Studies of renal injury III: Lipid-induced nephropathy in type II diabetes

Background. Nephrotoxicity from elevated circulating lipids occurs in exper imental and clinical situations. We tested the hypothesis that lipid-induce d nephropathy causes advanced renal failure in rats with type II diabetes a nd dyslipidemia. Methods. First generation (F1) hybrid rats derived from the spontaneous hyp ertensive heart failure rat (SHHF/Gmi-fa) and the LA/NIH-corpulent rat (LA/ N-fa) were studied for 41 weeks while being on specific diets. Group 1 (14 rats) ingested 11.5% protein, 47.9% fat, and 40.6% carbohydrate. Group 2 (8 rats) ingested 26.9% protein, 16.7% animal fat, and 56.4% carbohydrate, an d group 3 (20 rats) ingested 20.2% protein, 40.4% soy and coconut oil, and 39.4% carbohydrate. Results. Hyperglycemia was more severe in rat groups 1 and 2 than in group 3. In contrast, circulating cholesterol and hydroperoxide levels were highe st in group 3, intermediate in group 2, and lowest in group 1. Group 3 had severe renal failure secondary to glomerulosclerosis and tubulointerstitial disease, with striking deposition of the lipid peroxidation stress biomark er 4-hydroxynonenal in glomeruli and renal microvessels. Moreover, in group 3, increased arterial wall thickness also connoted vascular injury. In con trast, the glycoxidation stress biomarkers pentosidine and carboxymethyl-ly sine were preferentially localized to renal tubules of hyperglycemic rats i n groups 1 and 2 and did not segregate with the most severe renal injury. G lomerular and interstitial fibrosis was accompanied by proportional increas es in renal transforming growth factor-beta 1 levels, which were threefold higher in the hypercholesterolemic rats of group 3 than in the hyperglycemi c rats of group 1. Conclusions. Acquisition of non-nodular glomerular sclerosis and tubulointe rstitial disease is dependent on lipoxidation stress in rats with type II d iabetes. On the other hand, in the absence of hypercholesterolemia, prolong ed glycoxidation stress does not appear to be uniquely nephrotoxic.