Renal endothelial and macula densa NOS: integrated response to changes in extracellular fluid volume

Abstract

If, only 20 years ago, anyone had postulated that the absence of nitric oxide gas (NO) would lead to severe hypertension and destruction of the vascular bed of the kidney within weeks, it is not unlikely that smiles of pity would have appeared on the faces of fellow researchers. By now, this has become common knowledge, and hundreds of reports have appeared on the regulation of vascular and renal function by nitric oxide. The amount of information complicates the design of a concept on how NO participates in control of extracellular fluid volume (ECFV) by the kidney. This review analyzes the function of endothelial and macula densa NO synthase (NOS) in the regulation of renal function. From this analysis, endothelial NOS (eNOS)-derived NO is considered a modulator of vascular responses and of renal autoregulation in particular. Increases in renal perfusion pressure and sodium loading will increase eNOS activity, resulting in vasodilatation and depression of tubuloglomerular feedback system responsiveness. Endothelium-derived NO seems important to buffer minute-to-minute variations in perfusion pressure and rapid changes in ANG II activity. In contrast, macula densa NOS is proposed to drive adaptations to long-term changes in distal delivery and is considered a mediator of renin formation. Increases in perfusion pressure and distal delivery will depress the activity and expression of the enzyme that coincides with, and possibly mediates, diminished renin activity. Together, the opposite responses of eNOS and macula densa NOS-derived NO to changes in ECFV lead to an appropriate response to restore sodium balance. The concept that the two enzymes with different localizations in the kidney and in the cell are producing the same product, displaying contrasting responses to the same stimulus but nevertheless exhibiting an integrated response to perturbation of the most important regulated variable by the kidney, i.e., the ECFV, may be applicable to other tissues.