Protein kinase C-beta inhibition for diabetic kidney disease.
Amid the rapidly rising number of people with diabetes worldwide, the prevalence of diabetic kidney disease (DKD) is expected to increase considerably despite available treatments. Consequently, novel therapeutic agents are urgently needed. Ruboxistaurin mesylate is a bisindolylmaleimide that specifically inhibits the beta isoform of protein kinase C (PKC). In experimental models of DKD, ruboxistaurin normalized glomerular hyperfiltration, decreased urinary albumin excretion, preserved kidney function, and reduced mesangial expansion, glomerulosclerosis, and tubulointerstitial fibrosis. These beneficial effects of ruboxistaurin, both alone and combined with renin-angiotensin system inhibition, have been observed in a variety of experimental models of DKD. A phase 2 study of PKC-beta inhibition in persons with type 2 diabetes and DKD already treated with angiotensin converting enzyme inhibition and/or angiotensin receptor blockade has been conducted. Addition of ruboxistaurin for 1 year reduced urinary albumin, prevented an increase in urinary transforming growth factor-beta, and stabilized estimated glomerular filtration rate. Based on secondary analyses of clinical trials in patients with diabetic retinopathy or neuropathy, ruboxistaurin appears safe and may also prevent onset of DKD. PKC-beta inhibition holds promise as a new strategy to improve kidney disease outcomes in diabetes. Large-scale clinical trials will be required to confirm safety and to validate prospective benefits of ruboxistaurin on relevant clinical endpoints in DKD.
Tuttle
Katherine R
KR
Providence Medical Research Center at Sacred Heart Medical Center, Division of Nephrology, Department of Medicine, University of Washington School of Medicine, Spokane, WA 99204, USA. ktuttle@shmc.org
D000818:Animals; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D064546:Protein Kinase C beta; D016896:Treatment Outcome
D004791:Enzyme Inhibitors; D011493:Protein Kinase C; D064546:Protein Kinase C beta