CDK/GSK-3 inhibitors as a new approach for the treatment of proliferative renal diseases.

Proliferation of specific renal cell types leads to the development of many types of kidney disease. Given the central role that both cyclin-dependent kinases (CDKs) and glycogen synthase kinase-3 (GSK-3) play in promoting aberrant proliferation within the kidney, these paralogous serine/threonine kinases are being explored as therapeutic molecular targets in proliferative renal diseases. CDK/GSK-3 inhibitors have now demonstrated efficacy in preclinical models of mesangial proliferative glomerulonephritis, crescentic glomerulonephritis, proliferative lupus nephritis and collapsing glomerulopathy. Moreover, they have recently entered human clinical trials in IgA nephropathy. Since the pathogenesis of most proliferative renal diseases is multifactorial, there is the belief that CDK/GSK-3 inhibitors, as inherently promiscuous drugs, may have several modes of action. This is supported by recent studies in systems research delineating the antiinflammatory profile of CDK/GSK-3 inhibitors compared with other immunomodulators. Thus, CDK/GSK-3 inhibitors may emerge as effective drugs for proliferative renal diseases due to their integrative properties across several aspects of disease pathogenesis. This brief mini-review will highlight these issues.