Fenofibrate Improved Interstitial Fibrosis of Renal Allograft through Inhibited Epithelial-Mesenchymal Transition Induced by Oxidative Stress

Abstract

The best treatment for end-stage renal disease is renal transplantation. However, it is often difficult to maintain a renal allograft healthy for a long time following transplantation. Interstitial fibrosis and tubular atrophy (IF/TA) are significant histopathologic characteristics of a compromised renal allograft. There is no effective therapy to improve renal allograft function once IF/TA sets in. Although there are many underlying factors that can induce IF/TA, the pathogenesis of IF/TA has not been fully elucidated. It has been found that epithelial-mesenchymal transition (EMT) significantly contributes to the development of IF/TA. Oxidative stress is one of the main causes that induce EMT in renal allografts. In this study, we have used H2O2 to induce oxidative stress in renal tubular epithelial cells (NRK-52e) of rats. We also pretreated NRK-52e cells with an antioxidant (N-acetyl L-cysteine (NAC)) 1 h prior to the treatment with H2O2. Furthermore, we used fenofibrate (a peroxisome proliferator-activated receptor α agonist) to treat NRK-52e cells and a renal transplant rat model. Our results reveal that oxidative stress induces EMT in NRK-52e cells, and pretreatment with NAC can suppress EMT in these cells. Moreover, fenofibrate suppresses fibrosis by ameliorating oxidative stress-induced EMT in a rat model. Thus, fenofibrate may effectively prevent the development of fibrosis in renal allograft and improve the outcome.

microRNA Crosstalk Influences Epithelial-to-Mesenchymal, Endothelial-to-Mesenchymal, and Macrophage-to-Mesenchymal Transitions in the Kidney

“…Interstitial fibrosis is the key characteristics in chronic renal allograft injury (Boor and Floege, 2015; Bontha et al, 2017). In the chronic renal allograft injury, diverse ranges of immune and nonimmune responses cause the macrophages to undergo macrophage-to-mesenchymal transition (MMT) process (Wang et al, 2019; Zhou et al, 2019). Higher rate of MMT contributes in the development of interstitial fibrosis (Wang et al, 2017).…”

Bortezomib limits renal allograft interstitial fibrosis by inhibiting NF-κB/TNF-α/Akt/mTOR/P70S6K/Smurf2 pathway via IκBα protein stabilization

“…Our research has several limitations, the current validation of the effects of BZM on EMT and fibrosis was only conducted in a cell line 42 . In addition to myofibroblast differentiation, other factors were reported to have indirect profibrotic effects, such as oxidative stress 43,44 , activation of Wnt and Hedgehog signaling pathways [45][46][47] , fatty acids oxidation 48,49 , and cellular senescence 50,51 . Whether BZM inhibits allograft fibrosis through other factors remains to be further studied.…”

Fenofibrate inhibits TGF‐β‐induced myofibroblast differentiation and activation in human lung fibroblasts in vitro

“…Recent animal studies have shown that treatment with FF decreases experimental fibrosis in the retina, lungs, liver, heart, and kidneys [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. FF is a relatively safe and inexpensive agent widely used in clinical practice for treating hyperlipidemia.…”

“…Notably, recent clinical studies on patients with diabetes have revealed that FF has protective effects on retinopathy and nephropathy [ 11 , 12 ]. Moreover, several animal studies have shown that FF inhibits experimental fibrosis in different organs, including the retina, heart, liver, kidney, and lung [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. For example, the oral administration of FF in rats has been shown to attenuate the severity of bleomycin‐induced pulmonary fibrosis [ 20 ].…”