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Autophagy attenuates tubulointerstital fibrosis through regulating transforming growth factor-β and NLRP3 inflammasome signaling pathway

Title
Autophagy attenuates tubulointerstital fibrosis through regulating transforming growth factor-β and NLRP3 inflammasome signaling pathway
Authors
Nam S.A.Kim W.-Y.Kim J.W.Park S.H.Kim H.L.Lee M.-S.Komatsu M.Ha H.Lim J.H.Park C.W.Yang C.W.Kim J.Kim Y.K.
Ewha Authors
하헌주
SCOPUS Author ID
하헌주scopus
Issue Date
2019
Journal Title
Cell Death and Disease
ISSN
2041-4889JCR Link
Citation
Cell Death and Disease vol. 10, no. 2
Publisher
Nature Publishing Group
Indexed
SCIE; SCOPUS WOS scopus
Document Type
Article
Abstract
Renal fibrosis is the final common pathway of various renal injuries and it leads to chronic kidney disease. Autophagy is a cellular process of degradation of damaged cytoplasmic components and regulates cell death and proliferation. Cellular response during unilateral ureteral obstruction (UUO) is tubular segment specific. Thus the role of autophagy on renal tubulointerstitial fibrosis (TIF) after UUO may be different according to segment of nephron. The role of autophagy during UUO remains unclear especially in distal tubules. In this study, we investigated the role of autophagy in distal tubules on renal TIF using conditional knockout mice in which Atg7 was genetically ablated specifically in distal tubular epithelial cell (TEC). In green fluorescent protein (GFP)-LC3 transgenic mice, GFP-LC3 puncta was highly expressed in distal tubular cells of the obstructed kidneys after UUO. Genetic deletion of Atg7 specifically in distal TEC increased renal tubulointerstial fibrosis and epithelial-mesenchymal transition-like phenotype change after UUO through Smad4-dependent transforming growth factor (TGF)-β pathway. Distal tubule-specific autophagy-deficient mice increased the accumulation of damaged mitochondria and SQSTM1/p62-positive aggregates in the obstructed kidney and resulted in increased expression of NLRP3 inflammasome, interleukin (IL) 1-β and caspase-1. Distal TEC-specific Atg7 deletion enhanced apoptosis of TECs after UUO. In summary, our data showed that autophagy in distal TEC plays a protective role in development of renal tubulointerstial fibrosis through regulating the expression of TGF-β an IL1-β after UUO. © 2019, The Author(s).
DOI
10.1038/s41419-019-1356-0
Appears in Collections:
약학대학 > 약학과 > Journal papers
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