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1 National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
2 University of Cincinnati, Cincinnati, OH, USA
3 Department of Physiology, University of Southern Denmark, Odense, Denmark
* To whom correspondence should be addressed. E-mail: jurgens{at}intra.niddk.nih.gov.
Acute administration of loop diuretics like furosemide leads to a stimulation of renin secretion, an effect thought to result from inhibition of 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 in order to distinguish between effects of the loop diuretic involving NKCC2 and by implication the macula densa pathway, and effects that might occur via inhibition of NKCC1. Baseline PRC was 1212 ± 211 in NKCC1+/+ (n=13) and 3851 ± 579 ng Ang I/ml h in NKCC1-/- mice (n=14; p=.00024). Acute administration of furosemide (50 mg/kg i.p.) increased PRC significantly to 9324 ± 1018 ng Ang I/ml h in NKCC1+/+ (n=13; p<.0001 compared to basal), and to 14188 ± 2274 ng Ang I/ml h in NKCC1-/- mice (n=14; p=.0002 compared to basal; p=.034 compared to wild type plus furosemide). Renin mRNA expression was about 3 fold higher in NKCC1-/- compared to WT mice. There was considerable recruitment of granular cells to upstream regions of afferent arterioles in NKCC1-/- mice. Patch clamp studies on single JG cells from wild type mice showed an about 10% increase in membrane capacitance during incubation with furosemide (10-4 M) 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 (10-3 M) significantly stimulated renin release from primary cultures of JG cells from wild type 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 juxtaglomerular granular cells.
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