title: Mineralocorticoid receptor blockade confers renoprotection in preexisting chronic cyclosporine nephrotoxicity.
abstract: Recent studies from our laboratory have shown that the mineralocorticoid receptor (MR) blockade with spironolactone (Sp) prevented renal dysfunction and reduced renal injury in both acute and chronic cyclosporine (CsA) nephrotoxicity. This study was designed to evaluate whether Sp administration reduces functional and structural renal damage associated in the setting of preexisting chronic CsA nephrotoxicity. Twenty eight male Wistar rats were fed a low-sodium diet. Fourteen received vehicle (V) and the others were treated with CsA (15 mg/kg sc). After 18 days one half of each group received Sp (20 mg/kg po) for the subsequent 18 days. Creatinine clearance, arteriolopathy, tubulointerstitial fibrosis, arteriolar thickening, glomerular diameter, apoptosis index and TGF-beta, procaspase-3, and kidney injury molecule 1 (Kim-1) mRNA levels as well as Kim-1 shedding in urine were evaluated. Sp reduced the progression of renal dysfunction and tubulointerstitial fibrosis in preexisting chronic CsA nephrotoxicity. There was a significant reduction of arteriolar thickening in the CsA+Sp group that was associated with greater glomerular diameter and reduction of apoptosis index. These renoprotective effects were associated with reduction of TGF-beta, procaspase-3, and Kim-1 mRNA levels as well as Kim-1 shedding into the urine. In conclusion, MR blockade with Sp prevented the progression of renal injury in preexisting chronic CsA nephropathy. These results suggest that Sp may reduce CsA-induced established nephrotoxicity in patients.
authors.affiliation: Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México.
authors.forename: Jazmin
authors.initials: J
authors.lastname: Pérez-Rojas
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Blanco
authors.forename: Cristino
authors.initials: C
authors.lastname: Cruz
authors.forename: Joyce
authors.initials: J
authors.lastname: Trujillo
authors.forename: Vishal S
authors.initials: VS
authors.lastname: Vaidya
authors.forename: Norma
authors.initials: N
authors.lastname: Uribe
authors.forename: Joseph V
authors.initials: JV
authors.lastname: Bonventre
authors.forename: Gerardo
authors.initials: G
authors.lastname: Gamba
authors.forename: Norma A
authors.initials: NA
authors.lastname: Bobadilla
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001160:Arterioles / Q000473:pathology; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D053148:Caspase 3 / Q000096:biosynthesis; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D016572:Cyclosporine; D005355:Fibrosis; D007166:Immunosuppressive Agents; D020287:In Situ Nick-End Labeling; D007674:Kidney Diseases / Q000139:chemically induced* / Q000517:prevention & control*; D007678:Kidney Glomerulus / Q000473:pathology; D007684:Kidney Tubules / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D011188:Potassium / Q000097:blood; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013148:Spironolactone / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
chemical_list: D053148:Caspase 3; D015815:Cell Adhesion Molecules; D016572:Cyclosporine; D007166:Immunosuppressive Agents; D008565:Membrane Proteins; D000451:Mineralocorticoid Receptor Antagonists; D011188:Potassium; D012313:RNA; D013148:Spironolactone; D016212:Transforming Growth Factor beta; C110936:Havcr1 protein, rat