Reversal of collapsing glomerulopathy in mice with the cyclin-dependent kinase inhibitor CYC202.
Collapsing glomerulopathy (CG) has become an important cause of end-stage renal disease. Whether associated with HIV-1 or other potential etiologies, the pathogenesis of CG converges to induce aberrant proliferation of renal epithelium along the entire nephron. This raises the possibility that targeting cell-cycle progression may be an effective therapeutic strategy for CG. Here, we ask whether the cyclin-dependent kinase (CDK) inhibitor, CYC202 (R-roscovitine), could attenuate or reverse existing renal disease in Tg26 mice, a well characterized HIV-1 transgenic mouse model of CG. Tg26 mice were age and disease matched through analysis of urine (protein/creatinine) to generate 12 treatment pairs covering a range of mild to severe CG. One mouse from each pair received either vehicle or 75 mg/kg of CYC202 every 12 h for 20 d, a dose 20% above that needed to prevent the development of CG. After treatment, urinary, serologic, and histopathologic indices of nephrosis showed reversal of CG in 8 of 12 CYC202-treated mice compared with progression of CG in 10 of 12 vehicle-treated mice, demonstrating a significant therapeutic benefit from CYC202 (P < 0.05). Pharmacokinetic profiles showed that concentrations of CYC202 known to inhibit cell-cycle and transcriptional CDK in vitro were achieved in plasma at efficacious doses. However, amelioration of CG by CYC202 did not correlate with decreases in kidney HIV-1 transgene expression, indicating that suppression of HIV-1 transcription was not a prerequisite for the antiproliferative activity of CYC202. These results demonstrate a novel therapeutic strategy for CG.
Gherardi
Dana
D
Division of Nephrology, New York University School of Medicine, New York, USA.
D'Agati
Vivette
V
Chu
Te-Hua Tearina
TH
Barnett
Anna
A
Gianella-Borradori
Athos
A
Gelman
Irwin H
IH
Nelson
Peter J
PJ
D000818:Animals; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005923:Glomerulosclerosis, Focal Segmental / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control; D007668:Kidney / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D011687:Purines / Q000097:blood / Q000494:pharmacology*; D000077546:Roscovitine
D011687:Purines; D000077546:Roscovitine; D018844:Cyclin-Dependent Kinases