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.

Hyosang Kim,Jai Chang,Raymond Lee,Chung Baek,Sang Lee,Won Yang

doi:10.3390/ijms18020305

Abstract

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.

Highlights

Renal fibrosis, tubulointerstitial fibrosis, is considered to be a central event in the progression of chronic kidney diseases, regardless of the original cause of the kidney disease
We examined the effects of losartan, a classic drug of angiotensin II receptor blockers (ARBs), on the endoplasmic reticulum (ER) stress induced by both chemical inducers, such as tunicamycin, and non-chemical inducers, such as tumor growth factor-β (TGF-β), angiotensin II, high glucose, and albumin in tubular HK-2 cells
We examined whether the inhibitory effect of losartan on ER stress was mediated through up-regulation of SIRT1 via induction of Heme oxygenase-1 (HO-1) and thioredoxin

Summary

Introduction

Tubulointerstitial fibrosis, is considered to be a central event in the progression of chronic kidney diseases, regardless of the original cause of the kidney disease. The endoplasmic reticulum (ER) stress refers to physiological or pathological states that result in accumulation of misfolded proteins in the ER, which leads to cell stress conditions (ER stress). UPR reestablishes the homeostasis of ER through the activation of three major sensors known as PERK (PKR-like ER kinase), IRE-1 (inositol requiring enzyme-1), and ATF-6 (activating transcription factor 6). Under ER stress conditions, GRP78 dissociates from the ER stress sensors and binds to misfolded proteins, which leads to activation of these sensors and initiation of the UPR. ER stress and UPR are known to contribute to other ER stress-independent cellular responses [3].sustained ER stress has been implicated in the development and progression of many chronic diseases [4]

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