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2016 ; 17
(3
): ä Nephropedia Template TP
gab.com Text
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Twit Text #
English Wikipedia
Overexpression of angiotensinogen downregulates aquaporin 1 expression via
modulation of Nrf2-HO-1 pathway in renal proximal tubular cells of transgenic
mice
#MMPMID27638854
Chang SY
; Lo CS
; Zhao XP
; Liao MC
; Chenier I
; Bouley R
; Ingelfinger JR
; Chan JS
; Zhang SL
J Renin Angiotensin Aldosterone Syst
2016[Jul]; 17
(3
): ä PMID27638854
show ga
INTRODUCTION: We aimed to examine the regulation of aquaporin 1 expression in an
angiotensinogen transgenic mouse model, focusing on underlying mechanisms.
METHODS: Male transgenic mice overexpressing rat angiotensinogen in their renal
proximal tubular cells (RPTCs) and rat immortalised RPTCs stably transfected with
rat angiotensinogen cDNA were used. RESULTS: Angiotensinogen-transgenic mice
developed hypertension and nephropathy, changes that were either partially or
completely attenuated by treatment with losartan or dual renin-angiotensin system
blockade (losartan and perindopril), respectively, while hydralazine prevented
hypertension but not nephropathy. Decreased expression of aquaporin 1 and heme
oxygenase-1 and increased expression of nuclear factor erythroid 2-related factor
2 (Nrf2) and sodium-hydrogen exchanger 3 were observed in RPTCs of
angiotensinogen-transgenic mice and in angiotensinogen-transfected immortalised
RPTCs. These parameters were normalised by dual renin-angiotensin system
blockade. Both in vivo and in vitro studies identified a novel mechanism in which
angiotensinogen overexpression in RPTCs enhances the cytosolic accumulation of
Nrf2 via the phosphorylation of pGSK3? Y216. Consequently, lower intranuclear
Nrf2 levels are less efficient to trigger heme oxygenase-1 expression as a
defence mechanism, which subsequently diminishes aquaporin 1 expression in RPTCs.
CONCLUSIONS: Angiotensinogen-mediated downregulation of aquaporin 1 and Nrf2
signalling may play an important role in intrarenal renin-angiotensin
system-induced hypertension and kidney injury.