Ivabradine Ameliorates Kidney Fibrosis in L-NAME-Induced Hypertension

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.

Automated Computer-Assisted Image Analysis for the Fast Quantification of Kidney Fibrosis

“…The last stage of kidney damage by CKD is fibrosis, an exacerbated extracellular matrix deposition that decreases kidney function [ 2 ]. In this sense, an increased number of in vivo studies are being performed in the field of nephrology; most of them report the assessment of the percentage of fibrosis in the kidney tissue using hundreds of images on experimental animal models [ 4 , 8 , 9 , 11 , 12 , 13 , 14 ] or renal biopsies [ 15 ]. However, the measurement of fibrosis in that scenario is laborious when it is done using a manual approach, such as a score determined by a pathologist or employing a non-automated computer program [ 4 , 11 , 16 ].…”

“…Although there are better approaches such as artificial intelligence [ 17 ] and machine learning [ 18 ] that use convolutional neural networks trained to learn how to interpret the results of a given sample, reproducing the pathologist visual assessment [ 19 , 20 , 21 , 22 ], there are also more straightforward approaches such as image processing software. One of the most used is the free software ImageJ [ 13 , 23 , 24 , 25 , 26 , 27 ] and, more effectively, automated software such as CellProfiler™.…”

Lactacystin-induced kidney fibrosis: Protection by melatonin and captopril

“…The H-E-stained sections were analyzed using transmitted light microscopy at ×10 magnification and NIKON NIS-Elements Analysis software to assess glomerular morphometry, as previously described ( Pechanova et al, 2006 ; Hrenák et al, 2013 ; Stanko et al, 2020 ). Glomerular density was determined by counting preserved glomeruli in a 1 mm 2 digital frame put over the kidney cortex at 10 microscopic fields per section; i.e., 80 digital frames were investigated per group.…”

Ivabradine and Blood Pressure Reduction: Underlying Pleiotropic Mechanisms and Clinical Implications

“…In a pig model of chronic Ang II infusion-induced hypertension and diastolic LV dysfunction, the acute administration of ivabradine improved LV filling parameters by an HR-independent mechanism ( 75 ). Moreover, ivabradine exerted an antihypertrophic effect on the aorta in spontaneously hypertensive rats ( 24 ) and renoprotection in rats with l -NAME-induced hypertension ( 76 ).…”