| First Author | Jao TM | Year | 2019 |
| Journal | Kidney Int | Volume | 95 |
| Issue | 3 | Pages | 577-589 |
| PubMed ID | 30639234 | Mgi Jnum | J:295080 |
| Mgi Id | MGI:6459622 | Doi | 10.1016/j.kint.2018.09.023 |
| Citation | Jao TM, et al. (2019) ATF6alpha downregulation of PPARalpha promotes lipotoxicity-induced tubulointerstitial fibrosis. Kidney Int 95(3):577-589 |
| abstractText | Tubulointerstitial fibrosis is a strong predictor of progression in patients with chronic kidney disease, and is often accompanied by lipid accumulation in renal tubules. However, the molecular mechanisms modulating the relationship between lipotoxicity and tubulointerstitial fibrosis remain obscure. ATF6alpha, a transcription factor of the unfolded protein response, is reported to be an upstream regulator of fatty acid metabolism. Owing to their high energy demand, proximal tubular cells (PTCs) use fatty acids as their main energy source. We therefore hypothesized that ATF6alpha regulates PTC fatty acid metabolism, contributing to lipotoxicity-induced tubulointerstitial fibrosis. Overexpression of activated ATF6alpha transcriptionally downregulated peroxisome proliferator-activated receptor-alpha (PPARalpha), the master regulator of lipid metabolism, leading to reduced activity of fatty acid beta-oxidation and cytosolic accumulation of lipid droplets in a human PTC line (HK-2). ATF6alpha-induced lipid accumulation caused mitochondrial dysfunction, enhanced apoptosis, and increased expression of connective tissue growth factor (CTGF), as well as reduced cell viability. Atf6alpha-/- mice had sustained expression of PPARalpha and less tubular lipid accumulation following unilateral ischemia-reperfusion injury (uIRI), resulting in the amelioration of apoptosis; reduced expression of CTGF, alpha-smooth muscle actin, and collagen I; and less tubulointerstitial fibrosis. Administration of fenofibrate, a PPARalpha agonist, reduced lipid accumulation and tubulointerstitial fibrosis in the uIRI model. Taken together, these findings suggest that ATF6alpha deranges fatty acid metabolism in PTCs, which leads to lipotoxicity-mediated apoptosis and CTGF upregulation, both of which promote tubulointerstitial fibrosis. |
