The protein kinase C (PKC)-␤ isoform has been implicated to play a pivotal role in the development of diabetic kidney disease. We tested this hypothesis by inducing diabetic nephropathy in PKC-␤-deficient (PKC-␤ ؊/؊ ) mice. We studied nondiabetic and streptozotocin-induced diabetic PKC-␤ ؊/؊ mice compared with appropriate 129/SV wildtype mice. After 8 weeks of diabetes, the high-glucoseinduced renal and glomerular hypertrophy, as well as the increased expression of extracellular matrix proteins

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... such as collagen and fibronectin, was reduced in PKC-␤ ؊/؊ mice. Furthermore, the high-glucose-induced expression of the profibrotic cytokine transforming growth factor (TGF)-␤1 and connective tissue growth factor were significantly diminished in the diabetic PKC-␤ ؊/؊ mice compared with diabetic wild-type mice, suggesting a role of the PKC-␤ isoform in the regulation of renal hypertrophy. Notably, increased urinary albumin-to-creatinine ratio persisted in the diabetic PKC-␤ ؊/؊ mice. The loss of the basement membrane proteoglycan perlecan and the podocyte protein nephrin in the diabetic state was not prevented in the PKC-␤ ؊/؊ mice as previously demonstrated in the nonalbuminuric diabetic PKC-␣ ؊/؊ mice. In summary, the differential effects of PKC-␤ deficiency on diabetes-induced renal hypertrophy and albuminuria suggest that PKC-␤ contributes to high-glucose-induced TGF-␤1 expression and renal fibrosis, whereas perlecan, as well as nephrin, expression and albuminuria is regulated by other signaling pathways.