Persistent activation of autophagy in kidney tubular cells promotes renal interstitial fibrosis during unilateral ureteral obstruction
Man J. Livingston,Han Fei Ding,Shuang Huang,Joseph A. Hill,Xiao Ming Yin,Zheng Dong,Zheng Dong +6 more
TLDR
It is suggested that persistent activation of autophagy in kidney proximal tubules promotes renal interstitial fibrosis during UUO.Abstract:
Renal fibrosis is the final, common pathway of end-stage renal disease. Whether and how autophagy contributes to renal fibrosis remains unclear. Here we first detected persistent autophagy in kidney proximal tubules in the renal fibrosis model of unilateral ureteral obstruction (UUO) in mice. UUO-associated fibrosis was suppressed by pharmacological inhibitors of autophagy and also by kidney proximal tubule-specific knockout of autophagy-related 7 (PT-Atg7 KO). Consistently, proliferation and activation of fibroblasts, as indicated by the expression of ACTA2/α-smooth muscle actin and VIM (vimentin), was inhibited in PT-Atg7 KO mice, so was the accumulation of extracellular matrix components including FN1 (fibronectin 1) and collagen fibrils. Tubular atrophy, apoptosis, nephron loss, and interstitial macrophage infiltration were all inhibited in these mice. Moreover, these mice showed a specific suppression of the expression of a profibrotic factor FGF2 (fibroblast growth factor 2). In vitro, TGFB1 (transforming growth factor β 1) induced autophagy, apoptosis, and FN1 accumulation in primary proximal tubular cells. Inhibition of autophagy suppressed FN1 accumulation and apoptosis, while enhancement of autophagy increased TGFB1-induced-cell death. These results suggest that persistent activation of autophagy in kidney proximal tubules promotes renal interstitial fibrosis during UUO. The profibrotic function of autophagy is related to the regulation on tubular cell death, interstitial inflammation, and the production of profibrotic factors.read more
Citations
More filters
Journal ArticleDOI
Autophagy in major human diseases
Daniel J. Klionsky,Giulia Petroni,Ravi K. Amaravadi,Eric H. Baehrecke,Andrea Ballabio,Andrea Ballabio,Patricia Boya,José Manuel Bravo-San Pedro,Ken Cadwell,Francesco Cecconi,Francesco Cecconi,Augustine M.K. Choi,Augustine M.K. Choi,Mary E. Choi,Mary E. Choi,Charleen T. Chu,Patrice Codogno,Patrice Codogno,María Isabel Colombo,Ana Maria Cuervo,Vojo Deretic,Ivan Dikic,Zvulun Elazar,Eeva-Liisa Eskelinen,Gian Maria Fimia,David A. Gewirtz,Douglas R. Green,Malene Hansen,Marja Jäättelä,Terje Johansen,Gábor Juhász,Vassiliki Karantza,Claudine Kraft,Guido Kroemer,Nicholas T. Ktistakis,Sharad Kumar,Sharad Kumar,Carlos López-Otín,Kay F. Macleod,Frank Madeo,Jennifer Martinez,Alicia Meléndez,Alicia Meléndez,Noboru Mizushima,Christian Münz,Josef M. Penninger,Josef M. Penninger,Rushika M. Perera,Mauro Piacentini,Mauro Piacentini,Fulvio Reggiori,David C. Rubinsztein,Kevin M. Ryan,Junichi Sadoshima,Laura Santambrogio,Luca Scorrano,Hans-Uwe Simon,Hans-Uwe Simon,Anna Katharina Simon,Anne Simonsen,Anne Simonsen,Alexandra Stolz,Nektarios Tavernarakis,Nektarios Tavernarakis,Sharon A. Tooze,Tamotsu Yoshimori,Junying Yuan,Junying Yuan,Zhenyu Yue,Qing Zhong,Lorenzo Galluzzi,Federico Pietrocola +71 more
TL;DR: In this paper, preclinical data linking autophagy dysfunction to the pathogenesis of major human disorders including cancer as well as cardiovascular, neurodegenerative, metabolic, pulmonary, renal, infectious, musculoskeletal, and ocular disorders.
Journal ArticleDOI
Cellular and molecular mechanisms of kidney fibrosis.
Sonja Djudjaj,Peter Boor +1 more
TL;DR: This review summarized the different appearance, cellular origin and major emerging processes and mediators of fibrosis in each compartment of kidney's histological structure, and depicted and discussed the challenges in translation of anti-fibrotic treatment to clinical practice.
Journal ArticleDOI
AKI on CKD: heightened injury, suppressed repair, and the underlying mechanisms
Liyu He,Qingqing Wei,Jing Liu,Jing Liu,Mixuan Yi,Mixuan Yi,Yu Liu,Hong Liu,Lin Sun,Youming Peng,Fuyou Liu,Manjeri A. Venkatachalam,Zheng Dong,Zheng Dong +13 more
TL;DR: CKD is associated with significant changes in cell signaling in kidney tissues, including the activation of transforming growth factor-β, p53, hypoxia-inducible factor, and major developmental pathways, which may contribute to the heightened sensitivity of, and nonrecovery from, AKI.
Journal ArticleDOI
Autophagy in kidney homeostasis and disease.
TL;DR: The authors summarize the basics of autophagy and the signalling pathways involved in its regulation, and examine the multiple roles of autophile in kidney cells, from its involvement in kidney maintenance and responses to injury, to its potential contribution to glomerular and tubulointerstitial disease.
Journal ArticleDOI
Mitochondrial quality control in kidney injury and repair.
Chengyuan Tang,Juan Cai,Xiao Ming Yin,Joel M. Weinberg,Manjeri A. Venkatachalam,Zheng Dong,Zheng Dong +6 more
TL;DR: The role of mitochondrial quality control mechanisms in kidney injury and repair is discussed and their potential as therapeutic targets are highlighted.
References
More filters
Journal ArticleDOI
Autophagy in the Pathogenesis of Disease
TL;DR: This Review summarizes recent advances in understanding the physiological functions of autophagy and its possible roles in the causation and prevention of human diseases.
Journal ArticleDOI
Autophagy fights disease through cellular self-digestion
TL;DR: Understanding autophagy may ultimately allow scientists and clinicians to harness this process for the purpose of improving human health, and to play a role in cell death.
Journal ArticleDOI
Autophagy: Renovation of Cells and Tissues
Noboru Mizushima,Masaaki Komatsu +1 more
TL;DR: It is explored how recent mouse models in combination with advances in human genetics are providing key insights into how the impairment or activation of autophagy contributes to pathogenesis of diverse diseases, from neurodegenerative diseases such as Parkinson disease to inflammatory disorders such as Crohn disease.
Journal ArticleDOI
Methods in Mammalian Autophagy Research
TL;DR: Methods to monitor autophagy and to modulate autophagic activity are discussed, with a primary focus on mammalian macroautophagy.
Journal ArticleDOI
Self-eating and self-killing: crosstalk between autophagy and apoptosis
TL;DR: The functional relationship between apoptosis and autophagy is complex in the sense that, under certain circumstances,autophagy constitutes a stress adaptation that avoids cell death (and suppresses apoptosis), whereas in other cellular settings, it constitutes an alternative cell-death pathway.