Targeting the protein kinase C family in the diabetic kidney: lessons from analysis of mutant mice.
The protein kinase C (PKC) superfamily comprises proteins that are activated in response to various pathogenic stimuli in the diabetic state. Hyperglycaemia is the predominant stimulus that induces the activation of distinct PKC isoforms within a cell, each mediating specific functions, probably through differential subcellular localisation. The contribution of individual PKC isoforms can be directly addressed in vivo using innovative PKC-isoform-specific knockout (KO) mouse models, which are providing key insights into the physiological function of PKC isoform diversity in the development of diabetic nephropathy. Such studies can be a valuable complementary approach to more commonly used pharmacological analyses using agents such as ruboxistaurin mesylate (Arxxant, LY333531), which is claimed to specifically inhibit the PKC-beta-isoform. As expected given the multiple and specific properties of the isoforms in vitro, deletion of different PKC isoform signalling pathways leads to distinct phenotypes in mice. Notably, KOs of the individual PKCs assigned specific non-redundant biological functions to each isoform, which were not compensated for by the others. Thus, PKC isoform specificity and cellular diversity seem to be responsible for the divergent outcomes leading to albuminuria and/or renal fibrosis according to studies on the streptozotocin-induced mouse model of diabetes. This review discusses the role of individual PKC isoforms in diabetic nephropathy and their potential therapeutic implications. Defining and targeting mediators of increased intracellular activation in the diabetic microvasculature will have important clinical and therapeutic benefits and help in the design of novel effective therapies in the near future.
Meier
M
M
Department of Nephrology, Hannover Medical School, Hannover, Germany. KfNH_Hannover@web.de
Menne
J
J
Haller
H
H
D000818:Animals; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000201:enzymology*; D003929:Diabetic Neuropathies / Q000503:physiopathology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006801:Humans; D006943:Hyperglycemia / Q000201:enzymology; D007211:Indoles / Q000627:therapeutic use; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000201:enzymology; D008301:Maleimides / Q000627:therapeutic use; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D023421:Models, Animal; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D064546:Protein Kinase C beta; D012307:Risk Factors
D004791:Enzyme Inhibitors; D007211:Indoles; D007527:Isoenzymes; D008301:Maleimides; C099154:ruboxistaurin; D011493:Protein Kinase C; D064546:Protein Kinase C beta