Anti-Fibrotic Effect of Losartan, an Angiotensin II Receptor Blocker, Is Mediated through Inhibition of ER Stress via Up-Regulation of SIRT1, Followed by Induction of HO-1 and Thioredoxin.
Endoplasmic reticulum (ER) stress is increasingly identified as modulator of fibrosis. Losartan, an angiotensin II receptor blocker, has been widely used as the first choice of treatment in chronic renal diseases. We postulated that anti-fibrotic effect of losartan is mediated through inhibition of ER stress via SIRT1 (silent mating type information regulation 2 homolog 1) hemeoxygenase-1 (HO-1)/thioredoxin pathway. Renal tubular cells, tunicamycin (TM)-induced ER stress, and unilateral ureteral obstruction (UUO) mouse model were used. Expression of ER stress was assessed by Western blot analysis and immunohistochemical stain. ER stress was induced by chemical ER stress inducer, tunicamycin, and non-chemical inducers such as TGF-β, angiotensin II, high glucose, and albumin. Losartan suppressed the TM-induced ER stress, as shown by inhibition of TM-induced expression of GRP78 (glucose related protein 78) and p-eIF2α (phosphospecific-eukaryotic translation initiation factor-2α), through up-regulation of SIRT1 via HO-1 and thioredoxin. Losartan also suppressed the ER stress by non-chemical inducers. In both animal models, losartan reduced the tubular expression of GRP78, which were abolished by pretreatment with sirtinol (SIRT1 inhibitor). Sirtinol also blocked the inhibitory effect of losartan on the UUO-induced renal fibrosis. These findings provide new insights into renoprotective effects of losartan and suggest that SIRT1, HO-1, and thioredoxin may be potential pharmacological targets in kidney diseases under excessive ER stress condition.
Division of Nephrology, Department of Internal Medicine, Asan Medical Center, Asan Institute for Life Sciences, University of Ulsan, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea. mateus@amc.seoul.kr.
Hyosang
H
Kim
Division of Nephrology, Department of Internal Medicine, Asan Medical Center, Asan Institute for Life Sciences, University of Ulsan, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea. bch393@naver.com.
Chung Hee
CH
Baek
Division of Nephrology, Department of Internal Medicine, Asan Medical Center, Asan Institute for Life Sciences, University of Ulsan, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea. leerb@umich.edu.
Raymond Bok
RB
Lee
Division of Nephrology, Department of Internal Medicine, Asan Medical Center, Asan Institute for Life Sciences, University of Ulsan, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea. jwchang@amc.seoul.kr.
Jai Won
JW
Chang
Division of Nephrology, Department of Internal Medicine, Asan Medical Center, Asan Institute for Life Sciences, University of Ulsan, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea. wsyang@amc.seoul.kr.
Won Seok
WS
Yang
Division of Nephrology, Department of Internal Medicine, Asan Medical Center, Asan Institute for Life Sciences, University of Ulsan, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea. sklee2@amc.seoul.kr.
Sang Koo
SK
Lee
D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001786:Blood Glucose; D004195:Disease Models, Animal; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019808:Losartan / Q000494:pharmacology*; D051379:Mice; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014415:Tunicamycin / Q000494:pharmacology
D047228:Angiotensin II Type 1 Receptor Blockers; D001786:Blood Glucose; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse; D016212:Transforming Growth Factor beta; D014415:Tunicamycin; D000804:Angiotensin II; D013879:Thioredoxins; D051547:Heme Oxygenase-1; D056564:Sirtuin 1; D019808:Losartan
ER stress; HO-1; SIRT1; losartan; thioredoxin