Ivabradine Ameliorates Kidney Fibrosis in L-NAME-Induced Hypertension

Peter Stanko; Tomas Baka; Kristina Repova; Silvia Aziriova; Kristina Krajcirovicova; Andrej Barta; Pavol Janega; Michaela Adamcova; Ludovit Paulis; Fedor Simko

doi:10.3389/fmed.2020.00325

Ivabradine Ameliorates Kidney Fibrosis in L-NAME-Induced Hypertension

Front Med (Lausanne). 2020 Jul 10:7:325. doi: 10.3389/fmed.2020.00325. eCollection 2020.

Authors

Peter Stanko¹, Tomas Baka¹, Kristina Repova¹, Silvia Aziriova¹, Kristina Krajcirovicova¹, Andrej Barta², Pavol Janega^{2

3}, Michaela Adamcova⁴, Ludovit Paulis^{1

2}, Fedor Simko^{1

5

6}

Affiliations

¹ Institute of Pathophysiology, Faculty of Medicine, Comenius University, Bratislava, Slovakia.
² Institute of Normal and Pathological Physiology, Centre of Experimental Medicine, Slovak Academy of Sciences, Bratislava, Slovakia.
³ Institute of Pathological Anatomy, Faculty of Medicine, Comenius University, Bratislava, Slovakia.
⁴ Department of Physiology, School of Medicine, Charles University, Prague, Czechia.
⁵ 3rd Department of Internal Medicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia.
⁶ Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia.

Abstract

Hypertension-induced renal injury is characterized by structural kidney alterations and function deterioration. Therapeutics for kidney protection are limited, thus novel renoprotectives in hypertension are being continuously sought out. Ivabradine, an inhibitor of the I_f current in the sinoatrial node reducing heart rate (HR), was shown to be of benefit in various cardiovascular pathologies. Yet, data regarding potential renoprotection by ivabradine in hypertension are sparse. Thirty-six adult male Wistar rats were divided into non-diseased controls and rats with N^G-nitro-L-arginine methyl ester (L-NAME)-induced hypertension to assess ivabradine's site-specific effect on kidney fibrosis. After 4 weeks of treatment, L-NAME increased the average systolic blood pressure (SBP) (by 27%), decreased glomerular density (by 28%) and increased glomerular tuft area (by 44%). Moreover, L-NAME induced glomerular, tubulointerstitial, and vascular/perivascular fibrosis by enhancing type I collagen volume (16-, 19- and 25-fold, respectively). L-NAME also increased the glomerular type IV collagen volume and the tubular injury score (3- and 8-fold, respectively). Ivabradine decreased average SBP and HR (by 8 and 12%, respectively), increased glomerular density (by 57%) and reduced glomerular tuft area (by 30%). Importantly, ivabradine decreased type I collagen volume at all three of the investigated sites (by 33, 38, and 72%, respectively) and enhanced vascular/perivascular type III collagen volume (by 67%). Furthermore, ivabradine decreased the glomerular type IV collagen volume and the tubular injury score (by 63 and 34%, respectively). We conclude that ivabradine attenuated the alterations of glomerular density and tuft area and modified renal fibrosis in a site-specific manner in L-NAME-hypertension. It is suggested that ivabradine may be renoprotective in hypertensive kidney disease.

Keywords: L-NAME; fibrosis; hypertension; ivabradine; nephroprotection.