Regulatory and functional interaction of vasoactive factors in the kidney and extracellular pH

Abstract

A growing body of evidence suggests that vasoactive factors produced in the kidney such as nitric oxide, endothelins, angiotensin, and prostaglandins participate actively in the regulation of acid-base homeostasis under physiologic conditions. In addition, recent reports indicate that alterations in the systemic acid-base status may also influence the generation of vasoactive cytokines in the kidney, which in turn may mediate the renal effector processes that tend to restore normality under such conditions. Metabolic acidosis, which so frequently accompanies many forms of chronic renal failure (CRF), may contribute to down-regulation of intrarenal nitric oxide production that characterizes CRF. Reduced extracellular pH inhibits inducible nitric oxide production in mesangial cells by altering the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) oxidation, an important posttranslational mechanism in the inducible nitric oxide synthase (iNOS) activation. The underlying defects resulting in the uncoupling of NADPH oxidation in acidemic microenvironment are discussed. Acidosis stimulates renal production of endothelins, which mediate proximal tubular acidification by enhancing sodium-hydrogen exchanger-3 (NHE-3) activity. Renal endothelins mediate enhanced urinary acid excretion following dietary acid ingestion, an effect that is effectively blocked by endothelin receptor blockers. Reduced extracellular pH stimulates endothelin secretion from renal microvascular endothelial cells, which may promote enhanced acid excretion from the distal tubule under conditions of acidosis. These phenomena as well as the role of angiotensin and renal prostaglandins in mediating renal acidification in normal and acidotic conditions are discussed in this review, which describe the regulatory interaction between extracellular pH and renal vasoactive factors.