title: Dual inhibition of classical protein kinase C-α and protein kinase C-β isoforms protects against experimental murine diabetic nephropathy.
abstract: Activation of protein kinase C (PKC) has been implicated in the pathogenesis of diabetic nephropathy with proteinuria and peritubular extracellular matrix production. We have previously shown that the PKC isoforms α and β mediate different cellular effects. PKC-β contributes to hyperglycemia-induced renal matrix production, whereby PKC-α is involved in the development of albuminuria. We further tested this hypothesis by deletion of both isoforms and used a PKC inhibitor. We analyzed the phenotype of nondiabetic and streptozotocin (STZ)-induced diabetic homozygous PKC-α/β double-knockout mice (PKC-α/β(-/-)). After 8 weeks of diabetes mellitus, the high-glucose-induced renal and glomerular hypertrophy as well as transforming growth factor-β1) and extracellular matrix production were diminished in the PKC-α/β(-/-) mice compared with wild-type controls. Urinary albumin/creatinine ratio also was significantly reduced, however, it was not completely abolished in diabetic PKC-α/β(-/-) mice. Treatment with CGP41252, which inhibits PKC-α and PKC-β, is able to prevent the development of albuminuria and to reduce existing albuminuria in type 1 (STZ model) or type 2 (db/db model) diabetic mice. These results support our hypothesis that PKC-α and PKC-β contribute to the pathogenesis of diabetic nephropathy, and that dual inhibition of the classical PKC isoforms is a suitable therapeutic strategy in the prevention and treatment of diabetic nephropathy.
authors: Clinic for Nephrology and Hypertension, Hannover Medical School, Hannover, Germany. menne.jan@mh-hannover.de
authors: Jan
authors: J
authors: Menne
authors: Nelli
authors: N
authors: Shushakova
authors: Janina
authors: J
authors: Bartels
authors: Yulia
authors: Y
authors: Kiyan
authors: Robert
authors: R
authors: Laudeley
authors: Hermann
authors: H
authors: Haller
authors: Joon-Keun
authors: JK
authors: Park
authors: Matthias
authors: M
authors: Meier
mesh_terms: D000818:Animals; D001786:Blood Glucose; D001835:Body Weight; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000201:enzymology; D003928:Diabetic Nephropathies / Q000201:enzymology* / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007668:Kidney / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors*; D019311:Staurosporine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; D019311:Staurosporine; C059539:midostaurin