A novel potential therapy for diabetic nephropathy and vascular complications: protein kinase C beta inhibition.
Diabetic nephropathy is one of the most common microvascular complications of diabetes mellitus and the leading cause of end-stage renal disease in developed countries. Current treatment includes glycemic control, blood pressure control (with special emphasis on agents targeting the renin-angiotensin system), a low-protein (0.6 to 0.8 g/kg) diet, and the use of hypolipidemic agents. Although these therapeutic options may slow progression, the burden of disease remains large, and additional therapeutic agents are urgently needed. Ruboxistaurin (LY333531) mesylate is a bisindolylmaleimide that shows a high degree of specificity within the protein kinase C (PKC) gene family for inhibiting PKC beta isoforms. In animal models of diabetes, including the streptozotocin (STZ) rat, Lepr(db)/Lepr(db) mouse, and STZ-Ren 2 rat models, ruboxistaurin normalized glomerular hyperfiltration, decreased urinary albumin excretion, and reduced glomerular transforming growth factor-beta1 and extracellular matrix protein production. As a result, improvements were noted in mesangial expansion, glomerulosclerosis, tubulointerstitial fibrosis, and renal function. Other studies using less specific probes of PKC activity also have shown an important role for PKC in the development of diabetic nephropathy and a close relationship to pathways believed to be important in its pathogenesis. Inhibition of PKC beta, a common signaling molecule in diabetes-related renal and vascular injury, holds promise as a novel strategy to improve microvascular and macrovascular outcomes in diabetes. Such therapies are needed to reduce the occurrence of devastating diabetic complications.
Tuttle
Katherine R
KR
Heart Institute of Spokane, Research Department, Spokane, WA 99204-2340, USA. ktuttle@this.org
Anderson
Pamela W
PW
D000818:Animals; D030801:Animals, Genetically Modified; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D003925:Diabetic Angiopathies / Q000188:drug therapy* / Q000201:enzymology; D003928:Diabetic Nephropathies / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology; D004353:Drug Evaluation, Preclinical; D004730:Endothelium, Vascular / Q000201:enzymology / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D007676:Kidney Failure, Chronic / Q000209:etiology / Q000517:prevention & control; D008297:Male; D008301:Maleimides / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008817:Mice, Mutant Strains; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D064546:Protein Kinase C beta; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000235:genetics; D054411:Receptors, Leptin; D012083:Renin / Q000235:genetics
D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; C099154:ruboxistaurin; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D012083:Renin