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This Article Full Text Full Text (PDF) All Versions of this Article: 296/3/F521    most recent 00510.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Jadhav, A. Articles by Ndisang, J. F. Search for Related Content PubMed PubMed Citation Articles by Jadhav, A. Articles by Ndisang, J. F.

Hemin therapy attenuates kidney injury in deoxycorticosterone acetate-salt hypertensive rats

Departments of ²Physiology and ¹Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada

Submitted 30 October 2007 ; accepted in final form 26 December 2008

Upregulating the heme oxygenase (HO) system removes the prooxidant heme, and thus is cytoprotective. Additionally, the products from the HO pathway including, carbon monoxide, bilirubin, and biliverdin, scavenge reactive oxygen species, inhibit lipid peroxidation, and suppress tissue inflammation, while the iron formed enhances the synthesis of the antioxidant ferritin. Deoxycorticosterone acetate (DOCA)-salt hypertension, a model of human primary aldosteronism, causes oxidative stress and impairs renal function by stimulating inflammatory/oxidative transcription factors such as NF-B and activating protein (AP-1). The effect of the HO system in end-organ damage in mineralocorticoid-induced hypertension has not been fully characterized. In this study, the administration of the HO inducer hemin lowered blood pressure (191 vs. 135 mmHg; n = 22, P < 0.01), increased creatinine clearance, and reduced kidney hypertrophy proteinuria, albuminuria, and histopathological lesions, including glomerular hypertrophy, glomerulosclerosis, tubular dilation, tubular cast formation, and interstitial mononuclear cell infiltration in nephrectomy/DOCA-high-salt-hypertension. The renoprotection was accompanied by reduced levels of NF-B, AP-1, fibronectin, transforming growth factor (TGF)-β, and 8-isoprostane, a marker of oxidative stress. Correspondingly, a robust increase in total antioxidant capacity, HO activity, cGMP, and an antioxidant like ferritin was observed in hemin-treated animals. Our findings suggest that suppression of oxidative/inflammatory insults alongside the corresponding decline of fibronectin and TGF-β, an activator of extracellular matrix proteins, may account for the attenuation of renal histopathological lesions and the antihypertrophic effects of hemin. The multifaceted interaction among the HO system, TGF-β, fibronectin, AP-1, and NF-B may be explored to design new drugs against end-stage-organ damage.

heme oxygenase; DOCA-salt hypertension; hypertrophy; kidney; fibronectin; glomerulosclerosis; NF-B; inflammation; AP-1