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Downregulation of fatty acid oxidation led by Hilpda increases G2/M arrest/delay-induced kidney fibrosis.
- Source :
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BBA: Molecular Basis of Disease . Jun2023, Vol. 1869 Issue 5, pN.PAG-N.PAG. 1p. - Publication Year :
- 2023
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Abstract
- Hypoxia-regulated proximal tubular epithelial cells (PTCs) G2/M phase arrest/delay was involved in production of renal tubulointerstitial fibrosis (TIF). TIF is a common pathological manifestation of progression in patients with chronic kidney disease (CKD), and is often accompanied by lipid accumulation in renal tubules. However, cause-effect relationship between hypoxia-inducible lipid droplet-associated protein (Hilpda), lipid accumulation, G2/M phase arrest/delay and TIF remains unclear. Here we found that overexpression of Hilpda downregulated adipose triglyceride lipase (ATGL) promoted triglyceride overload in the form of lipid accumulation, leading to defective fatty acid β-oxidation (FAO), ATP depletion in a human PTC cell line (HK-2) under hypoxia and in mice kidney tissue treated with unilateral ureteral obstruction (UUO) and unilateral ischemia-reperfusion injury (UIRI). Hilpda-induced lipid accumulation caused mitochondrial dysfunction, enhanced expression of profibrogenic factors TGF-β1, α-SMA and Collagen I elevation, and reduced expression of G2/M phase-associated gene CDK1, as well as increased CyclinB1/D1 ratio, resulted in G2/M phase arrest/delay and profibrogenic phenotypes. Hilpda deficiency in HK-2 cell and kidney of mice with UUO had sustained expression of ATGL and CDK1 and reduced expression of TGF-β1, Collagen I and CyclinB1/D1 ratio, resulting in the amelioration of lipid accumulation and G2/M arrest/delay and subsequent TIF. Expression of Hilpda correlated with lipid accumulation, was positively associated with tubulointerstitial fibrosis in tissue samples from patients with CKD. Our findings suggest that Hilpda deranges fatty acid metabolism in PTCs, which leads to G2/M phase arrest/delay and upregulation of profibrogenic factors, and consequently promote TIF which possibly underlie pathogenesis of CKD. [Display omitted] • Hypoxia induced lipid accumulation and G2/M phase arrest/delay in PTCs. • Reduction of lipid accumulation alleviates G2/M arrest/delay in PTCs. • Hilpda inhibits FAO activity and promotes G2/M phase arrest/delay via suppression ATGL. • Hilpda deficiency sustains ATGL expression ameliorates UUO-induced TIF in mice. • Hilpda activation was associated with TIF in patients with CKD. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 09254439
- Volume :
- 1869
- Issue :
- 5
- Database :
- Academic Search Index
- Journal :
- BBA: Molecular Basis of Disease
- Publication Type :
- Academic Journal
- Accession number :
- 163468978
- Full Text :
- https://doi.org/10.1016/j.bbadis.2023.166701