Next Article in Journal
Jun Dimerization Protein 2 Activates Mc2r Transcriptional Activity: Role of Phosphorylation and SUMOylation
Previous Article in Journal
Cisplatin, Oxaliplatin, and Kiteplatin Subcellular Effects Compared in a Plant Model
Open AccessArticle

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

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
*
Author to whom correspondence should be addressed.
Academic Editor: Kurt A. Jellinger
Int. J. Mol. Sci. 2017, 18(2), 305; https://doi.org/10.3390/ijms18020305
Received: 8 December 2016 / Accepted: 23 January 2017 / Published: 31 January 2017
(This article belongs to the Section Biochemistry)
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. View Full-Text
Keywords: ER stress; HO-1; losartan; SIRT1; thioredoxin ER stress; HO-1; losartan; SIRT1; thioredoxin
Show Figures

Graphical abstract

MDPI and ACS Style

Kim, H.; Baek, C.H.; Lee, R.B.; Chang, J.W.; Yang, W.S.; Lee, S.K. 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. Int. J. Mol. Sci. 2017, 18, 305.

Show more citation formats Show less citations formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Search more from Scilit
 
Search
Back to TopTop