Contribution of the basolateral isoform of the Na-K-2Cl−cotransporter (NKCC1/BSC2) to renin secretion

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Abstract
Acute administration of loop diuretics like furosemide leads to a stimulation of renin secretion, an effect thought to result from inhibition of Na-K-2Cl cotransporter (NKCC2)-mediated salt transport at the luminal surface of the macula densa (MD). However, loop diuretics also inhibit NKCC1, the second isoform of the Na-K-2Cl cotransporter, with similar potency. In the present study, we examined the influence of furosemide on renin secretion in NKCC1-deficient mice to distinguish between effects of the loop diuretic involving NKCC2 and, by implication, the MD pathway, and effects that might occur via inhibition of NKCC1. Baseline plasma renin concentration (PRC) was 1,212 ± 211 in NKCC1+/+ ( n = 13) and 3,851 ± 579 ng ANG I·ml−1·h−1in NKCC1−/− mice ( n = 14; P = 0.00024). Acute administration of furosemide (50 mg/kg i.p.) increased PRC significantly to 9,324 ± 1,018 ng ANG I·ml−1·h−1in NKCC1+/+ ( n = 13; P < 0.0001 compared with basal) and to 14,188 ± 2,274 ng ANG I·ml−1·h−1in NKCC1−/− mice [ n = 14; P = 0.0002 compared with basal; P = 0.034 compared with wild-type (WT) plus furosemide]. Renin mRNA expression was about threefold higher in NKCC1−/− compared with WT mice. There was considerable recruitment of granular cells to upstream regions of afferent arterioles in NKCC1−/− mice. Patch-clamp studies in single juxtaglomerular granular (JG) cells from WT mice showed an ∼10% increase in membrane capacitance during incubation with furosemide (10−4M), indicating a direct effect of the loop diuretic on renin secretion. No effect of furosemide on membrane capacitance was observed in JG cells from NKCC1-deficient mice. Furosemide (10−3M) significantly stimulated renin release from primary cultures of JG cells from WT mice, whereas no response was observed in NKCC1−/− mice. Our data suggest that a functional NKCC1 suppresses basal renin release, at least in part, through a direct effect on JG cells.