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2017 ; 18
(2
): ä Nephropedia Template TP
gab.com Text
Twit Text FOAVip
Twit Text #
English Wikipedia
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
#MMPMID28146117
Kim H
; Baek CH
; Lee RB
; Chang JW
; Yang WS
; Lee SK
Int J Mol Sci
2017[Jan]; 18
(2
): ä PMID28146117
show ga
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-?, 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-eIF2? (phosphospecific-eukaryotic translation initiation factor-2?), 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.
|Angiotensin II Type 1 Receptor Blockers/*pharmacology
[MESH]