Prevention of renal apoB retention is protective against diabetic nephropathy: role of TGF-β inhibition.

Animal studies demonstrate that hyperlipidemia and renal lipid accumulation contribute to the pathogenesis of diabetic nephropathy. We previously demonstrated that renal lipoproteins co-localize with biglycan, a renal proteoglycan. The purpose of this study was to determine if prevention of renal lipid (apoB) accumulation attenuates diabetic nephropathy. Biglycan deficient and biglycan wildtype Ldlr-/- mice were made diabetic via streptozotocin and fed a high cholesterol diet. As biglycan deficiency is associated with elevated TGF-b, in some experiments mice were injected with either the TGF-b neutralizing antibody 1D11 or with 13C4, an irrelevant control antibody. Biglycan deficiency had no significant effect on renal apoB accumulation but led to modest attenuation of diabetic nephropathy with ≈30% reduction in albuminuria; however, biglycan deficiency caused a striking elevation in TGF-b. Use of 1D11 led to sustained suppression of TGF-b for approximately 8 weeks at a time. 1D11 treatment caused decreased renal apoB accumulation, decreased albuminuria, decreased renal hypertrophy and improved survival, compared to 13C4 treatment. Thus, prevention of renal apoB accumulation is protective against development of diabetic nephropathy. Furthermore, this study demonstrates that prevention of renal apoB accumulation is a mechanism by which TGF-b inhibition is nephroprotective.