Commentary on…Neuronal Nitric Oxide Synthase

Abstract

The macula densa control of renin secretion and tubuloglomerular feedback (TGF) both occur in the juxtaglomerular apparatus (JGA) of nephrons. The renin-angiotensin system has basked in attention for 2 decades, while TGF remains arcane to all but those who study it. Nonetheless, the body's internal environment is regulated, in large part, by these two systems.A decade ago, Wilcox and colleagues (1) identified nitric oxide synthase (NOS) I in the macula densa. This discovery spawned interest and experimentation. Subsequently, a sound consensus emerged that NO from the macula densa suppresses the TGF response. There is a weaker consensus that NO from the macula densa can stimulate renin secretion. It has been difficult to demonstrate a major consequence of NO-dependent renin secretion. In contrast, physiologic relevance of macula densa NOS as a modulator of TGF is easier to postulate and to prove. This is because NO from the macula densa shifts the TGF response rightward and makes it less steep (2). When macula densa NOS I is active, there will be increased distal salt delivery for any given GFR and increased GFR for any given distal salt delivery. The importance of this is revealed by positive salt balance and increased BP that gradually ensue when macula densa NOS I is inhibited (3).There are likely multiple determinants of macula densa NOS I activity. On the basis of the ubiquity of homeostasis-asnegative-feedback throughout physiology, one can expect each determinant of macula densa NO will also be affected by NO so as to serve the cause of homeostasis. To understand the role of macula densa NOS I in physiology, it is important to learn what affects it and what is affected by it. It is also important to quantify these relationships to predict the outcome when they come into conflict.The present study by Kovacs et al. (4) provides new information about certain effectors and affectors of macula densa NOS I. First, these studies confirm that NO from the macula densa suppresses apical Na:2CL:K transport in the same cell. Sodium entry via this symporter is the first step en route to TGF-mediated vasoconstriction, and reduced Na:2Cl:K symport is a leading candidate to explain how NO pushes the TGF response rightward, influencing GFR, distal salt delivery, and BP. Others have inhibited Na:2Cl:K symport using exogenous NO donors in Henle's loop (5), but this is the first demonstration that endogenous NO can have this effect. These authors also confirm that NO from the macula densa diffuses as far as the vascular pole of the glomerulus, where it could act as a paracrine vasodilator to oppose the influence of all locally active vasoconstrictors, including TGF.Is there a way to distinguish between the autocrine (transport) and paracrine (vasodilator) effects of macula densa NO as a modulator of TGF? A future approach might be to eliminate the autocrine effect by permeabilizing the macula densa to salt and then determining whether the TGF response to tubular salt is still being modulated by NOS I activity. Another way mi...