title: Studies of renal injury III: lipid-induced nephropathy in type II diabetes.
abstract: Studies of renal injury III: Lipid-induced nephropathy in type II diabetes.
  
  
  BACKGROUND
  Nephrotoxicity from elevated circulating lipids occurs in experimental and clinical situations. We tested the hypothesis that lipid-induced nephropathy causes advanced renal failure in rats with type II diabetes and dyslipidemia.
  
  
  METHODS
  First generation (F1) hybrid rats derived from the spontaneous hypertensive 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, and 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 highest 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 biomarker 4-hydroxynonenal in glomeruli and renal microvessels. Moreover, in group 3, increased arterial wall thickness also connoted vascular injury. In contrast, the glycoxidation stress biomarkers pentosidine and carboxymethyl-lysine were preferentially localized to renal tubules of hyperglycemic rats in groups 1 and 2 and did not segregate with the most severe renal injury. Glomerular and interstitial fibrosis was accompanied by proportional increases in renal transforming growth factor-beta1 levels, which were threefold higher in the hypercholesterolemic rats of group 3 than in the hyperglycemic rats of group 1.
  
  
  CONCLUSIONS
  Acquisition of non-nodular glomerular sclerosis and tubulointerstitial disease is dependent on lipoxidation stress in rats with type II diabetes. On the other hand, in the absence of hypercholesterolemia, prolonged glycoxidation stress does not appear to be uniquely nephrotoxic.
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA. jhdoming@iupui.edu
authors.forename: J H
authors.initials: JH
authors.lastname: Dominguez
authors.forename: N
authors.initials: N
authors.lastname: Tang
authors.forename: W
authors.initials: W
authors.lastname: Xu
authors.forename: A P
authors.initials: AP
authors.lastname: Evan
authors.forename: A N
authors.initials: AN
authors.lastname: Siakotos
authors.forename: R
authors.initials: R
authors.lastname: Agarwal
authors.forename: J
authors.initials: J
authors.lastname: Walsh
authors.forename: M
authors.initials: M
authors.lastname: Deeg
authors.forename: J H
authors.initials: JH
authors.lastname: Pratt
authors.forename: K L
authors.initials: KL
authors.lastname: March
authors.forename: V M
authors.initials: VM
authors.lastname: Monnier
authors.forename: M F
authors.initials: MF
authors.lastname: Weiss
authors.forename: J W
authors.initials: JW
authors.lastname: Baynes
authors.forename: R
authors.initials: R
authors.lastname: Peterson
mesh_terms: D000818:Animals; D008078:Cholesterol, LDL / Q000097:blood; D003928:Diabetic Nephropathies / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006937:Hypercholesterolemia / Q000150:complications*; D007150:Immunohistochemistry; D007677:Kidney Function Tests; D007678:Kidney Glomerulus / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D015227:Lipid Peroxidation; D008297:Male; D009765:Obesity / Q000150:complications / Q000378:metabolism; D051381:Rats; D012083:Renin / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D008078:Cholesterol, LDL; D017127:Glycation End Products, Advanced; D016212:Transforming Growth Factor beta; D012083:Renin