Overexpression of angiotensinogen downregulates aquaporin 1 expression via modulation of Nrf2–HO-1 pathway in renal proximal tubular cells of transgenic mice

Abstract

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 pGSK3β 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.

Effect of fish oil and telmisartan on dehydroepiandrosterone‐induced polycystic ovarian syndrome in rats: The role of oxidative stress, transforming growth factor beta‐1, and nuclear factor kappa B

“…Chang et al. (2016) found that drugs affecting the renin–angiotensin system may modulate Nrf2/HO‐1 pathway which may have a serious effect on the oxidant/antioxidant balance in the cells. Also, Qi et al.…”

Effect of high-salt diet on mean arterial pressure, renal epithelial sodium channels and aquaporin subunits expression levels in Spontaneously Hypertensive Rats

“…Aquaporin1 is the major water channel in renal proximal tubule and loop of Henle that is responsible for reabsorbing 80% of glomerular filtrate [75, 76]. It has been reported that renal and cardiac AQP1 expressions were downregulated in conditions such as renal fibrosis in mice [77] and HS-induced HPN [78].…”

“…Hence, the downregulation of AQP1 in both SHRs and WKY rats could be interpreted as a compensatory mechanism to prevent larger water reabsorption in the proximal tubule and the consequent expansion of extracellular fluid volume [27]. It has been claimed that in SHRs, the AQP1 expression in kidney [32, 75] and brain [75, 80] to be upregulated. However, the HS diet in the present study showed downregulation of both mRNA and protein levels of AQP1 (Fig 5A and 7A).…”

Aquaporin 11-Dependent Inhibition of Proliferation by Deuterium Oxide in Activated Hepatic Stellate Cells

“…Our previous studies have documented that BDMC induces apoptosis by regulating HO-1 protein expression in activated HSCs [19]. In the present study, we tested whether cotreatment with BDMC and D 2 O can modulate the AQP11-dependent inhibition of cell proliferation effectively [28]. Our data revealed that BDMC coadministered with D 2 O markedly decreased cell proliferation by downregulating some cellular proteins including HO-1 and AQP11 and by inducing p53 (Figure 3).…”