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Autophagy in Kidney Homeostasis and Disease
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Autophagy in Kidney Homeostasis and Disease

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Autophagy".

Deadline for manuscript submissions: 30 June 2024 | Viewed by 13695

Special Issue Editor

Dr. Alessandro Luciani

E-Mail Website
Guest Editor
Institute of Physiology, University of Zurich, Zurich, Switzerland
Interests: autophagy; differentiation; endocytosis; lysosome; proximal tubule epithelial cells; kidney disease

Special Issue Information

Dear Colleagues,

Over the past two and a half decades, the exploration of key genes that are essential for autophagy, originally identified in yeast, has revealed that autophagy maintains vital functions through the elimination of functionless cellular constituents by lysosomes. In the kidneys, this housecleaning pathway preserves the homeostasis from the glomerular tuft along the entire nephron, thereby sustaining many fundamental processes from glomerular filtration barrier selectivity to tubular transport. The dysregulation of this fundamental pathway disrupts cellular and physiological homeostasis, and may ultimately lead to chronic kidney diseases of varied aetiologias, including diabetic kidney disease, focal segmental glomerulosclerosis, and polycystic kidney disease. However, questions remain about the signaling circuitries controlling autophagy in different types of kidney cells and across the spectrum of kidney disease.

This Special Issue aims to highlight the recent advances in our understanding of the complex regulation of autophagy and its biological functions in the context of kidney homeostasis, disease, and pharmacological intervention. We encourage you to submit research articles as well as review articles that investigate the physiological role of autophagy in kidney cells and how its perturbation leads to kidney disease, including new therapeutics and methods for measuring different autophagic forms.

Dr. Alessandro Luciani
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • differentiation
  • endocytosis
  • macroautophagy
  • microautophagy
  • chaperone-mediated autophagy
  • metabolism
  • organelle quality control
  • oxidative stress
  • kidney cells
  • kidney disease

Published Papers (6 papers)

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Research

Jump to: Review

18 pages, 8893 KiB  
Article
GLA Mutations Suppress Autophagy and Stimulate Lysosome Generation in Fabry Disease
by Ping Li, Yuqian Xi, Yanping Zhang, Abdus Samad, Wenli Lan, Ya Wu, Jiayu Zhao, Guangxin Chen, Changxin Wu and Qiuhong Xiong
Cells 2024, 13(5), 437; https://doi.org/10.3390/cells13050437 - 01 Mar 2024
Viewed by 832
Abstract
Fabry disease (FD) is an X-linked recessive inheritance lysosomal storage disorder caused by pathogenic mutations in the GLA gene leading to a deficiency of the enzyme alpha-galactosidase A (α-Gal A). Multiple organ systems are implicated in FD, most notably the kidney, heart, and [...] Read more.
Fabry disease (FD) is an X-linked recessive inheritance lysosomal storage disorder caused by pathogenic mutations in the GLA gene leading to a deficiency of the enzyme alpha-galactosidase A (α-Gal A). Multiple organ systems are implicated in FD, most notably the kidney, heart, and central nervous system. In our previous study, we identified four GLA mutations from four independent Fabry disease families with kidney disease or neuropathic pain: c.119C>A (p.P40H), c.280T>C (C94R), c.680G>C (p.R227P) and c.801+1G>A (p.L268fsX3). To reveal the molecular mechanism underlying the predisposition to Fabry disease caused by GLA mutations, we analyzed the effects of these four GLA mutations on the protein structure of α-galactosidase A using bioinformatics methods. The results showed that these mutations have a significant impact on the internal dynamics and structures of GLA, and all these altered amino acids are close to the enzyme activity center and lead to significantly reduced enzyme activity. Furthermore, these mutations led to the accumulation of autophagosomes and impairment of autophagy in the cells, which may in turn negatively regulate autophagy by slightly increasing the phosphorylation of mTOR. Moreover, the overexpression of these GLA mutants promoted the expression of lysosome-associated membrane protein 2 (LAMP2), resulting in an increased number of lysosomes. Our study reveals the pathogenesis of these four GLA mutations in FD and provides a scientific foundation for accurate diagnosis and precise medical intervention for FD. Full article
(This article belongs to the Special Issue Autophagy in Kidney Homeostasis and Disease)
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24 pages, 12171 KiB  
Article
Astragaloside IV Blunts Epithelial–Mesenchymal Transition and G2/M Arrest to Alleviate Renal Fibrosis via Regulating ALDH2-Mediated Autophagy
by Dong Li, Yuzhe Liu, Quancao Zhan, Yan Zeng, Ze Peng, Qifeng He, Qi Tan, Wenfu Cao, Shang Wang and Jianwei Wang
Cells 2023, 12(13), 1777; https://doi.org/10.3390/cells12131777 - 04 Jul 2023
Viewed by 1522
Abstract
Previous studies show that astragaloside IV (ASIV) has anti-renal fibrosis effects. However, its mechanism remains elusive. In this study, we investigated the anti-fibrosis mechanisms of ASIV on chronic kidney disease (CKD) in vivo and in vitro. A CKD model was induced in rats [...] Read more.
Previous studies show that astragaloside IV (ASIV) has anti-renal fibrosis effects. However, its mechanism remains elusive. In this study, we investigated the anti-fibrosis mechanisms of ASIV on chronic kidney disease (CKD) in vivo and in vitro. A CKD model was induced in rats with adenine (200 mg/kg/d, i.g.), and an in vitro renal fibrosis model was induced in human kidney-2 (HK-2) cells treated with TGF-β1. We revealed that ASIV significantly alleviated renal fibrosis by suppressing the expressions of epithelial–mesenchymal transition (EMT)-related proteins, including fibronectin, vimentin, and alpha-smooth muscle actin (α-SMA), and G2/M arrest-related proteins, including phosphorylated p53 (p-p53), p21, phosphorylated histone H3 (p-H3), and Ki67 in both of the in vivo and in vitro models. Transcriptomic analysis and subsequent validation showed that ASIV rescued ALDH2 expression and inhibited AKT/mTOR-mediated autophagy. Furthermore, in ALDH2-knockdown HK-2 cells, ASIV failed to inhibit AKT/mTOR-mediated autophagy and could not blunt EMT and G2/M arrest. In addition, we further demonstrated that rapamycin, an autophagy inducer, reversed the treatment of ASIV by promoting autophagy in TGF-β1-treated HK-2 cells. A dual-luciferase report assay indicated that ASIV enhanced the transcriptional activity of the ALDH2 promoter. In addition, a further molecular docking analysis showed the potential interaction of ALDH2 and ASIV. Collectively, our data indicate that ALDH2-mediated autophagy may be a novel target in treating renal fibrosis in CKD models, and ASIV may be an effective targeted drug for ALDH2, which illuminate a new insight into the treatment of renal fibrosis and provide new evidence of pharmacology to elucidate the anti-fibrosis mechanism of ASIV in treating renal fibrosis. Full article
(This article belongs to the Special Issue Autophagy in Kidney Homeostasis and Disease)
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18 pages, 13120 KiB  
Article
HDAC6 Inhibition Alleviates Ischemia- and Cisplatin-Induced Acute Kidney Injury by Promoting Autophagy
by Lang Shi, Zhixia Song, Chenglong Li, Fangjing Deng, Yao Xia, Jing Huang, Xiongfei Wu and Jiefu Zhu
Cells 2022, 11(24), 3951; https://doi.org/10.3390/cells11243951 - 07 Dec 2022
Cited by 9 | Viewed by 1849
Abstract
Histone deacetylase (HDAC) 6 exists exclusively in cytoplasm and deacetylates cytoplasmic proteins such as α-tubulin. HDAC6 dysfunction is associated with several pathological conditions in renal disorders, including UUO-induced fibrotic kidneys and rhabdomyolysis-induced nephropathy. However, the role of HDAC6 in ischemic acute kidney injury [...] Read more.
Histone deacetylase (HDAC) 6 exists exclusively in cytoplasm and deacetylates cytoplasmic proteins such as α-tubulin. HDAC6 dysfunction is associated with several pathological conditions in renal disorders, including UUO-induced fibrotic kidneys and rhabdomyolysis-induced nephropathy. However, the role of HDAC6 in ischemic acute kidney injury (AKI) and the mechanism by which HDAC6 inhibition protects tubular cells after AKI remain unclear. In the present study, we observed that HDAC6 was markedly activated in kidneys subjected to ischemia- and cisplatin (cis)-induced AKI treatment. Pharmacological inhibition of HDAC6 alleviated renal impairment and renal tubular damage after ischemia and cisplatin treatment. HDAC6 dysfunction was associated with decreased acetylation of α-tubulin at the residue of lysine 40 and autophagy. HDAC6 inhibition preserved acetyl-α-tubulin-enhanced autophagy flux in AKI and cultured tubular cells. Genetic ablation of the renal tubular (RT) Atg7 gene or pharmacological inhibition of autophagy suppressed the protective effects of HDAC6. Taken together, our study indicates that HDAC6 contributes to ischemia- and cisplatin-induced AKI by inhibiting autophagy and the acetylation of α-tubulin. These results suggest that HDAC6 could be a potential target for ischemic and nephrotoxic AKI. Full article
(This article belongs to the Special Issue Autophagy in Kidney Homeostasis and Disease)
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Review

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16 pages, 681 KiB  
Review
The Role of Autophagy in Type 2 Diabetic Kidney Disease Management
by Che-Hao Tseng, Kavya M. Shah, I-Jen Chiu and Li-Li Hsiao
Cells 2023, 12(23), 2691; https://doi.org/10.3390/cells12232691 - 23 Nov 2023
Cited by 2 | Viewed by 1163
Abstract
Diabetic kidney disease (DKD), or diabetic nephropathy (DN), is one of the most prevalent complications of type 2 diabetes mellitus (T2DM) and causes severe burden on the general welfare of T2DM patients around the world. While several new agents have shown promise in [...] Read more.
Diabetic kidney disease (DKD), or diabetic nephropathy (DN), is one of the most prevalent complications of type 2 diabetes mellitus (T2DM) and causes severe burden on the general welfare of T2DM patients around the world. While several new agents have shown promise in treating this condition and potentially halting the progression of the disease, more work is needed to understand the complex regulatory network involved in the disorder. Recent studies have provided new insights into the connection between autophagy, a physiological metabolic process known to maintain cellular homeostasis, and the pathophysiological pathways of DKD. Typically, autophagic activity plays a role in DKD progression mainly by promoting an inflammatory response to tissue damage, while both overactivated and downregulated autophagy worsen disease outcomes in different stages of DKD. This correlation demonstrates the potential of autophagy as a novel therapeutic target for the disease, and also highlights new possibilities for utilizing already available DN-related medications. In this review, we summarize findings on the relationship between autophagy and DKD, and the impact of these results on clinical management strategies. Full article
(This article belongs to the Special Issue Autophagy in Kidney Homeostasis and Disease)
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17 pages, 1640 KiB  
Review
Autophagy as a Therapeutic Target for Chronic Kidney Disease and the Roles of TGF-β1 in Autophagy and Kidney Fibrosis
by Miss Ruby, Cody C. Gifford, RamendraPati Pandey, V. Samuel Raj, Venkata S. Sabbisetti and Amrendra K. Ajay
Cells 2023, 12(3), 412; https://doi.org/10.3390/cells12030412 - 26 Jan 2023
Cited by 8 | Viewed by 5229
Abstract
Autophagy is a lysosomal protein degradation system that eliminates cytoplasmic components such as protein aggregates, damaged organelles, and even invading pathogens. Autophagy is an evolutionarily conserved homoeostatic strategy for cell survival in stressful conditions and has been linked to a variety of biological [...] Read more.
Autophagy is a lysosomal protein degradation system that eliminates cytoplasmic components such as protein aggregates, damaged organelles, and even invading pathogens. Autophagy is an evolutionarily conserved homoeostatic strategy for cell survival in stressful conditions and has been linked to a variety of biological processes and disorders. It is vital for the homeostasis and survival of renal cells such as podocytes and tubular epithelial cells, as well as immune cells in the healthy kidney. Autophagy activation protects renal cells under stressed conditions, whereas autophagy deficiency increases the vulnerability of the kidney to injury, resulting in several aberrant processes that ultimately lead to renal failure. Renal fibrosis is a condition that, if chronic, will progress to end-stage kidney disease, which at this point is incurable. Chronic Kidney Disease (CKD) is linked to significant alterations in cell signaling such as the activation of the pleiotropic cytokine transforming growth factor-β1 (TGF-β1). While the expression of TGF-β1 can promote fibrogenesis, it can also activate autophagy, which suppresses renal tubulointerstitial fibrosis. Autophagy has a complex variety of impacts depending on the context, cell types, and pathological circumstances, and can be profibrotic or antifibrotic. Induction of autophagy in tubular cells, particularly in the proximal tubular epithelial cells (PTECs) protects cells against stresses such as proteinuria-induced apoptosis and ischemia-induced acute kidney injury (AKI), whereas the loss of autophagy in renal cells scores a significant increase in sensitivity to several renal diseases. In this review, we discuss new findings that emphasize the various functions of TGF-β1 in producing not just renal fibrosis but also the beneficial TGF-β1 signaling mechanisms in autophagy. Full article
(This article belongs to the Special Issue Autophagy in Kidney Homeostasis and Disease)
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11 pages, 1086 KiB  
Review
Mitochondrial Distress in Methylmalonic Acidemia: Novel Pathogenic Insights and Therapeutic Perspectives
by Svenja Aline Keller and Alessandro Luciani
Cells 2022, 11(19), 3179; https://doi.org/10.3390/cells11193179 - 10 Oct 2022
Cited by 5 | Viewed by 2405
Abstract
Mitochondria are highly dynamic, double-membrane-enclosed organelles that sustain cellular metabolism and, hence, cellular, and organismal homeostasis. Dysregulation of the mitochondrial network might, therefore, confer a potentially devastating vulnerability to high-energy-requiring cell types, contributing to a broad variety of hereditary and acquired diseases, which [...] Read more.
Mitochondria are highly dynamic, double-membrane-enclosed organelles that sustain cellular metabolism and, hence, cellular, and organismal homeostasis. Dysregulation of the mitochondrial network might, therefore, confer a potentially devastating vulnerability to high-energy-requiring cell types, contributing to a broad variety of hereditary and acquired diseases, which include inborn errors of metabolism, cancer, neurodegeneration, and aging-associated adversities. In this Review, we highlight the biological functions of mitochondria-localized enzymes, from the perspective of understanding the pathophysiology of the inherited disorders destroying mitochondrial homeostasis and cellular metabolism. Using methylmalonic acidemia (MMA) as a paradigm of mitochondrial dysfunction, we discuss how mitochondrial-directed signaling pathways sustain the physiological homeostasis of specialized cell types and how these may be disturbed in disease conditions. This Review also provides a critical analysis of molecular underpinnings, through which defects in the autophagy-mediated quality control and surveillance systems contribute to cellular dysfunction, and indicates potential therapeutic strategies for affected tissues. These insights might, ultimately, advance the discovery and development of new therapeutics, not only for methylmalonic acidemia but also for other currently intractable mitochondrial diseases, thus transforming our ability to modulate health and homeostasis. Full article
(This article belongs to the Special Issue Autophagy in Kidney Homeostasis and Disease)
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