Reciprocal regulation between ER stress and autophagy in renal tubular fibrosis and apoptosis

Shu, Shaoqun; Wang, Hui; Zhu, Jiefu; Liu, Zhiwen; Yang, Darong; Wu, Wenwen; Cai, Juan; Chen, Anqun; Tang, Chengyuan; Dong, Zheng

doi:10.1038/s41419-021-04274-7

Cited by 28 publications

(26 citation statements)

References 45 publications

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“…Knockdown of PERK can reduce ERS-mediated autophagy activity and regulation of myocardial fibrosis in H9c2 cardiomyoblasts [44]. A recent study suggested the PERK-eIF2α pathway has a critical role in autophagy activation and fibrotic changes during ER stress in renal tubular cells [45]. In our previous study, we confirmed that inhibiting the expression of ATF4 can promote autophagy in NRK-52E cells, thereby reducing tubular interstitial fibrosis in DN [17].…”

Section: Discussionsupporting

confidence: 77%

Deciphering the Pharmacological Mechanisms of Qidan Dihuang Decoction in Ameliorating Renal Fibrosis in Diabetic Nephropathy through Experimental Validation In Vitro and In Vivo

Liang

Bai

Xie

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Objective. QiDan DiHuang decoction (QDD) has been proven to have good efficacy in decreasing albuminuria levels, improving renal function, and inhibiting renal fibrosis in diabetic nephropathy (DN). However, the potential mechanism remains unclear. The purpose of this study was to explore the underlying mechanism of QDD for treating DN in vitro and in vivo. Methods. Db/db mice were treated with QDD or saline intragastrically for 12 weeks. Non-diabetic db/m mice were used as controls. Rat renal tubular epithelial cells (NRK-52E) were cultured in high glucose conditions. ATF4 siRNA was transfected into NRK-52E cells. Different indicators were detected via UPLC, RT-PCR, western blotting, cell viability assays and apoptosis, transmission electron microscopy, histology, and immunofluorescence staining. Results. Db/db mice experienced severe kidney damage and fibrosis, increased levels of PERK, eIF2α, and ATF4, and suppression of renal autophagy compared with db/m mice. The results showed a significant improvement in glucose intolerance, blood urea nitrogen, urine albumin, serum creatinine, and renal fibrosis in db/db mice with QDD treatment. Meanwhile, the application of QDD resulted in the downregulation of PERK, eIF2α, and ATF4 and the upregulation of autophagy in diabetic kidneys. In vitro, the exposure of NRK-52E cells to high glucose resulted in downregulation of the ratio of LC3-II/LC3-I and upregulation of P62, a reduction in the number of autophagosomes and upregulation of fibronectin (FN), collagen IV and TGF-β1 protein, which was reversed by QDD treatment through inhibiting ATF4 expression. Conclusions. Taken together, our results suggest that QDD effectively alleviates diabetic renal injuries and fibrosis by inhibiting the PERK-eIF2α-ATF4 pathway and promoting autophagy in diabetic nephropathy.

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Section: Discussionsupporting

confidence: 77%

Deciphering the Pharmacological Mechanisms of Qidan Dihuang Decoction in Ameliorating Renal Fibrosis in Diabetic Nephropathy through Experimental Validation In Vitro and In Vivo

Liang

Bai

Xie

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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“…Consistently, blockade of autophagy suppressed TGFB1-induced fibrotic changes in cultured renal tubular cells. Furthermore, our recent study demonstrated the reciprocal regulation between endoplasmic reticulum stress and autophagy in chronic kidney injury and fibrosis ( Shu et al, 2021 ). Specifically, autophagy was activated during ER stress and led to renal fibrosis.…”

Section: Discussionmentioning

confidence: 99%

“…The role of autophagy in maladaptive kidney repair including especially renal fibrosis has been very controversial ( Kim S. et al, 2012 ; Kim W. et al, 2012 ; Bernard et al, 2014 ; Ding et al, 2014 ; Li et al, 2016 ; Livingston et al, 2016 ; Shu et al, 2021 ). In previous work, we characterized the key features of maladaptive kidney repair in mice after RLDC treatment, including persistent inflammation, progressive interstitial fibrosis, “atubular” glomerulus and renal function decline, and further established an in vitro model of RLDC treatment of cultured renal tubular cells ( Fu et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Persistent Activation of Autophagy After Cisplatin Nephrotoxicity Promotes Renal Fibrosis and Chronic Kidney Disease

Xia

et al. 2022

Front. Pharmacol.

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Autophagy, a highly conserved catabolic pathway in eukaryotic cells, contributes to the maintenance of the homeostasis and function of the kidney. Upon acute kidney injury (AKI), autophagy is activated in renal tubular cells to act as an intrinsic protective mechanism. However, the role of autophagy in the development of chronic kidney pathologies including renal fibrosis after AKI remains unclear. In this study, we detected a persistent autophagy activation in mouse kidneys after nephrotoxicity of repeated low dose cisplatin (RLDC) treatment. 3-methyladenine (3-MA) and chloroquine (CQ), respective inhibitors of autophagy at the initiation and degradation stages, blocked autophagic flux and improved kidney repair in post-RLDC mice, as indicated by kidney weight, renal function, and less interstitial fibrosis. In vitro, RLDC induced a pro-fibrotic phenotype in renal tubular cells, including the production and secretion of pro-fibrotic cytokines. Notably, autophagy inhibitors blocked RLDC-induced secretion of pro-fibrotic cytokines in these cells. Together, the results indicate that persistent autophagy after AKI induces pro-fibrotic cytokines in renal tubular cells, promoting renal fibrosis and chronic kidney disease.

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“…ER stress markers such as PERK, ATF6, IRE1‐α and their downstream regulatory genes eIF2α, CHOP, XBP‐1 , regulate autophagy during AKI‐to‐CKD transition (Shu et al, 2021). Shu et al (2021) observed the reciprocal regulation between the ER stress and autophagy in AKI‐to‐CKD transition using the C57BL/6 mice model. On 7th day of tunicamycin administration, C57BL/6 mice showed higher expression of GRP78, PERK, and eIF2α compared to the normal group, demonstrating the activation of the PERK‐eIF2α axis (Figure 3).…”

Section: Crosstalk Between Er Stress and Autophagy In Aki Aki‐to‐ckd ...mentioning

confidence: 99%

“…On 7th day of tunicamycin administration, C57BL/6 mice showed higher expression of GRP78, PERK, and eIF2α compared to the normal group, demonstrating the activation of the PERK‐eIF2α axis (Figure 3). Moreover, the activation of autophagy occurs after the 7th day of tunicamycin administration (Shu et al, 2021). After 14th day, overexpression of the fibrotic markers‐fibronectin, collagen was observed, indicating interstitial fibrosis in the same animals.…”

Section: Crosstalk Between Er Stress and Autophagy In Aki Aki‐to‐ckd ...mentioning

confidence: 99%

Role of endoplasmic reticulum stress and autophagy in the transition from acute kidney injury to chronic kidney disease

Habshi

Shelke

Kale

et al. 2022

Journal Cellular Physiology

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Acute kidney injury (AKI) and chronic kidney disease (CKD) are global health concerns with increasing rates in morbidity and mortality. Transition from AKI-to-CKD is common and requires awareness in the management of AKI survivors. AKIto-CKD transition is a main risk factor for the development of cardiovascular disease and progression to end-stage kidney disease. The mechanisms driving AKI-to-CKD transition are being explored to identify potential molecular and cellular targets for renoprotective drug interventions. Endoplasmic reticulum (ER) stress and autophagy are involved in the process of AKI-to-CKD transition. Excessive ER stress results in the persistent activation of unfolded protein response, which is an underneath cause of kidney cell death. Moreover, ER stress modulates autophagy and vice-versa.Autophagy is a degradation defensive mechanism protecting cells from malfunction.However, the underlying pathological mechanism involved in this interplay in the context of AKI-to-CKD transition is still unclear. In this review, we discuss the crosstalk between ER stress and autophagy in AKI, AKI-to-CKD transition, and CKD progression. In addition, we explore possible therapeutic targets that can regulate ER stress and autophagy to prevent AKI-to-CKD transition to improve the long-term prognosis of AKI survivors.

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Reciprocal regulation between ER stress and autophagy in renal tubular fibrosis and apoptosis

Cited by 28 publications

References 45 publications

Deciphering the Pharmacological Mechanisms of Qidan Dihuang Decoction in Ameliorating Renal Fibrosis in Diabetic Nephropathy through Experimental Validation In Vitro and In Vivo

Deciphering the Pharmacological Mechanisms of Qidan Dihuang Decoction in Ameliorating Renal Fibrosis in Diabetic Nephropathy through Experimental Validation In Vitro and In Vivo

Persistent Activation of Autophagy After Cisplatin Nephrotoxicity Promotes Renal Fibrosis and Chronic Kidney Disease

Role of endoplasmic reticulum stress and autophagy in the transition from acute kidney injury to chronic kidney disease

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