Collecting duct NOS1 activation is necessary for increased GFR in response to high salt diet

Abstract

We previously reported that nitric oxide synthase‐1 (NOS1) in the collecting duct (CD) is critical for maintaining fluid‐electrolyte balance during high salt diet. Lack of NOS1 in the CD (CDNOS1KO) results in reduced sodium excretion, urine output, and urinary nitrite/nitrate excretion compared to control mice after 1 day of a high salt diet. By day 7 of a high salt diet, CDNOS1KO mice display significantly increased systolic blood pressure with normalized sodium excretion. We also previously reported that after 7 days of high salt diet there is inappropriate suppression of plasma and urinary aldosterone excretion, renal angiotensin II levels, and CD ENaC activity. This inability to appropriately suppress renal angiotensin II and systemic aldosterone with high salt diet in CDNOS1KO mice lead us to hypothesize that the loss of activation of CD NOS1 during high salt diet challenges blunts the physiological renal hemodynamic response to high salt diet. The purpose of the current study was to determine if CDNOS1KO mice on high salt diets have attenuated glomerular filtration rate (GFR) response. To test this, GFR was measured by transdermal FITC‐sinistrin clearance in conscious male control and CDNOS1KO mice on sodium deficient (LS, n=4), normal salt (NS, n=11) or after 1 day and 7 days of high salt (HS1, n=4 and HS7, n=10) diets. On LS and NS, GFR was similar between control (LS: 263 ± 14 ml/min, NS: 224 ± 6 ml/min) and CDNOS1KO mice (LS: 237.2 ± 10 ml/min, NS: 218 ± 10 ml/min) (Pgenotype = 0.4, Pdiet = 0.7, Pgenotypexdiet = 0.3). HS1 control mice had a significant increase in GFR (333 ± 10 ml/min, P=0.008), while GFR remained unchanged in CDNOS1KO mice (255 ± 23 ml/min, P=0.2) compared with LS. HS7 control and CDNOS1KO mice had similar levels of GFR (251 ± 16 and 291 ± 27 ml/min, respectively). Taken together these data indicate, that CD NOS1 is critical for the adaptation to a high salt diet, such that CDNOS1KO mice are volume expanded, have inappropriately high RAAS activation, and fail to increase GFR. After a few days of high salt diet, blood pressure is increased resulting in a rightward shift in the pressure natriuresis curve, with GFR and sodium excretion normalized to control levels. In conclusion, CD NOS1 activation is critical for regulation of tubular and hemodynamic pathways during consumption of HS diets.Support or Funding InformationK01‐DK‐105038 KAH, HL136936 JSP and DMP.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.