Theranostics 2022; 12(8):3758-3775. doi:10.7150/thno.71722 This issue Cite
1. Department of Nephrology, Xijing Hospital, Fourth Military Medical University, No. 127 Chang le West Road, Xi'an, Shaanxi, 710032, China.
2. School of Medicine, Northwest University, 229 Taibai North Road, Xi'an, Shaanxi, 710069, China.
3. Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, No. 127 Chang le West Road, Xi'an, Shaanxi, 710032, China.
*These authors contributed equally to this work.
Rationale: A deficiency of fatty acid oxidation (FAO) is the metabolic hallmark in proximal tubular cells (PTCs) in renal fibrosis owing to utilization of fatty acids by PTCs as the main energy source. Lipid accumulation may promote lipotoxicity-induced pathological injury in renal tissue. However, the molecular mechanism underlying lipotoxicity and renal tubulointerstitial fibrosis (TIF) remains unclear. Twist1 has been identified to play an essential role in fatty acid metabolism. We hypothesized that Twist1 may regulate FAO in PTCs and consequently facilitate lipotoxicity-induced TIF.
Methods: We used hypoxia-induced Twist1 overexpression to incite defective mitochondrial FAO in PTCs, and used renal ischemia-reperfusion or unilateral ureteral obstruction to induce renal injury in mice. We used knockout cells, mice of Twist1, and Harmine to determine the role of Twist1 in FAO and TIF.
Results: Overexpression of Twist1 downregulates the transcription of PGC-1α and further inhibits the expression of FAO-associated genes, such as PPARα, CPT1 and ACOX1. Consequently, reduced FAO and increased intracellular lipid droplet accumulation in a human PTC line (HK-2), leads to mitochondrial dysfunction, and production of increased profibrogenic factors. Twist1 knockout mice with renal injury had increased expression of PGC-1α, which restored FAO and obstructed progression of TIF. Strikingly, pharmacological inhibition of Twist1 by using Harmine reduced lipid accumulation and restored FAO in vitro and in vivo.
Conclusion: Our findings suggest that Twist1-mediated inhibition of FAO in PTCs results in TIF and suggest that Twist1-targeted inhibition could provide a potential strategy for the treatment of renal fibrosis.
Keywords: Renal tubulointerstitial fibrosis, hypoxia, fatty acid metabolism, Twist1, pharmacological inhibition strategy