Cyclic GMP Mediates Influence of Macula densa Nitric Oxide over Tubuloglomerular Feedback

Abstract

Background: Tubuloglomerular feedback (TGF) stabilizes nephron function by eliciting reciprocal changes in single-nephron glomerular filtration rate in response to changes in salt reaching the macula densa. Nitric oxide (NO) modulates TGF, making it less reactive. NO could come from NO synthase (NOS) in mesangium or microvessels (NOS III) or from neuronal NOS (NOS I) in the macula densa. Cyclic GMP is second messenger for many NO functions. Methods: Rat micropuncture was performed to confirm that macula densa NOS I makes the NO which modulates TGF and that cyclic GMP is a second messenger for this. The range of TGF was determined by measuring the single-nephron glomerular filtration rate while perfusing Henle’s loop. The TGF slope was calculated from the response to flow perturbations in free-flowing nephrons using a noninvasive optical technique to measure flow. The NO-cyclic GMP axis was manipulated by tubular microperfusion of the antagonists S-methyl-thiocitrulline (SMTC) and 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ) and NO donor (spermine NONOate). Results: SMTC and ODQ each increased slope and range of TGF and tended to shift it leftward. NONOate reversed the effects of SMTC, but not of ODQ. Conclusion: Cyclic GMP mediates desensitization of TGF by macula densa NOS I.

Commentary on…Neuronal Nitric Oxide Synthase

“…The simplest route to this end would be for NO formation to vary in proportion to physiologic changes in macula densa salt. The present findings call this into question, but one might reconcile these data, the opposite finding from Liu et al (7), and the micropuncture data from various labs (1,6) by making the reasonable supposition that there are sodium-dependent and sodium-independent pathways competing for control of NOS I in the macula densa and that circumstances can arise where one or the other dominates. In fact, we observed this in micropuncture experiments where NOS I activity was dominated by macula densa salt in normal rats, but not in rats with streptozotocin diabetes (unpublished observation).…”

“…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 might become available if someone discovers that the autocrine effect of NO in the macula densa is not mediated by cGMP, because cGMP mediates the overall effect of NO on TGF (6).…”

“…Those efforts have led us to theorize that NO provides an intermediate link between steady state salt delivery and the amount of salt required to elicit a TGF response. The supporting data for this are complex and eclectic, but one simple observation is worth noting, namely that the vasoconstrictor response to NOS I blockade is usually greater when there is more salt being delivered to the macula densa (1)(2)(3)(4)(5)(6). The simplest route to this end would be for NO formation to vary in proportion to physiologic changes in macula densa salt.…”

Role of soluble guanylate cyclase in renal hemodynamics and autoregulation in the rat

“…However, the signaling pathways remain unclear. In general, sGC is thought to be the primary target of NO (16), and the effects of NO on TGF (50,58) and microvascular autoregulation (9) seem to be mediated predominantly via cGMP. However, sGC-independent signaling has also been postulated, e.g., via inhibition of 20-hydroxyeicosatrienoic acid (20-HETE) (41,56).…”

“…This suggests depression of the physiological oscillations of TGF and thus its feedback gain. Indeed, NO is known to attenuate TGF gain (30,64,65) via the cGMP pathway (50,58). With regard to impaired autoregulation, it is noteworthy that cinaciguat also reduced AP, which might approach the lower limit of autoregulation.…”