Use of transgenic mice in acid-base balance studies.

ABSTRACT

The kidney is essential in maintaining body acid-base status. Recently, the use of transgenic mice has largely contributed to the understanding of the mechanisms involved. Important issues have been addressed in terms of the function of proteins or their regulation. In the proximal tubule, the role of Na+/HCO3-cotransport has been established, although further studies are needed to understand how its mutations lead to renal disease. Na+/H+ exchange has also been extensively studied, and its role in diuretic and natriuretic responses following an increase in blood pressure has been elucidated. The interaction of other transport proteins, such as the Na+/phosphate cotransporter NaPi II-a, with the Na+/H+ exchanger has also been investigated. In the medullary thick ascending limb of Henle's loop (MTAL), a role for NHE1 in transepithelial HCO3- absorption has been demonstrated basolateral NHE1 controls the function of apical NHE3. As for the distal nephron, the majority of observations suggest that the regulation of H+-ATPase activity in response to acid-base status is mediated by the trafficking of pumps or pump sub-units, especially for the a4 subunit, rather than changes in subunit expression levels. Furthermore, the function of pendrin, a chloride/anion exchanger, has been assessed in response to changes in acid-base status. Important results have been obtained regarding the regulation of proximal tubule transport by several mechanisms, such as microvilli changes and the inducible and endothelial isoform of nitric oxide synthase (NOS). Finally, the interaction of chloride channels and potassium-chloride cotransporter with proton secretion has been evaluated. These findings highlight the importance of knockout animal models in studying kidney regulation of acid-base balance.