title: Nebivolol attenuates maladaptive proximal tubule remodeling in transgenic rats.
abstract: OBJECTIVE
  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 beta(1)-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-beta-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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Internal Medicine, University of Missouri-Columbia School of Medicine, USA.
authors.forename: Melvin R
authors.initials: MR
authors.lastname: Hayden
authors.forename: Javad
authors.initials: J
authors.lastname: Habibi
authors.forename: Adam
authors.initials: A
authors.lastname: Whaley-Connell
authors.forename: Dilek
authors.initials: D
authors.lastname: Sowers
authors.forename: Megan
authors.initials: M
authors.lastname: Johnson
authors.forename: Roger
authors.initials: R
authors.lastname: Tilmon
authors.forename: Deepika
authors.initials: D
authors.lastname: Jain
authors.forename: Carlos
authors.initials: C
authors.lastname: Ferrario
authors.forename: James R
authors.initials: JR
authors.lastname: Sowers
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D004983:Ethanolamines / Q000494:pharmacology*; D005355:Fibrosis; D006977:Hypertension, Renal / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D008854:Microscopy, Electron; D000068577:Nebivolol; D018384:Oxidative Stress / Q000187:drug effects; D011507:Proteinuria / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D012083:Renin / Q000235:genetics; D014617:Vacuoles / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D000319:Adrenergic beta-Antagonists; D001578:Benzopyrans; D004983:Ethanolamines; D026561:Low Density Lipoprotein Receptor-Related Protein-2; C535029:Ren2 protein, rat; D000068577:Nebivolol; D012083:Renin