The role of the farnesoid X receptor in kidney health and disease: a potential therapeutic target in kidney diseases

Abstract

The prevalence of kidney diseases has been increasing worldwide due to the aging population and has results in an increased socioeconomic burden as well as increased morbidity and mortality. A deep understanding of the mechanisms underlying the physiological regulation of the kidney and the pathogenesis of related diseases can help identify potential therapeutic targets. The farnesoid X receptor (FXR, NR1H4) is a primary nuclear bile acid receptor that transcriptionally regulates bile acid homeostasis as well as glucose and lipid metabolism in multiple tissues. The roles of FXR in tissues other than hepatic and intestinal tissues are poorly understood. In studies over the past decade, FXR has been demonstrated to have a protective effect against kidney diseases through its anti-inflammatory and antifibrotic effects; it also plays roles in glucose and lipid metabolism in the kidney. In this review, we discuss the physiological role of FXR in the kidney and its pathophysiological roles in various kidney diseases, including acute kidney injury and chronic kidney diseases, diabetic nephropathy, and kidney fibrosis. Therefore, the regulatory mechanisms involving nuclear receptors, such as FXR, in the physiology and pathophysiology of the kidney and the development of agonists and antagonists for modulating FXR expression and activation should be elucidated to identify therapeutic targets for the treatment of kidney diseases.

Peroxisome proliferator-activated receptors, farnesoid X receptor, and dual modulating drugs in hypertension

“…Although FXR regulates bile acids and lipid and glucose metabolism, FXR is expressed in the kidney and FXR agonism has beneficial effects to prevent kidney inflammation and fibrosis in disease animal models (Jiao et al, 2022;Kim et al, 2023). In addition, in the unilateral ureter obstruction (UUO)-induced kidney fibrosis mouse model, FXR agonism reduces tubulointerstitial fibrosis by decreasing TGFβ-Smad3 signaling (Li et al, 2019).…”

“…The main function for FXR is regulating bile acid synthesis, conjugation, and transport, as well as lipid and glucose metabolism (Mori, et al, 2022;Rausch, et al, 2022). Emerging evidence demonstrates that FXR agonism can have positive actions on metabolic diseases and chronic kidney diseases (Jiao, et al, 2022;Kim, et al, 2023). The fact that metabolic and kidney diseases impact blood pressure regulation provide impetus for exploring PPAR and FXR manipulation to combat hypertension associated with metabolic and kidney diseases.…”

Dual soluble epoxide hydrolase inhibitor – farnesoid X receptor agonist interventional treatment attenuates renal inflammation and fibrosis

“…Potential targets for combating inflammation and renal fibrosis in CKD are the nuclear farnesoid X receptor (FXR) and the soluble epoxide hydrolase (sEH) enzyme ( 13 , 14 ). FXR expression is decreased in the human and rodent models of kidney disease and this decrease correlated with the level of inflammation and fibrosis in the kidney ( 13 , 15 ). Activation of FXR demonstrated kidney protective actions in animal models by decreasing kidney inflammation, oxidative stress, and fibrosis ( 16 , 17 ).…”

On the Cholesterol Raising Effect of Coffee Diterpenes Cafestol and 16-O-Methylcafestol: Interaction with Farnesoid X Receptor

“…Its endogenous ligands are conjugated and unconjugated bile acids such as cholic acid (CA) and chenodeoxycholic acid (CDCA), synthesized in the liver, and their derivatives lithocholic acid (LCA) and deoxycholic acid (DCA) ( Figure 1 ). The potency of bile acids in activating FXR is ranked as CDCA > DCA> LCA > CA [ 38 ].…”