Abstract
IntroductionAngiotensin II (Ang II) contributes to the pathological process of vascular structures, including renal glomeruli by hemodynamic and nonhemodynamic direct effects. On renal effects, Ang II plays an important role in the development of proteinuria and glomerulosclerosis by the modification of podocyte molecules and cell survival. In the present study, we investigated the effect of Ang II on endoplasmic reticulum (ER) stress in podocytes.MethodsWe cultured mouse podocytes with increasing doses of Ang II and evaluated ER stress markers by Western blotting.ResultsAng II increased Bip protein, an ER chaperone, in a dose-dependent manner at 24 h, which was ameliorated by losartan, an angiotensin II type 1 receptor antagonist. Ang II also increased ER stress markers, such as phospho-PERK, phospho-eIF2α, and ATF4 proteins of podocyte, significantly in a dose-dependent manner at 24 h. Increased phospho-PERK and ATF4 proteins were further augmented by phosphoinositide 3 (PI3)-kinase inhibitor, LY294002, which suggested that Ang II could induce podocyte ER stress of PERK-eIF2α-ATF4 axis via PI3-kinase pathway.DiscussionThese studies suggest that Ang II could induce podocyte ER stress of PERK-eIF2α-ATF4 axis via PI3-kinase pathway, which would contribute to the development of podocyte injury induced by Ang II, and the augmentation of PI3-kinase would be a therapeutic target.
Highlights
Angiotensin II (Ang II) contributes to the pathological process of vascular structures, including renal glomeruli by hemodynamic and nonhemodynamic direct effects
The primary antibodies for Western blotting were purchased as follows: anti-phospho-PERK and anti-β-tubulin antibodies from Santa Cruz Biotechnology (CA, USA) and anti-Bip, anti-ATF4, antiphospho-eukaryotic translation initiation factor 2α (eIF2α), and anti-eIF2α antibodies from Cell Signaling (Beverly, MA, USA)
In experimental diabetic nephropathy and nephrotic syndrome (NS) models, activation of rapamycin-sensitive protein kinase complex TORC1, which contributes to multiple cellular processes associated with proteostasis, triggers unfolded protein response (UPR) activation in podocytes, leading to podocyte injury [30,31]. These findings demonstrate that are mutations in podocyte protein folding associated with ER stress (ERS) but acquired renal diseases that induce podocyte injury are as well
Summary
Angiotensin II (Ang II) contributes to the pathological process of vascular structures, including renal glomeruli by hemodynamic and nonhemodynamic direct effects. In addition to its hypertensinogenic effect, locally produced Ang II in the kidney activates multiple signaling pathways and mediates inflammation, renal cell growth, mitogenesis, apoptosis, extracellular matrix accumulation, proteinuria, and glomerulosclerosis via the angiotensin II type 1 receptor (AT1R) [3,4,5,6]. These effects of Ang II play an important role in the pathogenesis of renal tissue injury. The ER is a highly dynamic organelle responsible for multiple
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