Soos Timothy J, Meijer Laurent, Nelson Peter J
Division of Nephrology, New York University School of Medicine, New York, NY 10016, USA.
Drug News Perspect. 2006 Jul-Aug;19(6):325-8. doi: 10.1358/dnp.2006.19.6.985939.
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.
特定肾细胞类型的增殖会导致多种类型肾脏疾病的发生。鉴于细胞周期蛋白依赖性激酶（CDK）和糖原合酶激酶-3（GSK-3）在促进肾脏内异常增殖中所起的核心作用，这些同源的丝氨酸/苏氨酸激酶正被作为增殖性肾脏疾病的治疗分子靶点进行研究。CDK/GSK-3抑制剂现已在系膜增生性肾小球肾炎、新月体性肾小球肾炎、增殖性狼疮性肾炎和塌陷性肾小球病的临床前模型中显示出疗效。此外，它们最近已进入IgA肾病的人体临床试验。由于大多数增殖性肾脏疾病的发病机制是多因素的，人们认为CDK/GSK-3抑制剂作为本质上具有多效性的药物，可能有多种作用模式。系统研究中最近的研究将CDK/GSK-3抑制剂与其他免疫调节剂的抗炎特性进行了对比，这支持了上述观点。因此，CDK/GSK-3抑制剂因其在疾病发病机制多个方面的综合特性，可能成为治疗增殖性肾脏疾病的有效药物。本简要综述将重点介绍这些问题。
