Prevention of obesity‐linked renal disease: Effect of inhibition of the beta‐isoform of protein kinase C (PKC‐beta)

The obese Zucker rat fed develops the metabolic syndrome, glomerular and tubular injury, and early death. PKC-beta inhibition with ruboxistaurin (LY333531; Eli Lilly and Co., Indianapolis, IN) attenuates kidney injury in experimental diabetic nephropathy (J Am Soc Nephrol 16:, 2005). We examined the effects of LY333531 (provided by Eli Lilly) on the development of glomerular and tubular injury in the obese Zucker rat. Obese rats were divided into two groups, Control and those treated with 10 mg/100g BWt/day (in the diet) from age 6 to 38 weeks (PKC-beta Inhibitor group). Cortical transforming growth factor–beta-1 protein concentrations (TGF-beta-1) were determined by ELISA. Data are means ± SE. PKC-beta inhibition did not affect food intake, body weight, or blood pressure. However, chronic treatment reduced proteinuria, decreased tubular injury, decreased the incidence and severity of glomerular sclerosis, and decreased cortical [TGF-beta1]. Conclusion: Obesity-linked kidney disease is mediated, in part, through mechanisms involving the activation of renal PKC-β and chronic inhibition of this enzyme provides some degree of renal protection possibly mediated by inhibition of TGF-beta-1 production.