Dual inhibition of classical protein kinase C-α and protein kinase C-β isoforms protects against experimental murine diabetic nephropathy.

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 alpha and beta mediate different cellular effects. PKC-beta contributes to hyperglycemia-induced renal matrix production, whereby PKC-alpha 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-alpha/beta double-knockout mice (PKC-alpha/beta(-/-)). After 8 weeks of diabetes mellitus, the high-glucose-induced renal and glomerular hypertrophy as well as transforming growth factor-beta 1) and extracellular matrix production were diminished in the PKC-alpha/beta(-/-) mice compared with wild-type controls. Urinary albumin/creatinine ratio also was significantly reduced, however, it was not completely abolished in diabetic PKC-alpha/beta(-/-) mice. Treatment with CGP41252, which inhibits PKC-alpha and PKC-beta, 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-alpha and PKC-beta 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. Diabetes 62:1167-1174, 2013