Role of FXR in Renal Physiology and Kidney Diseases

Abstract

Farnesoid X receptor, also known as the bile acid receptor, belongs to the nuclear receptor (NR) superfamily of ligand-regulated transcription factors, which performs its functions by regulating the transcription of target genes. FXR is highly expressed in the liver, small intestine, kidney and adrenal gland, maintaining homeostasis of bile acid, glucose and lipids by regulating a diverse array of target genes. It also participates in several pathophysiological processes, such as inflammation, immune responses and fibrosis. The kidney is a key organ that manages water and solute homeostasis for the whole body, and kidney injury or dysfunction is associated with high morbidity and mortality. In the kidney, FXR plays an important role in renal water reabsorption and is thought to perform protective functions in acute kidney disease and chronic kidney disease, especially diabetic kidney disease. In this review, we summarize the recent advances in the understanding of the physiological and pathophysiological function of FXR in the kidney.

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

“…Indeed, genetic or pharmacological sEH inhibition markedly reduced renal fibrosis and extracellular matrix protein formation in UUO mice by acting on multiple fibrotic pathophysiological events ( 19 , 20 ). The other pharmacophore of DM509, FXR is highly expressed within the kidney, and studies have demonstrated that FXR activation can mitigate renal injury ( 13 , 16 ). FXR levels were inversely correlated with CKD progression in mice and the degree of interstitial fibrosis in humans ( 34 ).…”

“…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 ).…”

FXR Friend-ChIPs in the Enterohepatic System

“…In the brain, FXR expression is correlated with Alzheimer's disease and loss of FXR reduces -amyloid induced brain injury (46). FXR increases water reabsorption and promotes renal medullary collecting duct cell survival, ultimately affecting urine concentration during dehydration (47). Besides, adipose-specific overexpression of FXR promotes brown adipose tissue whitening and fibrosis (48).…”

“…There is little information on FXR function in important sensory cells like cholangiocytes, tuft cells in the intestine, or chromaffin cells of the adrenals (PMID: 24068255, PMID: 35245089, PMID: 17963822). The ubiquitous expression of FXR in various organs, while less than in hepatocytes and ileal enterocytes, makes it crucial to understand FXR activation in a whole-body setting (PMID: 36988391) (44)(45)(46)(47)49).…”

Nuclear Receptors in Health and Diseases

“…FXR is also known to play a critical role in renal water reabsorption and is believed to provide a protective effect in both acute and chronic renal diseases, including those related to diabetes. Xiaoyan Zhang's laboratory has summarized the recent developments in understanding the physiological and pathophysiological roles of FXR in the kidney [17].…”