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Sheffield, United Kingdom

Nutter F.,Academic Unit of Nephrology | Khwaja A.,Sheffield Kidney Institute | Haylor J.,Academic Unit of Nephrology
Nephron - Experimental Nephrology | Year: 2013

Background: 5/6 subtotal nephrectomy (SNx) is a non-immune stimulus used to induce renal fibrosis. The ability of seliciclib, a cyclin-dependent kinase inhibitor, to reduce kidney hypertrophy and extracellular matrix (ECM) deposition has been examined in the SNx rat. Methods: Wistar rats were subjected to SNx under isoflurane anaesthesia. The acute effect of seliciclib 28 mg/kg (5 days) on compensatory renal growth (CRG), kidney protein and DNA was determined. In chronic studies albuminuria, hypertension and GFR were monitored. Ki67, apoptag and -smooth muscle actin were determined by immunohistochemistry together with Masson's trichrome staining. The effect of a maximum non-hypotensive dose of seliciclib 28 mg/kg (8 weeks) was determined. Results: Acutely, the remnant kidney developed CRG. Seliciclib 28 mg/kg inhibited both CRG by 45% and increased kidney protein by 48% without affecting increased kidney DNA. Chronically, SNx rats developed albuminuria, hypertension, low GFR with increased tubulointerstitial cell proliferation, apoptosis, myofibroblast accumulation and enhanced ECM deposition. Seliciclib 28 mg/kg (8 weeks) had no effect on either renal function or renal pathology. Plasma concentrations of seliciclib exceeded 5 μM throughout the study. Conclusions: Despite inhibition of early renal hypertrophy, a maximum non-hypotensive dose of seliciclib 28 mg/kg had no impact on the progression of kidney fibrosis in the SNx rat. Copyright © 2013 S. Karger AG, Basel. Source

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