Autophagy and Renal Fibrosis

Liang, Shan; Wu, Yun-Shan; Li, Dong-Yi; Tang, Ji‐Xin; Liu, Huafeng

doi:10.14336/ad.2021.1027

Cited by 40 publications

(20 citation statements)

References 185 publications

(209 reference statements)

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“…Activation of autophagy protects kidney cells under stress, while lack of autophagy increases kidney susceptibility to injury, leading to impaired renal function and accumulation of damaged mitochondria, which in turn leads to more severe renal fibrosis. However, other studies have found that persistent activation of autophagy is detrimental after severe renal injury, leading to renal cell senescence and promoting renal fibrosis by secreting pro-fibrotic cytokines (Liang et al, 2022). Therefore, maintaining the balance of autophagy is crucial for improving renal fibrosis.…”

Section: Discussionmentioning

confidence: 99%

“…Autophagy is closely related to renal fibrosis, and a recent study found that sustained activation of autophagy is detrimental to the kidney after severe injury, leading to renal cell senescence and promoting renal fibrosis through the secretion of pro-fibrotic cytokines (Zheng et al, 2019). mTOR is one of the key regulators of autophagy in mammalian cells and can be activated by signal transducers including PI3K and Akt activation in response to insulin, IGF and other growth signals, which in turn inhibit autophagy (Liang et al, 2022). And further studies have shown that IGF-1, as a PI3K/Akt activator, improves renal fibrosis indicators in UUO rats (Wu et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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Heidihuangwan alleviates renal fibrosis in rats with 5/6 nephrectomy by inhibiting autophagy

Tian

Pan

et al. 2022

Front. Pharmacol.

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Renal fibrosis is a common pathway for the progression of various chronic kidney diseases (CKD), and the formation and deterioration will eventually lead to end-stage renal failure, which brings a heavy medical burden to the world. HeidihuangWan (HDHW) is a herbal formulation with stable and reliable clinical efficacy in the treatment of renal fibrosis. However, the mechanism of HDHW in treating renal fibrosis is not clear. In this study, we aimed to investigate the mechanism of HDHW to improve renal fibrosis. Wistar rats were randomly divided into the normal control group, 5/6 Nephrectomy group, astragaloside IV (AS-IV) group, HDHW group, and HDHW + IGF-1R inhibitor (JB1) group. Except for the normal control group, the rat renal fibrosis model was established by 5/6 nephrectomy and intervened with drugs for 8 weeks. Blood samples were collected to evaluate renal function. Hematoxylin-Eosin (HE), Periodic Acid-Schiff (PAS), Modified Masson’s Trichrome (Masson) staining were used to evaluate the pathological renal injury, and immunohistochemistry and Western blotting were used to detect the protein expression of renal tissue. The results showed that HDHW was effective in improving renal function and reducing renal pathological damage. HDHW down-regulated the levels of fibrosis marker proteins, including α-smooth muscle actin (α-SMA), vimentin, and transforming growth factors–β(TGF-β), which in turn reduced renal fibrosis. Further studies showed that HDHW down-regulated the expression of autophagy-related proteins Beclin1 and LC3II, indicating that HDHW inhibited autophagy. In addition, we examined the activity of the class I phosphatidylinositol-3 kinase (PI3K)/serine-threonine kinase (Akt)/mTOR pathway, an important signaling pathway regulating autophagy, and the level of insulin-like growth factor 1 (IGF-1), an upstream activator of PI3K/Akt/mTOR. HDHW upregulated the expression of IGF-1 and activated the PI3K/Akt/mTOR pathway, which may be a vital pathway for its inhibition of autophagy. Application of insulin-like growth factor 1 receptor (IGF-1R) inhibitor further confirmed that the regulation of autophagy and renal fibrosis by HDHW was associated with IGF-1-mediated activation of the PI3K/Akt/mTOR pathway. In conclusion, our study showed that HDHW inhibited autophagy by upregulating IGF-1 expression, promoting the binding of IGF-1 to IGF-1R, and activating the PI3K/Akt/mTOR signaling pathway, thereby reducing renal fibrosis and protecting renal function. This study provides support for the application and further study of HDHW.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Heidihuangwan alleviates renal fibrosis in rats with 5/6 nephrectomy by inhibiting autophagy

Tian

Pan

et al. 2022

Front. Pharmacol.

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“…As the common final pathway of nearly all chronic and progressive kidney diseases to progress to end-stage renal failure, renal fibrosis refers to the accumulation of ECM in the renal parenchyma, which affects about 10% of the global population ( 90 – 92 ). The main function of the mammalian kidney is to keep the water, electrolyte, and acid-base balance of the body, while meanwhile excreting metabolic waste from the body.…”

Section: Macrophage Autophagy In Organ Fibrosismentioning

confidence: 99%

Macrophage autophagy in macrophage polarization, chronic inflammation and organ fibrosis

Wen

Liang

et al. 2022

Front. Immunol.

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As the essential regulators of organ fibrosis, macrophages undergo marked phenotypic and functional changes after organ injury. These changes in macrophage phenotype and function can result in maladaptive repair, causing chronic inflammation and the development of pathological fibrosis. Autophagy, a highly conserved lysosomal degradation pathway, is one of the major players to maintain the homeostasis of macrophages through clearing protein aggregates, damaged organelles, and invading pathogens. Emerging evidence has shown that macrophage autophagy plays an essential role in macrophage polarization, chronic inflammation, and organ fibrosis. Because of the high heterogeneity of macrophages in different organs, different macrophage types may play different roles in organ fibrosis. Here, we review the current understanding of the function of macrophage autophagy in macrophage polarization, chronic inflammation, and organ fibrosis in different organs, highlight the potential role of macrophage autophagy in the treatment of fibrosis. Finally, the important unresolved issues in this field are briefly discussed. A better understanding of the mechanisms that macrophage autophagy in macrophage polarization, chronic inflammation, and organ fibrosis may contribute to developing novel therapies for chronic inflammatory diseases and organ fibrosis.

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“…When kidney cells are exposed to oxidative stress and ER stress, autophagy activation plays a vital role in cell survival [ 31 ]. Autophagy also participates in the intracellular degradation of collagen, prevents the continuous accumulation of ECM, and plays a crucial role in inhibiting renal fibrosis [ 32 ]. Autophagy is mainly regulated by the mechanistic target of rapamycin (mTOR) signaling pathway, and its upstream is managed by AMP-activated protein kinase (AMPK).…”

Section: Signaling Pathways For Dkd Progressionmentioning

confidence: 99%

Molecular Mechanistic Pathways Targeted by Natural Compounds in the Prevention and Treatment of Diabetic Kidney Disease

et al. 2022

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Diabetic kidney disease (DKD) is one of the most common complications of diabetes, and its prevalence is still growing rapidly. However, the efficient therapies for this kidney disease are still limited. The pathogenesis of DKD involves glucotoxicity, lipotoxicity, inflammation, oxidative stress, and renal fibrosis. Glucotoxicity and lipotoxicity can cause oxidative stress, which can lead to inflammation and aggravate renal fibrosis. In this review, we have focused on in vitro and in vivo experiments to investigate the mechanistic pathways by which natural compounds exert their effects against the progression of DKD. The accumulated and collected data revealed that some natural compounds could regulate inflammation, oxidative stress, renal fibrosis, and activate autophagy, thereby protecting the kidney. The main pathways targeted by these reviewed compounds include the Nrf2 signaling pathway, NF-κB signaling pathway, TGF-β signaling pathway, NLRP3 inflammasome, autophagy, glycolipid metabolism and ER stress. This review presented an updated overview of the potential benefits of these natural compounds for the prevention and treatment of DKD progression, aimed to provide new potential therapeutic lead compounds and references for the innovative drug development and clinical treatment of DKD.

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Autophagy and Renal Fibrosis

Cited by 40 publications

References 185 publications

Heidihuangwan alleviates renal fibrosis in rats with 5/6 nephrectomy by inhibiting autophagy

Heidihuangwan alleviates renal fibrosis in rats with 5/6 nephrectomy by inhibiting autophagy

Macrophage autophagy in macrophage polarization, chronic inflammation and organ fibrosis

Molecular Mechanistic Pathways Targeted by Natural Compounds in the Prevention and Treatment of Diabetic Kidney Disease

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