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Reversal of Collapsing Glomerulopathy in Mice with the Cyclin-Dependent Kinase Inhibitor CYC202

Dana Gherardi^*, Vivette D’Agati, Te-Hua Tearina Chu, Anna Barnett^||, Athos Gianella-Borradori^||, Irwin H. Gelman and Peter J. Nelson^*

*Division of Nephrology, New York University School of Medicine, Department of Pathology, Columbia University College of Physicians and Surgeons, Shared Microarray Facility, Mount Sinai School of Medicine, New York, and Roswell Park Cancer Institute, Buffalo, New York; and ^||Cyclacel Ltd., Dundee, United Kingdom.

Correspondence to Dr. Peter J. Nelson, Division of Nephrology, OBV-CD696, Department of Medicine, NYU School of Medicine, 550 First Avenue, New York, NY 10016. Phone: 212-263-7681; Fax: 212-263-7683; E-mail: nelsop02{at}popmail.med.nyu.edu

ABSTRACT. 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.

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