title: Seliciclib inhibits renal hypertrophy but not fibrosis in the rat following subtotal nephrectomy.
abstract: 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 α-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.
authors.affiliation: Academic Unit of Nephrology, Department of Infection and Immunity, Medical School Sheffield, Sheffield, UK.
authors.forename: F
authors.initials: F
authors.lastname: Nutter
authors.forename: A
authors.initials: A
authors.lastname: Khwaja
authors.forename: J
authors.initials: J
authors.lastname: Haylor
mesh_terms: D000419:Albuminuria / Q000209:etiology; D000818:Animals; D056750:Cyclin A1 / Q000037:antagonists & inhibitors; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors; D018450:Disease Progression; D005109:Extracellular Matrix / Q000378:metabolism; D005355:Fibrosis; D005923:Glomerulosclerosis, Focal Segmental / Q000473:pathology; D006973:Hypertension / Q000209:etiology; D006984:Hypertrophy / Q000517:prevention & control; D007668:Kidney / Q000187:drug effects / Q000254:growth & development / Q000473:pathology*; D009392:Nephrectomy; D011687:Purines / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D051436:Renal Insufficiency, Chronic / Q000209:etiology / Q000517:prevention & control*; D000077546:Roscovitine
chemical_list: C503748:Ccna1 protein, rat; D056750:Cyclin A1; D011687:Purines; D000077546:Roscovitine; C495892:Cdk2 protein, rat; D051357:Cyclin-Dependent Kinase 2