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

Jesus Dominguez, Nianjun Tang, Wei Xu, Andrew Evan, Aristotle N. Siakotos, Rajiv Agarwal, James Walsh, Mark Deeg, J. Howard Pratt, Keith L. March, Vincent M. Monnier, Miriam F. Weiss, John W. Baynes, Richard Peterson

Research output: Contribution to journalArticle

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Abstract

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-β1 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.

Original languageEnglish
Pages (from-to)92-104
Number of pages13
JournalKidney International
Volume57
Issue number1
DOIs
StatePublished - 2000

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Type 2 Diabetes Mellitus
Kidney
Wounds and Injuries
Carbohydrates
Renal Insufficiency
Lipid III
Biomarkers
Fats
Lipids
Soybean Proteins
Vascular System Injuries
Transforming Growth Factors
Sclerosis
Dyslipidemias
Microvessels
Hypercholesterolemia
Hyperglycemia
Lipid Peroxidation
Proteins
Fibrosis

Keywords

  • Diabetic nephropathy
  • Glomerulosclerosis
  • Hyperglycemia
  • Nephrotoxicity
  • Oxidant-mediated injury

ASJC Scopus subject areas

  • Nephrology

Cite this

Studies of renal injury III : Lipid-induced nephropathy in type II diabetes. / Dominguez, Jesus; Tang, Nianjun; Xu, Wei; Evan, Andrew; Siakotos, Aristotle N.; Agarwal, Rajiv; Walsh, James; Deeg, Mark; Pratt, J. Howard; March, Keith L.; Monnier, Vincent M.; Weiss, Miriam F.; Baynes, John W.; Peterson, Richard.

In: Kidney International, Vol. 57, No. 1, 2000, p. 92-104.

Research output: Contribution to journalArticle

Dominguez, J, Tang, N, Xu, W, Evan, A, Siakotos, AN, Agarwal, R, Walsh, J, Deeg, M, Pratt, JH, March, KL, Monnier, VM, Weiss, MF, Baynes, JW & Peterson, R 2000, 'Studies of renal injury III: Lipid-induced nephropathy in type II diabetes', Kidney International, vol. 57, no. 1, pp. 92-104. https://doi.org/10.1046/j.1523-1755.2000.00814.x
Dominguez, Jesus ; Tang, Nianjun ; Xu, Wei ; Evan, Andrew ; Siakotos, Aristotle N. ; Agarwal, Rajiv ; Walsh, James ; Deeg, Mark ; Pratt, J. Howard ; March, Keith L. ; Monnier, Vincent M. ; Weiss, Miriam F. ; Baynes, John W. ; Peterson, Richard. / Studies of renal injury III : Lipid-induced nephropathy in type II diabetes. In: Kidney International. 2000 ; Vol. 57, No. 1. pp. 92-104.
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AU - Siakotos, Aristotle N.

AU - Agarwal, Rajiv

AU - Walsh, James

AU - Deeg, Mark

AU - Pratt, J. Howard

AU - March, Keith L.

AU - Monnier, Vincent M.

AU - Weiss, Miriam F.

AU - Baynes, John W.

AU - Peterson, Richard

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N2 - 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-β1 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.

AB - 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-β1 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.

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KW - Oxidant-mediated injury

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