Cyclooxygenase-2 Mediates Increased Renal Renin Content Induced by Low-Sodium Diet

Abstract

We hypothesized that neuronal mtrtc oxide synthase and cyclooxygenase-2, which both exist m the renal cortex, predommantly m the macula densa, play a role m the control of renal renm tissue content We studied the possible role of neuronal mtrrc oxide synthase m regulating renal renm content by using mice m which the neuronal nitric oxide synthase gene has been disrupted (nNOS -/-) compared with its two progemtor strains, the 129/SvEv and the C57BU6, to determine if the absence of neuronal mtrrc oxide synthase would result m decreased renal renm content or blunt the increase observed durmg low sodium intake. Renal remn content from cortical shces was determined m adult mice from all three strams maintained on a normal sodium diet Renal remn content was sigmficantly reduced m the nNOS -/-mice compared with the 129/SvEv and the C57BW6 mice (3 11 t0 23 versus 5 66+0 50 and 7 552 1 17 pg angrotensm Vmg dry weight, respectively, P< 005), suggestmg that neuronal nitric oxide synthase may stimulate renal renm content under basal condmons Neither selectrve pharmacologtcal mhlbition of neuronal mtrm oxide synthase using 7-mtromdazole or disruption of the neuronal nitric oxide synthase gene affected the increase m renal renm content observed during dietary sodium restriction The influence of cyclooxygenase-2 on renal renm content through a macula densa-mediated pathway was studied using a selecttve cyclooxygenase-2 Inhibitor, NS398, m 129/SvEv mace A low-sodium diet increased renal renm content from 6.97tO 52 to 11 5920 79 pg angrotensm Umg dry weight (P< 005), but thus increase was blocked by NS398 In addition, treatment with NS398 reduced renm mRNA m response to a low-sodium diet Thus, increased renal renm content m response to dietary sodmm restriction appears to require the mduction of cyclooxygenase-2, while neuronal nitric oxide synthase appears to affect basal but not stimulated renal renm content (Hypertenszon. 1997;29[part 2]:297-302.) Key Words l renm l cyclooxygenase l nitric oxide l mace T he mechanism by which a decreased sodmm chloride delivery to the macula densa IS sensed, resulting m increased renm secretion by the JUXtaglomerular cells, remains unknown. However, since humoral factors are known to affect rerun, attentton has focused on NO, which IS localized m a prime position to affect remn secretion and which has been imphcated m renm regulation by both m viva and m vitro studies.l-4 The enzyme NOS acts on its substrate L-argmme to produce NO It exists in three known isoforms that are discreetly localized throughout the nephron Briggs et a15 demonstrated that the macula densa is rich m nNOS, whereas nNOS does not appear to be expressed m the glomerulus, mesangium, or juxtaglomerular cells. In contrast, eNOS is expressed in the glomerulus and blood vessels 6 Smgh et a17 have also shown that the activity of nNOS m the macula densa is increased by a low-salt diet, whereas it does not affect eNOS. Therefore, NO produced m the macula densa could exert an effect directly on the adJoining juxtaglomerul...

Augmented cyclooxygenase-2 effects on renal function during varying states of angiotensin II

“…In contrast to our findings, Harding et al (11) reported that COX-2 inhibition does not change RPF in NS or LS animals. Harding et al administered a 100-l bolus of 10 Ϫ5 M NS-398 solution intravenously to 300-to 400-g rats, an ϳ1 g/kg dose.…”

“…We observed that COX-2 inhibition does not elicit significant alterations of RPF and GFR under NS conditions. This finding is consistent with previous in vivo studies under NS conditions that have not demonstrated a discernible consequence of acutely attenuated prostaglandin biosynthesis on renal hemodynamics (11,26,30). Furthermore, afferent arteriolar diameters of juxtamedullary nephrons in NS rats were not changed by COX-2 inhibition with NS-398 (16).…”

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