1. Reversal of Collapsing Glomerulopathy in Mice with the Cyclin-Dependent Kinase Inhibitor CYC202
- Author
-
Irwin H. Gelman, Vivette D. D'Agati, Athos Gianella-Borradori, Te Hua Tearina Chu, Anna Barnett, Dana Gherardi, and Peter J. Nelson
- Subjects
Nephrology ,Genetically modified mouse ,medicine.medical_specialty ,Transgene ,Nephrosis ,Mice, Transgenic ,Biology ,Kidney ,Pathogenesis ,Mice ,Cyclin-dependent kinase ,Internal medicine ,Roscovitine ,medicine ,Animals ,Dose-Response Relationship, Drug ,Glomerulosclerosis, Focal Segmental ,Kinase ,General Medicine ,medicine.disease ,Cyclin-Dependent Kinases ,Disease Models, Animal ,medicine.anatomical_structure ,Endocrinology ,Purines ,biology.protein - 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.
- Published
- 2004