Abstract
Animal studies demonstrate that hyperlipidemia and renal lipid accumulation contribute to the pathogenesis of diabetic nephropathy (DN). We previously demonstrated that renal lipoproteins colocalize with biglycan, a renal proteoglycan. The purpose of this study was to determine whether prevention of renal lipid (apoB) accumulation attenuates DN. Biglycan-deficient and biglycan wild-type Ldlr−/− mice were made diabetic via streptozotocin and fed a high cholesterol diet. As biglycan deficiency is associated with elevated transforming growth factor-β (TGF-β), in some experiments mice were injected with either the TGF-β-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 DN with ∼30% reduction in albuminuria; however, biglycan deficiency caused a striking elevation in TGF-β. Use of 1D11 led to sustained suppression of TGF-β for approximately 8 weeks at a time. The 1D11 treatment caused decreased renal apoB accumulation, decreased albuminuria, decreased renal hypertrophy, and improved survival, compared with the 13C4 treatment. Thus, prevention of renal apoB accumulation is protective against development of DN. Furthermore, this study demonstrates that prevention of renal apoB accumulation is a mechanism by which TGF-β inhibition is nephroprotective.
Highlights
Animal studies demonstrate that hyperlipidemia and renal lipid accumulation contribute to the pathogenesis of diabetic nephropathy (DN)
Biglycan deficiency had no impact on susceptibility to STZinduced diabetes and all mice that received STZ had elevated glucose levels compared with control mice (P < 0.001 for diabetic vs. nondiabetic mice for both genders; Fig. 1A, B)
There were no significant differences between groups in male mice, but female diabetic mice of both genotypes had decreased survival compared with female nondiabetic mice (P = 0.012); there was no significant effect of biglycan genotype on survival (Table 1)
Summary
Animal studies demonstrate that hyperlipidemia and renal lipid accumulation contribute to the pathogenesis of diabetic nephropathy (DN). Biglycan deficiency had no significant effect on renal apoB accumulation, but led to modest attenuation of DN with 30% reduction in albuminuria; biglycan deficiency caused a striking elevation in TGF-. This study demonstrates that prevention of renal apoB accumulation is a mechanism by which TGF- inhibition is nephroprotective.— Wilson, P. Prevention of renal apoB retention is protective against diabetic nephropathy: role of TGF- inhibition. Renal deposition of apoB and apoE accelerates the progression of glomerulosclerosis in many renal diseases [3] While it is unknown how lipid accumulates in the mesangium, we previously demonstrated that renal proteoglycans have a binding affinity for LDL in the physiological range [4].
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