Autophagy is activated to protect against podocyte injury in adriamycin-induced nephropathy

Yi, Mixuan; Zhang, Lei; Liu, Yu; Livingston, Man J.; Chen, Jian Kang; Nahman, N. S.; Liu, Fuyou; Dong, Zheng

doi:10.1152/ajprenal.00114.2017

Cited by 67 publications

(54 citation statements)

References 32 publications

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“…Fibrosis can be regulated through autophagy, a biological regulatory program that maintains homeostasis. 42,43 Autophagy plays a pivotal role in homeostasis and survival of renal cells, and dysregulation of autophagy might contribute to the development of kidney diseases. 14,44 There has been extensive work in renal fibrosis models, in which autophagy activity is increased and serves as a renal protective response.…”

Section: Discussionmentioning

confidence: 99%

Aloe-Emodin Ameliorates Renal Fibrosis Via Inhibiting PI3K/Akt/mTOR Signaling PathwayIn VivoandIn Vitro

Dou

Liu

et al. 2019

Rejuvenation Research

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Fibrosis is the major pathological feature of chronic kidney disease (CKD). Aloe-emodin (AE), one of the main active compounds in Rhubarb, is widely used for renal protection. However, mechanisms implied in the modulation of kidney fibrosis after AE treatment for CKD remain elusive. Here, we explored the protective effects of AE for renal fibrosis and the involved mechanisms in vivo and in vitro. The renal fibrosis mice model was established by unilateral ureteral obstruction (UUO). We found that AE administration significantly ameliorated UUO-induced impairment of kidney, evidenced by improved histopathological abnormalities, body weight, and abnormal renal function in mice model. Immunohistochemical staining showed that TGF-β1 and Fibronectin expressions were significantly decreased in UUO mice compared with sham group. Meanwhile, we found that AE suppressed the activation of the PI3K/Akt/mTOR pathway induced by TGF-β1 in vivo. AE improved cell survival and decreased the level of fibrosis-related proteins under TGF-β1-induced fibrosis in HK-2 cells as well as in vitro. Furthermore, both wortmannin, an inhibitor of PI3K, and short-hairpin RNAs of PI3K knockdown abrogated TGF-β1-induced phosphorylation of Akt and mTOR, and decreased the suppression of fibrosis. These findings indicated that AE alleviated fibrosis by inhibiting PI3K/Akt/mTOR pathway in vivo and in vitro, which may provide a potential therapeutic option for CKD.

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Section: Discussionmentioning

confidence: 99%

Aloe-Emodin Ameliorates Renal Fibrosis Via Inhibiting PI3K/Akt/mTOR Signaling PathwayIn VivoandIn Vitro

Dou

Liu

et al. 2019

Rejuvenation Research

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“…In cultured podocytes, adriamycin-induced podocyte injury was prevented by activation of autophagy with rapamycin, and in inducible podocyte-specific Atg7 knockout (Podo-Atg7-KO) mice, podocyte injury was enhanced compared to control mice [86]. The G1 and G2 generic variants in the APOL1 gene in podocytes, involved in an increased risk of developing chronic kidney disease in African Americans, were able to suppress podocyte autophagy flux [111].…”

Section: Mtorc1-ulk1-mediated Autophagy In Renal Injurymentioning

confidence: 99%

Autophagy Function and Regulation in Kidney Disease

et al. 2020

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Autophagy is a dynamic process by which intracellular damaged macromolecules and organelles are degraded and recycled for the synthesis of new cellular components. Basal autophagy in the kidney acts as a quality control system and is vital for cellular metabolic and organelle homeostasis. Under pathological conditions, autophagy facilitates cellular adaptation; however, activation of autophagy in response to renal injury may be insufficient to provide protection, especially under dysregulated conditions. Kidney-specific deletion of Atg genes in mice has consistently demonstrated worsened acute kidney injury (AKI) outcomes supporting the notion of a pro-survival role of autophagy. Recent studies have also begun to unfold the role of autophagy in progressive renal disease and subsequent fibrosis. Autophagy also influences tubular cell death in renal injury. In this review, we reported the current understanding of autophagy regulation and its role in the pathogenesis of renal injury. In particular, the classic mammalian target of rapamycin (mTOR)-dependent signaling pathway and other mTOR-independent alternative signaling pathways of autophagy regulation were described. Finally, we summarized the impact of autophagy activation on different forms of cell death, including apoptosis and regulated necrosis, associated with the pathophysiology of renal injury. Understanding the regulatory mechanisms of autophagy would identify important targets for therapeutic approaches.

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“…Doxorubicin, an anthracycline antibiotic used for cancer treatment, has been shown to induce glomerular nephrotoxicity both in vitro and clinically [20][21][22][23] . To assess the capacity of 3D…”

Section: Application Of Bioprinted Organoids In Toxicity Screeningmentioning

confidence: 99%

Bioprinted pluripotent stem cell-derived kidney organoids provide opportunities for high content screening

Higgins

Chambon

Bishard

et al. 2018

Preprint

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Recent advances in the directed differentiation of human pluripotent stem cells to kidney brings with it the prospect of drug screening and disease modelling using patient-derived stem cell lines. Development of such an approach for high content screening will require substantial quality control and improvements in throughput. Here we demonstrate the use of the NovoGen MMX 3D bioprinter for the generation of highly reproducible kidney organoids from as few as 4,000 cells. Histological and immunohistochemical analyses confirmed the presence of renal epithelium, glomeruli, stroma and endothelium, while single cell RNAseq revealed equivalence to the cell clusters present within previously described organoids. The process is highly reproducible, rapid and transferable between cell lines, including genetically engineered reporter lines. We also demonstrate the capacity to bioprint organoids in a 96-well format and screen for response to doxorubicin toxicity as a proof of concept for high content compound screening.

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Autophagy is activated to protect against podocyte injury in adriamycin-induced nephropathy

Cited by 67 publications

References 32 publications

Aloe-Emodin Ameliorates Renal Fibrosis Via Inhibiting PI3K/Akt/mTOR Signaling PathwayIn VivoandIn Vitro

Aloe-Emodin Ameliorates Renal Fibrosis Via Inhibiting PI3K/Akt/mTOR Signaling PathwayIn VivoandIn Vitro

Autophagy Function and Regulation in Kidney Disease

Bioprinted pluripotent stem cell-derived kidney organoids provide opportunities for high content screening

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