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...
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MDPI AG
2017-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | http://www.mdpi.com/1422-0067/18/2/305 |
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| author | Hyosang Kim Chung Hee Baek Raymond Bok Lee Jai Won Chang Won Seok Yang Sang Koo Lee |
| author_facet | Hyosang Kim Chung Hee Baek Raymond Bok Lee Jai Won Chang Won Seok Yang Sang Koo Lee |
| author_sort | Hyosang Kim |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T04:33:36Z |
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| id | doaj.art-91ed9f2d08a54dc3b127c5a9db60eb77 |
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| issn | 1422-0067 |
| language | English |
| last_indexed | 2024-04-12T04:33:36Z |
| publishDate | 2017-01-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-91ed9f2d08a54dc3b127c5a9db60eb772022-12-22T03:47:52ZengMDPI AGInternational Journal of Molecular Sciences1422-00672017-01-0118230510.3390/ijms18020305ijms18020305Anti-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 ThioredoxinHyosang Kim0Chung Hee Baek1Raymond Bok Lee2Jai Won Chang3Won Seok Yang4Sang Koo Lee5Division 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, KoreaDivision 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, KoreaDivision 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, KoreaDivision 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, KoreaDivision 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, KoreaDivision 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, KoreaEndoplasmic 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.http://www.mdpi.com/1422-0067/18/2/305ER stressHO-1losartanSIRT1thioredoxin |
| spellingShingle | Hyosang Kim Chung Hee Baek Raymond Bok Lee Jai Won Chang Won Seok Yang Sang Koo Lee 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 International Journal of Molecular Sciences ER stress HO-1 losartan SIRT1 thioredoxin |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | ER stress HO-1 losartan SIRT1 thioredoxin |
| url | http://www.mdpi.com/1422-0067/18/2/305 |
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