Increased Expression of Renal Cyclooxygenase-2 and Neuronal Nitric Oxide Synthase in Hypertensive Cx40-Deficient Mice

Abstract

Cx40-deficient mice (Cx40–/–) are hypertensive due to increased renin secretion. We evaluated the renal expression of neuronal nitric oxide synthase (nNOS) and cyclooxygenases COX-1 and COX-2, three macula densa enzymes. The levels of nNOS were increased in kidneys of Cx40–/– mice, as well as in those of wild-type (WT) mice subjected to the two-kidney one-clip model of hypertension. In contrast, the levels of COX-2 expression were only increased in the hypoperfused kidney of Cx40–/– mice. Treatment with indomethacin lowered blood pressure and renin mRNA in Cx40–/– mice without affecting renin levels, indicating that changes in COX-2 do not cause the altered secretion of renin. Suppression of NOS activity by N^G-nitro-L-arginine methyl ester (L-NAME) decreased renin levels in Cx40–/– animals, indicating that NO regulates renin expression in the absence of Cx40. Treatment with candesartan normalized blood pressure in Cx40–/– mice, and decreased the levels of both COX-2 and nNOS. After a treatment combining candesartan and L-NAME, the blood pressure of Cx40–/– mice was higher than that of WT mice, showing that NO may counterbalance the vasoconstrictor effects of angiotensin II in Cx40–/– mice. These data document that renal COX-2 and nNOS are differentially regulated due to the elevation of renin-dependent blood pressure in mice lacking Cx40.

Physiology of Kidney Renin

“…Similar results were obtained in experiments examining the involvement of the macula densa-derived NO in the regulation of renin expression in mice lacking Cx40. The kidneys of the Cx40 knockout mice demonstrate a large increase in the expression of the neuronal nitric oxide synthase isoform (nNOS) and show decreased renin levels after the pharmacological inhibition of NOS activity (464). These observations demonstrate that COX-2-derived prostaglandins and NO act as tonic stimulators of the renin system in the kidney of both normal and Cx40 knockout mice.…”

“…Investigations into the involvement of cyclooxygenase (COX)-2-derived prostanoids have revealed a clear increase in the expression of COX-2 mRNA and protein levels in mice lacking Cx40 (464,921), which underlines the parallel control mechanism of renin and COX-2 genes by the macula densa cells (127,769). The treatment with COX-2 inhibitors markedly reduced renin mRNA levels in Cx40-deficient mice, similar to wild-type mice, and diminished the increase in the number of renin-producing cells (921).…”

Direct assessment of tubuloglomerular feedback responsiveness in connexin 40-deficient mice

“…Furthermore, TGF responses are enhanced by angiotensin II, but angiotensin II levels are likely to be higher, not lower in the Cx40-deficient compared with WT animals (14,22). An interesting possibility is that an increase in nitric oxide generated by neuronal nitric oxide synthase (nNOS) in macula densa cells contributes to TGF attenuation since the level of macula densa nNOS has been reported to be upregulated in Cx40-deficient mice (10).…”

Connexins: Key Mediators of Endocrine Function

“…Chronic stimulation of renin production induces an increase in the number of renin-producing cells within the afferent arterioles and, under certain conditions, also ectopically within the mesangium (276,283). The recruitement of these ectopic cells may associate with altered differentiation of the renin cell lineage (477).…”