Nuclear farnesoid X receptor attenuates acute kidney injury through fatty acid oxidation

Sujuan Xu; Ping Jia; Yi Fang; Jifu Jin; Zhaoxing Sun; Weiran Zhou; Jie Li; Yunlu Zhang; Xiaoyan Wang; Ting Ren; Zhouping Zou; Xiaoqiang Ding

doi:10.1016/j.kint.2022.01.029

Nuclear farnesoid X receptor attenuates acute kidney injury through fatty acid oxidation

Kidney Int. 2022 May;101(5):987-1002. doi: 10.1016/j.kint.2022.01.029. Epub 2022 Feb 26.

Authors

Sujuan Xu¹, Ping Jia², Yi Fang², Jifu Jin¹, Zhaoxing Sun¹, Weiran Zhou¹, Jie Li¹, Yunlu Zhang¹, Xiaoyan Wang¹, Ting Ren¹, Zhouping Zou¹, Xiaoqiang Ding³

Affiliations

¹ Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.
² Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Medical Center of Kidney Disease, Shanghai, China; Kidney and Dialysis Institute of Shanghai, Shanghai, China; Kidney and Blood Purification Key Laboratory of Shanghai, Shanghai, China; Hemodialysis Quality Control Center of Shanghai, Shanghai, China.
³ Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Medical Center of Kidney Disease, Shanghai, China; Kidney and Dialysis Institute of Shanghai, Shanghai, China; Kidney and Blood Purification Key Laboratory of Shanghai, Shanghai, China; Hemodialysis Quality Control Center of Shanghai, Shanghai, China. Electronic address: ding.xiaoqiang@zs-hospital.sh.cn.

PMID: 35227690
DOI: 10.1016/j.kint.2022.01.029

Abstract

Acute kidney injury (AKI) is a life-threatening condition that is one of most common side effects of cisplatin therapy. Fatty acid oxidation (FAO) is the main source of energy production in kidney proximal tubular epithelial cells (PTECs) but it is inhibited in AKI. Recent work demonstrated that activation of the farnesoid X receptor (FXR) protects against AKI, but the underlying mechanism remains elusive. Using a model of cisplatin-induced AKI, we found that FXR and FAO-related genes were remarkably downregulated while kidney lipid accumulated. Proximal tubule-specific or whole body FXR knockout worsened, while pharmacological activation attenuated these effects. Conversely, FXR knockout in non-proximal tubules did not. RNA-sequencing of PTECs demonstrated increased transcripts involved in metabolic pathways in cells overexpressing FXR versus control after cisplatin treatment, specifically transcripts associated with FAO and peroxisome proliferator-activated receptor-γ (PPARγ) signaling. Furthermore, FXR overexpression or activation improved FAO and inhibited intracellular lipid accumulation in cisplatin-treated cells. In vivo studies have shown that pharmacological activation of PPARγ can prevent cisplatin-induced lipid accumulation, kidney tubule injury and kidney function decline. However, inhibition of PPARγ eliminated the protective effects of FXR compared to control mice during the cisplatin treatment phase and after ischemia-reperfusion injury. Consistent with findings in vivo, FXR/PPARγ reduced lipid accumulation by improving FAO in cisplatin-treated cells. Furthermore, the inhibition of carnitine palmitoyltransferase 1α abolished the protective effect of FXR in cisplatin-treated mice. Thus, FXR improves FAO and reduced lipid accumulation via PPARγ in PTECs of the kidney. Hence, reconstruction of the FXR/PPARγ/FAO axis may be a novel therapeutic strategy for preventing or treating AKI.

Keywords: AKI; FAO; FXR; PPARγ; lipid accumulation; proximal tubule.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acute Kidney Injury* / chemically induced
Acute Kidney Injury* / drug therapy
Acute Kidney Injury* / prevention & control
Animals
Cisplatin* / adverse effects
Fatty Acids / metabolism
Female
Humans
Lipids
Male
Mice
Mice, Inbred C57BL
PPAR gamma / genetics

Substances

Fatty Acids
Lipids
PPAR gamma
Cisplatin