Protein kinase C beta inhibition: the promise for treatment of diabetic nephropathy.
OBJECTIVE
The prevalence of diabetes mellitus is increasing rapidly worldwide. The number of patients with diabetic nephropathy is also expected to increase considerably in the future despite currently available treatments that may prevent or slow kidney disease progression. Additional therapeutic agents are therefore urgently needed.


RESULTS
Ruboxistaurin mesylate is a bisindolylmaleimide that specifically inhibits the beta-isoform of protein kinase C. In animal models of diabetic nephropathy, ruboxistaurin normalized glomerular hyperfiltration, decreased urinary albumin excretion, preserved renal function and reduced mesangial expansion, glomerulosclerosis, and tubulointerstitial fibrosis. In humans with type 2 diabetes and nephropathy already treated with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, treatment with ruboxistaurin for 1 year reduced albuminuria and urinary transforming growth factor-beta, and maintained estimated glomerular filtration rate. Ruboxistaurin has so far been shown to be well tolerated at the doses tested.


CONCLUSIONS
Inhibition of protein kinase C beta may represent a novel strategy to improve kidney outcomes in patients with diabetes mellitus. Large-scale, prospective trials are needed to confirm the safety and potential benefits of ruboxistaurin in patients with diabetic nephropathy.
Anderson
Pamela W
PW
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46234, USA. ruby2@lilly.com
McGill
Janet B
JB
Tuttle
Katherine R
KR
D000818:Animals; D002986:Clinical Trials as Topic; D003928:Diabetic Nephropathies / Q000201:enzymology / Q000628:therapy*; D005919:Glomerular Filtration Rate; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D008956:Models, Chemical; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D064546:Protein Kinase C beta; D016896:Treatment Outcome
D007211:Indoles; D008301:Maleimides; C099154:ruboxistaurin; D011493:Protein Kinase C; D064546:Protein Kinase C beta; C088060:bisindolylmaleimide