A Study on the Role and Mechanism of Fenofibrate in Mice Renal Fibrosis Induced by Unilateral Ureteral Obstruction

XU Shan-shan, LI Sha, ZHANG Xia-xia, QI Jun-zhi, LI Gui-ying

Abstract

To investigate the role and mechanism of fenofibrate in renal fibrosis induced by unilateral ureteral obstruction in mice, and to provide a potential therapeutic target for renal fibrosis.  Methods  31 adult male C57BL/6J mice were randomly divided into Sham operation group (Sham, n=9), unilateral ureteral obstruction group (UUO, n=10) and unilateral ureteral obstruction+ fenofibrate group (UUO+Feno, n=12). Mice in both the UUO group and UUO+Feno groups were ligated with left ureter, and the the mice in Sham group freed the left ureter without ligation. From the second day after the operation, the UUO+Feno group was daily intragastrically administrated with 10 mg/kg of fenofibrate normal saline solution (final concentration was 0.08 mg/mL) for 15 d, and the other two groups were intragastrically administrated with the same amount of normal saline solution. At 15th day postoperation after intragastric administration, mice were sacrificed, and the concentration of serum creatinine and blood urea nitrogen were detected, the kidney tissues were performed HE staining, Masson dyeing and Sirius Red staining, and the content of renal tissue hydroxyproline were determined. Besides, immunohistochemical staining was used to explore the expressions of α-smooth muscle actin (α-SMA), Collegan-Ⅰ (COL Ⅰ) protein in renal tissue, Western blot was carried out to observe the changes of the expression levels of kidney α-SMA and COL Ⅰ proteins, and real-time fluorescent quantitative (RT)-PCR method was performed to detect the changes of mRNA expression levels of renal tissue fibrosis related genes matrix metalloproteinase (MMP)2, MMP9, COLⅠA1, COLⅠA2, tissue inhibitors of metalloproteinases (TIMP)-1, transforming growth factor (TGF)-β1, α-SMA.  Results  Compared with the Sham group, the serum creatinine and blood urea nitrogen levels of UUO group increased (P<0.05); compared with UUO group, the serum creatinine and blood urea nitrogen levels of UUO+Feno group were significantly lower (P<0.05). The results of HE staining, Masson staining, Sirius Red staining and renal hydroxyproline content indicated that the collagen deposition in UUO+Feno group was significantly reduced compared with that in UUO group. Immunohistochemical staining results showed that, compared with UUO group, the expression levels of α-SMA, COL Ⅰin kidney tissues of UUO+Feno group were significantly reduced; Western blot and RT-PCR results showed that compared with the UUO group, the mRNA and protein expression levels of fibrotic factors were significantly reduced in the UUO+Feno group (P<0.05).  Conclusion  Fenofibrate reduced mice renal fibrosis caused by unilateral ureteral obstruction and its mechanism may be relate to its regulation effect on the expressions of renal tissue fibrosis related genes.

 

Keywords: Renal fibrosis, Fenofibrate, Unilateral ureteral obstruction

 

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References


O'DONNELL M P. Renal tubulointerstitial fibrosis. New thoughts on its development and progression. Postgrad Med，2000，108: 159–162.

GRABACKA M， REISS K. Anticancer properties of PPARα—effects on cellular metabolism and inflammation. PPAR Res， 2008， 2008: 930705 [2019-10-24]. https://doi.org/10.1155/2008/930705.

XU N， WANG Q， JIANG S， et al. Fenofibrate improves vascular endothelial function and contractility in diabetic mice. Redox Bio，2019， 20: 87–97.

LI L， EMMETT N， MANN D， et al. Fenofibrate attenuates tubulointerstitial fibrosis and inflammation through suppression of nuclear factor-κB and transforming growth factor-β1/Smad3 in diabetic nephropathy. Exp Biol Med，2010，235(3): 383–391.

PAW M， WNUK D， KADZIOLKA D， et al. Fenofibrate reduces the asthma-related fibroblast-to-myofibroblast transition by TGF-Β/Smad2/3 signaling attenuation and connexin 43-dependent phenotype destabilization. Int J Mol Sci，2018，19(9): 2571.

LING L， YANG M， DING W， et al. Ghrelin attenuates UUO-induced renal fibrosis via attenuation of Nlrp3 inflammasome and endoplasmic reticulum stress. Am J Transl Res，2019，11(1): 131–141.

LIU Y. Cellular and molecular mechanisms of renal fibrosis. Nat Rev Nephrol，2011，7(12): 684–696.

NIKOLIC-PATERSON D J， WANG S， LAN H Y. Macrophages promote renal fibrosis through direct and indirect mechanisms. Kidney Int Suppl， 2014，4(1): 34–38.

WADA T， FURUICHI K， SAKAI N， et al. Gene therapy via blockade of monocyte chemoattractant protein-1 for renal fibrosis. J Am Soc Nephrol，2004，15(4): 940–948.

XUE H Y， YUAN L， CAO Y J， et al. Resveratrol ameliorates renal injury in spontaneously hypertensive rats by inhibiting renal micro-inflammation. Bioscience Rep，2016，36(3): e00339[2019-10-24].https://doi.org/10.1042/bsr20160035.

GILMORE T D. Introduction to NF-kappa B: players, pathways, perspectives. Oncogene，2006，25(51): 6680–6684.

NAGARAJAN R P， CHEN F， LI W， et al. Repression of transforming-growth-factor-β-mediated transcription by nuclear factor κB. Biochem J， 2000，348(3): 591–596.

CONWAY B， HUGHES J. Cellular orchestrators of renal fibrosis. QJM， 2012，105(7): 611–615.

SUN YB， QU X， CARUANA G， et al. The origin of renal fibroblasts/myofibroblasts and the signals that trigger fibrosis. Differentiation，2016，92(3): 102–107.

YISHU W， LEI P， YANGHE Z， et al. Fenofibrate improved interstitial fibrosis of renal allograft through inhibited epithelial-mesenchymal transition induced by oxidative stress. Oxid Med Cell Longev，2019，2019: 8936856[2019-12-22].https://doi.org/10.1155/2019/8936856..

KANG H M， AHN S H， CHOI P， et al. Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development. Nat Med，2015，21(1): 37–46.

PAGE-MCCAW A， EWALD A J， WERB Z. Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol，2007，8: 221–233.

ZEISBERG M， NEILSON E G. Mechanisms of tubulointerstitial fibrosis. Am Soc Nephrol，2010，21: 1819–1834.

XIA Z E， XI J L， SHI L. 3, 3'-Diindolylmethane ameliorates renal fibrosis through the inhibition of renal fibroblast activation in vivo and in vitro. Ren Fail，2018，40(1): 447–454.

LI H Y， LUI F， GAO C， et al. Protective effect of simvastatin on arterial plaque instability induced by p-cresyl sulfate. Eur Rev Med Pharmacol Sci，2018，22(18): 6149–6155.

AL-RASHEED N M， AL-AMIN M A. Fenofibrate attenuates diabetic nephropathy in experimental diabetic rat's model via suppression of augmented TGF-β1/Smad3 signaling pathway. Arch Physiol Biochem， 2016，122(4): 186–194.


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