ATF4 promotes renal tubulointerstitial fibrosis by suppressing autophagy in diabetic nephropathy

Liang, Qiuer; Liu, Tianhao; Guo, Tingting; Tao, Wencong; Chen, Xudong; Chen, Wei-Hao; Chen, Liguo; Ye, Xiao

doi:10.1016/j.lfs.2020.118686

Cited by 17 publications

(20 citation statements)

References 38 publications

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“…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]. It is increasingly recognized that the activation of endoplasmic reticulum stress (ERS) plays an important role in the development and progression of tubular interstitial fibrosis in DN [46][47][48].…”

Section: Discussionsupporting

confidence: 80%

“…Studies suggested that the PERK/eIF2α/ATF4 pathway was involved in the regulation of autophagy [16]. Our previous study showed that the ERS-inducible transcription factor ATF4 promotes tubulointerstitial fibrosis by inhibiting autophagy in DN [17]. erefore, we speculate that the mechanism of QDD delaying renal fibrosis in DN is related to the regulation of autophagy via the PERK/eIF2α/ ATF4 signaling pathway.…”

Section: Introductionmentioning

confidence: 80%

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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: 80%

Section: Introductionmentioning

confidence: 80%

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

Self Cite

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“…ATF4 is a basic leucine zipper transcription factor best known to be induced by stress responses. ATF4 has long been considered a profibrotic molecule because it enhances fibroblast proliferation, collagen synthesis, migration, and differentiation to myofibroblasts and induces fibroblasts’ apoptosis in tissue fibrosis [ 30 , 31 , 32 , 33 ]. Despite being less studied in lung disease, ATF4 was a profibrotic role in lung fibroblast activation and renal tubulointerstitial fibrosis [ 29 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

“…ATF4 has long been considered a profibrotic molecule because it enhances fibroblast proliferation, collagen synthesis, migration, and differentiation to myofibroblasts and induces fibroblasts’ apoptosis in tissue fibrosis [ 30 , 31 , 32 , 33 ]. Despite being less studied in lung disease, ATF4 was a profibrotic role in lung fibroblast activation and renal tubulointerstitial fibrosis [ 29 , 30 ]. For instance, ATF4 is an important regulator of metabolic reprogramming in myofibroblasts [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

TRIB3 Mediates Fibroblast Activation and Fibrosis though Interaction with ATF4 in IPF

Wang

Zhao

Xia

et al. 2022

IJMS

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Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterized by fibroblast activation, excessive deposition of extracellular matrix, and progressive scarring; the pathogenesis remains elusive. The present study explored the role of Tribbles pseudokinase 3 (TRIB3), a well-known stress and metabolic sensor, in IPF. TRIB3 is down-regulated in the lungs of IPF patients in comparison to control subjects. Deficiency of TRIB3 markedly inhibited A549 epithelial cells’ proliferation and migration, significantly reducing wound healing. Conversely, overexpression of TRIB3 promoted A549 cell proliferation and transmigration while it inhibited its apoptosis. Meanwhile, overexpressed TRIB3 inhibited fibroblast activation and decreased ECM synthesis and deposition in MRC5 cells. TRIB3 attenuated pulmonary fibrosis by negative regulation of ATF4, while TRIB3 expression markedly inhibited ATF4 promoter-driven transcription activity and down-regulated ATF4 expression. A co-culture system showed that TRIB3 is important to maintain the normal epithelial–mesenchymal crosstalk and regulate fibroblast activation. Taken together, our data suggested that an axis of TRIB3‒ATF4 is a key mediator in IPF which might be a potential target for fibroproliferative lung disease treatment.

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“…To investigate the specific mechanism of fenofibrate on the DKD model, researchers found that fenofibrate induced autophagy and acted as an antioxidant via the AMPK pathway ( Sohn et al, 2017 ). In addition, researchers have experimentally demonstrated that the use of therapeutic agents and approaches such as mitoQ (mitochondria-targeted antioxidant) and NSC697923 inhibitor and t-AUCB (an inhibitor of soluble epoxide hydrolase) can slow down the progression of DKD by improving autophagy ( Xiao et al, 2017 ; Pontrelli et al, 2018 ; Jiang et al, 2020 ; Han et al, 2021 ; Liang et al, 2021 ; Zheng et al, 2021 ). In summary, autophagy plays an important role in maintaining the homeostasis and function of renal tubular epithelial cells.…”

Section: Dkd and Autophagymentioning

confidence: 99%

The critical role of dysregulated autophagy in the progression of diabetic kidney disease

et al. 2022

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Diabetic kidney disease (DKD) is one of the major public health problems in society today. It is a renal complication caused by diabetes mellitus with predominantly microangiopathy and is a major cause of end-stage renal disease (ESRD). Autophagy is a metabolic pathway for the intracellular degradation of cytoplasmic products and damaged organelles and plays a vital role in maintaining homeostasis and function of the renal cells. The dysregulation of autophagy in the hyperglycaemic state of diabetes mellitus can lead to the progression of DKD, and the activation or restoration of autophagy through drugs is beneficial to the recovery of renal function. This review summarizes the physiological process of autophagy, illustrates the close link between DKD and autophagy, and discusses the effects of drugs on autophagy and the signaling pathways involved from the perspective of podocytes, renal tubular epithelial cells, and mesangial cells, in the hope that this will be useful for clinical treatment.

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ATF4 promotes renal tubulointerstitial fibrosis by suppressing autophagy in diabetic nephropathy

Cited by 17 publications

References 38 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

TRIB3 Mediates Fibroblast Activation and Fibrosis though Interaction with ATF4 in IPF

The critical role of dysregulated autophagy in the progression of diabetic kidney disease

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