Angiotensin II induces renal oxidant stress in vivo and heme oxygenase-1 in vivo and in vitro.
BACKGROUND
Angiotensin II is strongly incriminated in progressive renal injury. There is recent evidence that angiotensin II induces oxidative stress in vitro. We examined the capacity of angiotensin II to induce oxidative stress in vivo and the functional significance of such stress. The capacity of angiotensin II to induce the oxidant-sensitive gene heme oxygenase (HO) in vivo and in vitro was also examined.


METHODS
Angiotensin II was administered via mini-osmotic pumps to rats maintained on standard diets. Indices of oxidative stress, including thiobarbituric acid reactive substance, carbonyl protein content, and HO activity, were determined. Indices of oxidative stress and functional markers were also determined in the DOCA salt model. The effect of angiotensin II was studied in rats maintained on antioxidant-deficient diets so as to examine the functional significance of oxidative stress induced by angiotensin II. We also explored the inductive effect of angiotensin II on HO in vivo and whether such actions occur in vitro.


RESULTS
Angiotensin II administered in vivo increased kidney content of thiobarbituric acid reactive substances protein carbonyl content, and HO activity. These indices were not present in the kidney of rats treated with DOCA salt for three weeks. Such oxidative stress was functionally significant, since the administration of angiotensin II to rats maintained on a prooxidant diet demonstrated increased proteinuria and decreased creatinine clearance. The stimulatory effect on HO activity was due to induction of HO-1 mRNA, with HO-2 mRNA remaining unchanged. Expression of HO-1 was localized to the renal proximal tubules in vivo. We also demonstrate that angiotensin II at concentrations of 10-8 and 10-7 mol/L induces expression of HO-1 mRNA in LLC-PK1 cells.


CONCLUSIONS
Angiotensin II induces oxidative stress in vivo, which contributes to renal injury. This study also demonstrates that angiotensin II induces renal HO activity caused by up-regulation of HO-1 in renal proximal tubules. Finally, angiotensin II directly induces HO-1 in renal proximal tubular epithelial cells in vitro.
Haugen
E N
EN
Nephrology Research Unit and Department of Medicine, Mayo Clinic/Foundation, Rochester, MN 55905, USA.
Croatt
A J
AJ
Nath
K A
KA
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D015152:Blotting, Northern; D003900:Desoxycorticosterone; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism*; D051547:Heme Oxygenase-1; D006977:Hypertension, Renal / Q000378:metabolism; D066298:In Vitro Techniques; D007676:Kidney Failure, Chronic / Q000378:metabolism; D007684:Kidney Tubules / Q000098:blood supply / Q000166:cytology / Q000378:metabolism*; D018374:LLC-PK1 Cells / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009392:Nephrectomy; D018384:Oxidative Stress / Q000187:drug effects*; D011507:Proteinuria / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000502:physiology; D013552:Swine; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D000975:Antioxidants; D012333:RNA, Messenger; D017392:Thiobarbituric Acid Reactive Substances; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D003900:Desoxycorticosterone; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C105245:heme oxygenase-2