Selenium-deficient diet induces renal oxidative stress and injury via TGF-beta1 in normal and diabetic rats.
BACKGROUND
Oxidative stress has been implicated in the pathogenesis of diabetic nephropathy. Although glucose itself can initiate oxidative stress, deficiency of essential trace elements such as selenium (Se) may exacerbate this oxidative stress in diabetic rats. The mechanism by which Se deficiency causes oxidative stress and renal injury is not completely understood. This study tested the hypothesis that Se deficiency induces renal oxidative stress and renal injury via transforming growth factor-beta1 (TGF-beta1).


METHODS
Fifty-four male Wistar rats were used. Diabetes was induced in 27 rats by streptozotocin, and the other 27 rats received buffer only. Ten weeks after induction of diabetes, both normal and diabetic rats were killed, their kidneys removed, and glomeruli were isolated. Glomeruli from normal and diabetic rats were incubated in the presence of TGF-beta1 alone or its neutralizing antibody. Antioxidant enzyme (Cu-Zn) superoxide dismutase (Cu-Zn SOD), catalase, and glutathione peroxidase (GSH-Px) activities; total glutathione; and lipid peroxidation were determined. For Se studies, 15 normal and 15 diabetic rats were divided into groups of five each and fed either a regular, Se-deficient, or Se-supplemented diet one week after induction of diabetes. Ten weeks after feeding these diets, rats were killed and glomeruli were isolated. Oxidative stress was examined by determining the mRNA expressions for antioxidant enzymes and also for TGF-beta1. Plasma glucose and albuminuria were determined. Histology of the kidney and interlobular artery was evaluated by light microscopy.


RESULTS
In vitro studies showed that TGF-beta1 significantly reduced glomerular catalase and GSH-Px activities as well as total glutathione levels with an increase in lipid peroxidation in both normal and diabetic rats. Antibody to TGF-beta abrogated these changes. There was no effect of TGF-beta1 on Cu-Zn SOD. Like TGF-beta1, a Se-deficient diet caused a significant decrease in glomerular mRNA expression for Cu-Zn SOD, catalase, and GSH-Px, but a significant increase in TGF-beta1 mRNA expression. Also, a Se-deficient diet caused an increase in albuminuria, glomerular sclerosis, and plasma glucose levels in both normal and diabetic rats. The deficient diet caused a decrease in the lumen size of the interlobular artery. Se supplementation to diabetic rats up-regulated mRNA expression for antioxidant enzymes, and significantly reduced but did not normalize that of TGF-beta1. Glomerular sclerosis was normalized and the interlobular artery lumen size was greatly enlarged in diabetic rats by Se supplementation. Also, the tubulointerstitium was preserved by Se supplementation in diabetic rats.


CONCLUSIONS
The data show that TGF-beta1 is a pro-oxidant and Se deficiency increases oxidative stress via this growth factor. In addition, Se deficiency may simulate hyperglycemic conditions. Se supplementation to diabetic rats prevents not only oxidative stress but renal structural injury, as well.
Division of Nephrology and Hypertension, Department of Medicine, UMD-New Jersey Medical School, Newark, New Jersey 07103, USA. redddiaa@umdnj.edu
A S
AS
Reddi
J S
JS
Bollineni
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology*; D004032:Diet; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012016:Reference Values; D012077:Renal Artery / Q000473:pathology; D012643:Selenium / Q000172:deficiency* / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology*; D053773:Transforming Growth Factor beta1
D000975:Antioxidants; D012333:RNA, Messenger; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D012643:Selenium