport proteins. The aim of this study, therefore, was to determine the effect of systemic acid-base status on renal expression of the epithelial Ca2+ channel TRPV5, the Ca2+-binding protein calbindin-D28K, and the epithelial Mg2+ channel TRPM6 in relation to Ca2+ and Mg2+ excretion. Chronic metabolic acidosis that was induced by NH4Cl loading or administration of the carbonic anhydrase inhibitor acetazolamide for 6 d enhanced calciuresis accompanied by decreased renal TRPV5 and calbindin-D28K mRNA and protein abundance in wild-type mice. In contrast, metabolic acidosis did not affect Ca2+ excretion in TRPV5 knockout (TRPV5-/-) mice, in which active Ca2+ reabsorption is effectively abolished. This demonstrates that downregulation of renal Ca2+ transport proteins is responsible for the hypercalciuria. Conversely, chronic metabolic alkalosis that was induced by NaHCO3 administration for 6 d increased the expression of Ca2+ transport proteins accompanied by diminished urine Ca2+ excretion in wild-type mice. However, this Ca2+-sparing action persisted in TRPV5-/- mice, suggesting that additional mechanisms apart from upregulation of active Ca2+ transport contribute to the hypocalciuria. Furthermore, chronic metabolic acidosis decreased renal TRPM6 expression, increased Mg2+ excretion, and decreased serum Mg2+ concentration, whereas chronic metabolic alkalosis resulted in the exact opposite effects. In conclusion, these data suggest that regulation of Ca2+ and Mg2+ transport proteins contributes importantly to the effects of acid-base status on renal divalent handling.
Journal of the American Society of Nephrology 04/2006; 17(3):617-26. DOI:10.1681/ASN.2005070732 · 9.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Our recent studies demonstrated the localization of protein 4.1B, a member of the 4.1 skeletal membrane proteins, to the basolateral membranes of the S1-S2 renal proximal tubules. In the present studies, we investigated the presence of binding partners that could form a molecular complex with the 4.1B protein. Immunohistochemistry revealed the localization of p55, a membrane-associated guanylate kinase, and the sodium bicarbonate cotransporter1 (NBC1), to the basolateral membrane domain of S1-S2 in mouse renal proximal tubules. Using immunoprecipitation of kidney lysates with anti-p55 antibody, a positive band was blotted with anti-4.1B antibody. GST fusion proteins including the NBC1 and 4.1B regions were confirmed to bind with each other by electrophoresis after mixing. Both NBC1- and 4.1B-specific bands were detected in renal protein mixtures immunoprecipated by either anti-4.1B- or NBC1-specific antibodies. It is likely that NBC1, 4.1B, and p55 form a molecular complex in the basolateral membrane of the kidney S1-S2 proximal tubules. We propose that the 4.1B-containing membrane skeleton may play a role in regulating the Na(+) and HCO(3)(-) reabsorption in S1-S2 proximal tubules.
Journal of Histochemistry and Cytochemistry 01/2008; 55(12):1199-206. DOI:10.1369/jhc.7A7266.2007 · 1.96 Impact Factor
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