Deletion of protein kinase C beta does not protect against the development of albuminuria in streptozotocin-induced experimental murine diabetic nephropathy

PKC activation is a key factor in the development of diabetic microangiopathy. Deletion of the classical PKC-isoform-alpha e.g. protects against the development of albuminuria due to a diminished loss of proteoglycans whereas increased TGF-beta1 and renal hypertrophy is not prevented. We now tested the hypothesis that deletion of PKC-beta-expression, another classical PKC isoform which has been involved in diabetic microvascular complications, will lead to protection against the development of murine experimental diabetic nephropathy. We studied PKC-beta knock-out (KO) mice (n=4/5) compared to SV129 wild type (WT) mice (n=9/9) in nondiabetic and diabetic condition. Hyperglycaemia was induced in 8 week old mice by intraperitoneal streptozotocin (STZ) injection (50mg/kg/body weight on day 1 to 5). Diabetic mice (blood glucose >15 mmol/l) remained hyperglycaemic for 8 weeks before animals were sacrificed. Light microscopy showed glomerular and tubulointerstitial fibrosis in both diabetic groups with less prominent pathological changes in the diabetic PKC-beta-KO mice. Urinary albumin/creatinine ratio was significantly increased in the diabetic WT compared to control and non-diabetic PKC-beta-KO animals (36.3±15.1 vs. 11.3±2.4 respectively 11.5±3.2g/mol, p<0.05). Notably, diabetic PKC-beta-KO mice were not protected against the development of diabetic albuminuria (31.7±12.5g/mol, p>0.05). Immunhistochemistry demonstrated that the expression of the basal membrane proteoglycan perlecan was not prevailed in the PKC-beta KO mice under diabetic conditions which we had previously demonstrated in nonalbuminuric diabetic PKC-alpha KO mice. We than further investigated the expression of the profibrotic cytokine TGF-beta1 which was significantly stimulated in the diabetic KO animals indicating a role for PKC-beta in renal fibrosis but not albuminuria in diabetic kidney disease. Our data suggest that both classical PKC-isoforms, alpha and beta, are involved in the development of diabetic nephropathy but mediate distinct physiological effects.