Sacubitril/valsartan ameliorates renal tubulointerstitial injury through increasing renal plasma flow in a mouse model of type 2 diabetes with aldosterone excess

Author:

Nishio Haruomi1,Ishii Akira1,Yamada Hiroyuki12,Mori Keita P13,Kato Yukiko1,Ohno Shoko1,Handa Takaya1,Sugioka Sayaka1,Ishimura Takuya1,Ikushima Akie1,Inoue Yui1,Minamino Naoto4,Mukoyama Masashi5,Yanagita Motoko16,Yokoi Hideki1ORCID

Affiliation:

1. Department of Nephrology, Graduate School of Medicine, Kyoto University , Kyoto, Kyoto , Japan

2. Department of Primary Care and Emergency Medicine, Graduate School of Medicine, Kyoto University , Kyoto, Kyoto, Japan

3. Department of Nephrology and Dialysis, Medical Research Institute KITANO HOSPITAL, PIIF Tazuke-Kofukai , Osaka, Osaka , Japan

4. Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute , Suita, Osaka , Japan

5. Department of Nephrology, Graduate School of Medical Sciences, Kumamoto University , Kumamoto, Kumamoto , Japan

6. Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University , Kyoto, Kyoto , Japan

Abstract

ABSTRACT Background Aldosterone has been assumed to be one of aggravating factors in diabetic kidney disease (DKD). Natriuretic peptides/guanylyl cyclase-A/cGMP signalling has been shown to ameliorate aldosterone-induced renal injury in mice. Sacubitril/valsartan (SAC/VAL) is used clinically for chronic heart failure and hypertension, in part by augmenting natriuretic peptide bioavailability. The effects of SAC/VAL on renal pathophysiology including in DKD, however, have remained unclarified. Methods Eight-week-old male db/db mice fed on a high-salt diet (HSD) were treated with vehicle or aldosterone (0.2 μg/kg/min), and divided into four groups: HSD control, ALDO (aldosterone), ALDO + VAL (valsartan), and ALDO + SAC/VAL group. After 4 weeks, they were analysed for plasma atrial natriuretic peptide (ANP) levels, renal histology, and haemodynamic parameters including glomerular filtration rate (GFR) by FITC-inulin and renal plasma flow (RPF) by para-amino hippuric acid. Results The ALDO + SAC/VAL group showed significantly increased plasma ANP concentration and creatinine clearance, and decreased tubulointerstitial fibrosis and neutrophil gelatinase-associated lipocalin expression compared to ALDO and ALDO + VAL groups. SAC/VAL treatment increased GFR and RPF, and suppressed expression of Tgfb1, Il1b, Ccl2, and Lcn2 genes compared to the ALDO group. The percentage of tubulointerstitial fibrotic areas negatively correlated with the RPF and GFR. Conclusion In a mouse model of type 2 diabetes with aldosterone excess, SAC/VAL increased RPF and GFR, and ameliorated tubulointerstitial fibrosis. Furthermore, RPF negatively correlated well with tubulointerstitial injury, suggesting that the beneficial effects of SAC/VAL could be through increased renal plasma flow with enhanced natriuretic peptide bioavailability.

Funder

JSPS

Mochida Memorial Foundation for Medical and Pharmaceutical Research

Smoking Research Foundation

Japanese Association of Dialysis Physicians

Publisher

Oxford University Press (OUP)

Subject

Transplantation,Nephrology

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