Nebivolol Attenuates Maladaptive Proximal Tubule Remodeling in Transgenic Rats

Abstract

Background/Aims: The impact of nebivolol therapy on the renal proximal tubular cell (PTC) structure and function was investigated in a transgenic (TG) rodent model of hypertension and the cardiometabolic syndrome. The TG Ren2 rat develops nephropathy with proteinuria, increased renal angiotensin II levels and oxidative stress, and PTC remodeling. Nebivolol, a β₁-antagonist, has recently been shown to reduce albuminuria, in part, through reductions in renal oxidative stress. Accordingly, we hypothesized that nebivolol therapy would attenuate PTC damage and tubulointerstitial fibrosis. Methods: Young Ren2 (R2-N) and SD (SD-N) rats were treated with nebivolol (10 mg/kg/day) or vehicle (R2-C; SD-C) for 3 weeks. PTC structure and function were tested using transmission electron microscopy and functional measurements. Results: Nebivolol treatment decreased urinary N-acetyl-β-D-glucosaminidase, tubulointerstitial ultrastructural remodeling and fibrosis, NADPH oxidase activity, 3-nitrotyrosine levels, and increased megalin and lysosomal-associated membrane protein-2 immunostaining in PTCs. Ultrastructural abnormalities that were improved with therapy included altered canalicular structure, reduced endosomes/lysosomes and PTC vacuoles, basement membrane thickening, and mitochondrial remodeling/fragmentation. Conclusion: These observations support the notion that nebivolol may improve PTC reabsorption of albumin and other glomerular filtered small molecular weight proteins in association with the attenuation of oxidative stress, tubulointerstitial injury and fibrosis in this rat model of metabolic kidney disease.

Childhood-Adolescent Obesity in the Cardiorenal Syndrome: Lessons from Animal Models

“…5) changes that have been described in humans and are termed obesity-related glomerulopathy. Additionally, there is marked ultrastructural remodeling of the proximal tubule, which is similar to that in another rodent model of insulin resistance and excess angiotensin II production (due to renin transfection with mouse renin gene) [32]. The kidney proximal tubule cells also undergo marked ultrastructural remodeling consisting of loss of basolateral polarity, loss of elongated mitochondria with spherical rounded mitochondria (mitochondrial fragmentation), abnormal mitochondrial cristae and matrix, decreased basilar invaginating canalicular infoldings, and chronic inflammation (fig.…”

“…The young ZO rat model of insulin resistance and obesity develops microalbuminuria and therefore may serve as a good model of early renal disease in the CRS [20,21,23,31,32,33,34]. The kidney glomerulus undergoes marked ultrastructural remodeling consisting of glomerular hypertrophy and widening of Bowman’s space, inflammation, loss of podocytes (podocytopenia), and podocyte remodeling (fig.…”

Beta-adrenoblockers of third generation as medicines for drug therapy of patients with chronic kidney disease

“…Введение Ren2-крысам этого препарата в дозе, снижающей АД, в течение 3 недель оказывало выраженный анти-гипертензивный эффект, который сопровождался подавлением в коре почек активности НАДФ(Н)-оксидазы и связанной с ней продукции О 2¯ и Н 2 О 2 , восстановлением содержания в почечной ткани бел-ков -маркеров нефрина и мегалина, отражающих соответственно повреждение подоцитов и клеток ПК, и существенным ослаблением ультраструктурных при-знаков ремоделирования канальцевых клеток и окру-жающей их соединительной ткани. Одновременно у животных отмечалось существенное снижение аль-буминурии и выделения с мочой NAG (N-ацетил-бета-(D)-глюкозаминидазы) -наиболее активного лизосо-мального фермента ПК, который является маркером тубулоинтерстициального повреждения почек [19,35].…”

“…Наибольший интерес среди них представляют кар-ведилол и небиволол, которые не только улучшают кровоснабжение почек [17], но и препятствуют раз-витию в клубочках, проксимальных канальцах (ПК) и других структурах почечной ткани оксидативного стресса и связанного с ним воспалительного и фи-бротического повреждения, ведущего к потере по-чечной функции [19,28].…”

Overnutrition and the Cardiorenal Syndrome: Use of a Rodent Model to Examine Mechanisms

“…Importantly, increased renal NO appears to counter-regulate the effects of both the sympathetic nervous system and the RAAS in the renal regulation of salt and fluid homeostasis, as well as renal injury [52]. Treatment strategies which reduce oxidative stress and increase bioavailable NO are renoprotective in several rodent models of RAAS- and sympathetic nervous system-mediated renal injury, including the ZO rat model [49,50,51,52,53,54]. …”