Heme-oxygenase upregulation ameliorates angiotensin II-induced tubulointerstitial injury and salt-sensitive hypertension.
BACKGROUND
Heme oxygenase-1 (HO-1) has been implicated in the modulation of several diseases including hypertension (HTN) and renal injury. The tubulointerstitial (TI) injuries are supposed to be the main determinants for the development of salt-sensitive HTN. Therefore, this study examined the role of HO-1 in angiotensin II (AngII)-induced TI injury and salt-sensitive HTN.


METHODS
Sprague-Dawley rats on a high salt diet were treated by AngII infusion plus either hemin, an inducer of HO-1, or hemin + zinc protoporphyrin, a HO-1 inhibitor, for 2 weeks, and then followed for 6 weeks.


RESULTS
The AngII infusion resulted in acute HTN and proteinuria. Light microscopy revealed focal areas of tubular atrophy with mononuclear cell infiltration and interstitial expansion. The overexpression of osteopontin and TGF-beta(1) accompanied by diminished expression of rat endothelial cell antigen-1, the hallmarks of TI injury, were observed. At 2 weeks, all interventions were withdrawn and systolic blood pressure returned towards normal. After a brief normal salt diet, rats were again placed on high salt diet, resulting in progressive increase in systolic blood pressure in the HO-1-inhibited group.


CONCLUSIONS
The induction of HO-1 attenuated the development of HTN, suggesting that HO-1 plays a crucial role in significant attenuation of AngII-mediated TI injury and resultant salt-sensitive HTN.
Pradhan
Ashok
A
Division of Nephrology and Dialysis Center, Kobe University School of Medicine, Kobe, Japan.
Umezu
Michio
M
Fukagawa
Masafumi
M
D000804:Angiotensin II / Q000633:toxicity; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000187:drug effects / Q000378:metabolism*; D006427:Hemin / Q000494:pharmacology; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009395:Nephritis, Interstitial / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017673:Sodium Chloride, Dietary / Q000633:toxicity; D015854:Up-Regulation
D016207:Cytokines; D017673:Sodium Chloride, Dietary; D000804:Angiotensin II; D006427:Hemin; D051547:Heme Oxygenase-1