Farnesoid X receptor activation protects the kidney from ischemia-reperfusion damage

Abstract

Farnesoid X receptor (FXR) activation has been reported to reduce inflammation and oxidative stress. Because both inflammation and oxidative stress are critical for tissue destruction during kidney ischemia reperfusion (I/R) injury, we investigated the protective role of FXR against kidney damage induced by I/R in mice. Mice undergoing renal I/R developed the typical features of acute kidney injury (AKI): increased creatinine, albuminuria, tubular necrosis and apoptosis. Inflammatory cytokine production and oxidative stress were also markedly increased. In mice pretreated with 6-ethyl-chenodeoxycholic acid (6-ECDCA), a selective FXR agonist, I/R induced changes were prevented and renal function and structure were improved. Moreover, FXR activation also effectively prevented the subsequent progression of AKI to chronic kidney disease (CKD) by ameliorating glomerulosclerosis and interstitial fibrosis and by suppressing fibrogenic gene expression. FXR mRNA levels were inversely correlated with the progression to CKD in mice and with the degree of interstitial fibrosis in human biopsies. In further experiments administering 6-ECDCA to renal proximal tubular cells cultured under hypoxia, the renoprotective effects of FXR activation were associated with inhibition of oxidative and ER stress and with increased antioxidant activity. In conclusion, FXR agonists may have a therapeutic role in conditions associated with ischemic kidney damage.

The farnesoid X receptor agonist EDP‐305 reduces interstitial renal fibrosis in a mouse model of unilateral ureteral obstruction

“…FXR is highly expressed within the kidney, and studies have demonstrated that FXR activation can mitigate renal injury. FXR activation using obeticholic acid has been shown to decrease inflammation antioxidative stress as well as tubulointerstitial fibrosis in an ischemic reperfusion model of renal injury (37). Consistently, we demonstrated the expression of FXR is decreased during chronic injury after ureteral ligation.…”

Betulinic acid alleviates endoplasmic reticulum stress‐mediated nonalcoholic fatty liver disease through activation of farnesoid X receptors in mice

“…Notably, the pathological characteristics associated with chronic ER stress are strikingly similar to hepatic FXR depletion. Furthermore, several studies have demonstrated amelioration of maladaptive ER signalling via FXR agonism in the kidney (Gai et al, ; Marquardt et al, ). These observations support the notion that FXR agonism may be involved in hepatic ER stress alleviation, although a recent study indicated that FXR activation induces hepatic ER stress via targeting XBP1/IRE1α signalling (Liu et al, ).…”

“…Notably, previous studies have revealed that intrahepatic bile acid metabolism is associated with ER stress (Chung, Kim, Lee, An, & Kwon, ), most hepatic ER stress coexists with a lowered expression of FXRs in ageing mice (Lefebvre & Staels, ), and multiple FXR agonists have been shown to protect cells from ER stress (Chung et al, ; Ozcan et al, ). FXR activation has a cytoprotective effect in the kidney, which is mediated by supressing ER stress (Gai et al, ). These findings suggest that FXR activation could reduce hepatic ER stress, and this effect may be involved in the anti‐NAFLD effect of FXR agonists.…”

Effects of Farnesiferol B on Ischemia-Reperfusion-Induced Renal Damage, Inflammation, and NF-κB Signaling

“…I/R is often associated with oxidative stress, with existing evidence suggesting that oxidative stress is a paramount contributor in causing kidney damage [25]. Therefore, the effect of Farnesiferol B on oxidative stress in the kidney after I/R was evaluated.…”