https://doi.org/10.4081/ejh.2024.3917
Emodin improves renal fibrosis in chronic kidney disease by regulating mitochondrial homeostasis through the mediation of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α)
Submitted: 20 November 2023
Accepted: 27 March 2024
Published: 13 May 2024
Accepted: 27 March 2024
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All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Authors
Chronic kidney disease (CKD) is a leading public health issue associated with high morbidity worldwide. However, there are only a few effective therapeutic strategies for CKD. Emodin, an anthraquinone compound from rhubarb, can inhibit fibrosis in tissues and cells. Our study aims to investigate the antifibrotic effect of emodin and the underlying molecular mechanism. A unilateral ureteral obstruction (UUO)-induced rat model was established to evaluate the effect of emodin on renal fibrosis development. Hematoxylin and eosin staining, Masson’s trichrome staining, and immunohistochemistry staining were performed to analyze histopathological changes and fibrotic features after emodin treatment. Subsequently, a transforming growth factor-beta 1 (TGF-β1)-induced cell model was used to assess the inhibition of emodin on cell fibrosis in vitro. Furthermore, Western blot analysis and real-time quantitative reverse transcription-polymerase chain reaction were performed to validate the regulatory mechanism of emodin on renal fibrosis progression. As a result, emodin significantly improved histopathological abnormalities in rats with UUO. The expression of fibrosis biomarkers and mitochondrial biogenesis-related proteins also decreased after emodin treatment. Moreover, emodin blocked TGF-β1-induced fibrotic phenotype, lipid accumulation, and mitochondrial homeostasis in NRK-52E cells. Conversely, peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α) silencing significantly reversed these features in emodin-treated cells. Collectively, emodin plays an important role in regulating PGC-1α-mediated mitochondria function and energy homeostasis. This indicates that emodin exhibits great inhibition against renal fibrosis and acts as a promising inhibitor of CKD.
Lv JC, Zhang LX. Prevalence and disease burden of chronic kidney disease. Adv Exp Med Biol 2019;1165:3-15.
DOI: https://doi.org/10.1007/978-981-13-8871-2_1
Kovesdy CP. Epidemiology of chronic kidney disease: an update 2022. Kidney Int Suppl (2011) 2022;12:7-11.
DOI: https://doi.org/10.1016/j.kisu.2021.11.003
Matsushita K, van der Velde M, Astor BC, Woodward M, Levey AS, de Jong PE, et al. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet 2010;375:2073-81.
DOI: https://doi.org/10.1016/S0140-6736(10)60674-5
Mazzuchi N, Schwedt E, Sola L, Gonzalez C, Ferreiro A. Risk factors and prevention of end stage renal disease in Uruguay. Ren Fail 2006;28:617-25.
DOI: https://doi.org/10.1080/08860220600925677
Liu Y. Cellular and molecular mechanisms of renal fibrosis. Nat Rev Nephrol 2011;7:684-96.
DOI: https://doi.org/10.1038/nrneph.2011.149
Wei L-B, Ma Z-G, Ye R-G, Chen B-T, Zhan S-C, Huang H. Progress of intervention of renal interstitial fibrosis with Chinese traditional herbal medicine. Di Yi Jun Yi Da Xue Xue Bao 2002;22:946-8.
Muñoz-Félix JM, Martínez-Salgado C. Dissecting the involvement of Ras GTPases in kidney fibrosis. Genes (Basel) 2021;12:800.
DOI: https://doi.org/10.3390/genes12060800
Nogueira A, Pires MJ, Oliveira PA. Pathophysiological mechanisms of renal fibrosis: a review of animal models and therapeutic strategies. In Vivo 2017;31:1-22.
DOI: https://doi.org/10.21873/invivo.11019
Chevalier RL, Forbes MS, Thornhill BA. Ureteral obstruction as a model of renal interstitial fibrosis and obstructive nephropathy. 2009;75:1145-52.
DOI: https://doi.org/10.1038/ki.2009.86
Martínez-Klimova E, Aparicio-Trejo OE, Tapia E, Pedraza-Chaverri J. Unilateral ureteral obstruction as a model to investigate fibrosis-attenuating treatments. Biomoleculs 2019;9:141.
DOI: https://doi.org/10.3390/biom9040141
Boor P, Ostendorf T, Floege J. Renal fibrosis: novel insights into mechanisms and therapeutic targets. Nat Rev Nephrol 2010;6:643-56.
DOI: https://doi.org/10.1038/nrneph.2010.120
Liu Y. Renal fibrosis: new insights into the pathogenesis and therapeutics. Kidney Int 2006;69:213-7.
DOI: https://doi.org/10.1038/sj.ki.5000054
Eddy AA. Molecular basis of renal fibrosis. Pediatr Nephrol 2000;15:290-301.
DOI: https://doi.org/10.1007/s004670000461
Ma TT, Meng XM. TGF-beta/Smad and renal fibrosis. Adv Exp Med Biol 2019;1165:347-64.
DOI: https://doi.org/10.1007/978-981-13-8871-2_16
Martinez-Klimova E, Aparicio-Trejo OE, Gomez-Sierra T, Jimenez-Uribe AP, Bellido B, Pedraza-Chaverri J. Mitochondrial dysfunction and endoplasmic reticulum stress in the promotion of fibrosis in obstructive nephropathy induced by unilateral ureteral obstruction. Biofactors 2020;46:716-33.
DOI: https://doi.org/10.1002/biof.1673
Scarpulla RC. Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochim Biophys Acta 2011;1813:1269-78.
DOI: https://doi.org/10.1016/j.bbamcr.2010.09.019
Nam BY, Jhee JH, Park J, Kim S, Kim G, Park JT, et al. PGC-1alpha inhibits the NLRP3 inflammasome via preserving mitochondrial viability to protect kidney fibrosis. Cell Death Dis 2022;13:31.
DOI: https://doi.org/10.1038/s41419-021-04480-3
Chambers JM, Wingert RA. PGC-1alpha in disease: recent renal insights into a versatile metabolic regulator. Cells 2020;9:2234.
DOI: https://doi.org/10.3390/cells9102234
Han SH, Wu MY, Nam BY, Park JT, Yoo TH, Kang SW, et al. PGC-1alpha protects from notch-induced kidney fibrosis development. J Am Soc Nephrol 2017;28:3312-22.
DOI: https://doi.org/10.1681/ASN.2017020130
HaoShang, Jia X, Liu H, Zhang X, Shao Y. A comprehensive review of emodin in fibrosis treatment. Fitoterapia 2023;165:105358.
DOI: https://doi.org/10.1016/j.fitote.2022.105358
Ma L, Li H, Zhang S, Xiong X, Chen K, Jiang P, et al. Emodin ameliorates renal fibrosis in rats via TGF-beta1/Smad signaling pathway and function study of Smurf 2. Int Urol Nephrol 2018;50:373-82.
DOI: https://doi.org/10.1007/s11255-017-1757-x
Yang F, Deng L, Li J, Chen M, Liu Y, Hu Y, Zhong W. Emodin retarded renal fibrosis through regulating HGF and TGFbeta-Smad signaling pathway. Drug Des Devel Ther 2020;14:3567-75.
DOI: https://doi.org/10.2147/DDDT.S245847
Xu L, Gao J, Huang D, Lin P, Yao D, Yang F, et al. Emodin ameliorates tubulointerstitial fibrosis in obstructed kidneys by inhibiting EZH2. Biochem Biophys Res Commun 2021;534:279-85.
DOI: https://doi.org/10.1016/j.bbrc.2020.11.094
Meng X-M, Nikolic-Paterson DJ, Lan HY. TGF-β: the master regulator of fibrosis. Nat Rev Nephrol 2016;12:325-38.
DOI: https://doi.org/10.1038/nrneph.2016.48
Tanaka Y, Kume S, Araki S, Isshiki K, Chin-Kanasaki M, Sakaguchi M, et al. Fenofibrate, a PPARalpha agonist, has renoprotective effects in mice by enhancing renal lipolysis. Kidney Int 2011;79:871-82.
DOI: https://doi.org/10.1038/ki.2010.530
Li L, Emmett N, Mann D, Zhao X. Fenofibrate attenuates tubulointerstitial fibrosis and inflammation through suppression of nuclear factor-κ B and transforming growth factor-β 1/Smad3 in diabetic nephropathy. Exp Biol Med (Maywood) 2010;235:383-91.
DOI: https://doi.org/10.1258/ebm.2009.009218
Kurtz DM, Rinaldo P, Rhead WJ, Tian L, Millington DS, Vockley J, et al. Targeted disruption of mouse long-chain acyl-CoA dehydrogenase gene reveals crucial roles for fatty acid oxidation. Proc Natl Acad Sci USA 1998;95:15592-7.
DOI: https://doi.org/10.1073/pnas.95.26.15592
Hu G, Xu L, Ma Y, Kohzuki M, Ito O. Chronic exercise provides renal-protective effects with upregulation of fatty acid oxidation in the kidney of high fructose-fed rats. Am J Physiol Renal Physiol 2020;318:F826-34.
DOI: https://doi.org/10.1152/ajprenal.00444.2019
Gai Z, Wang T, Visentin M, Kullak-Ublick GA, Fu X, Wang Z. Lipid accumulation and chronic kidney disease. Nutrients 2019;11:722.
DOI: https://doi.org/10.3390/nu11040722
Kang HM, Ahn SH, Choi P, Ko YA, Han SH, Chinga F, et al. Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development. Nat Med 2015;21:37-46.
DOI: https://doi.org/10.1038/nm.3762
Zschiedrich S, Bork T, Liang W, Wanner N, Eulenbruch K, Munder S, et al. Targeting mTOR signaling can prevent the progression of FSGS. J Am Soc Nephrol 2017;28:2144-57.
DOI: https://doi.org/10.1681/ASN.2016050519
Villena JA. New insights into PGC-1 coactivators: redefining their role in the regulation of mitochondrial function and beyond. FEBS J 2015;282:647-72.
DOI: https://doi.org/10.1111/febs.13175
Tontonoz P, Hu E, Spiegelman BM. Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell 1994;79:1147-56.
DOI: https://doi.org/10.1016/0092-8674(94)90006-X
Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 1998;92:829-39.
DOI: https://doi.org/10.1016/S0092-8674(00)81410-5
Lin J, Handschin C, Spiegelman BM. Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab 2005;1:361-70.
DOI: https://doi.org/10.1016/j.cmet.2005.05.004
Fontecha-Barriuso M, Martin-Sanchez D, Martinez-Moreno JM, Monsalve M, Ramos AM, Sanchez-Nino MD, et al. The role of PGC-1alpha and mitochondrial biogenesis in kidney diseases. Biomolecules 2020;10:347.
DOI: https://doi.org/10.3390/biom10020347
Miguel V, Tituaña J, Herrero JI, Herrero L, Serra D, Cuevas P, et al. Renal tubule Cpt1a overexpression protects from kidney fibrosis by restoring mitochondrial homeostasis. J Clin Invest 2021;131:e140695.
DOI: https://doi.org/10.1172/JCI140695
Afshinnia F, Rajendiran TM, Soni T, Byun J, Wernisch S, Sas KM, et al. Impaired β-oxidation and altered complex lipid fatty acid partitioning with advancing CKD. J Am Soc Nephrol 2018;29:295.
DOI: https://doi.org/10.1681/ASN.2017030350
Ethics Approval
The animal experiments were conducted with protocols approved by the Experimental Animal Ethics Committee of Shenzhen Hospital of Beijing University of Traditional Chinese MedicineSupporting Agencies
Shenzhen Hospital of Beijing University of Traditional Chinese MedicineHow to Cite
Feng, L., Lin, Z., Tang, Z., Zhu, L., Xu, S., Tan, X., … Tan, Q. (2024). Emodin improves renal fibrosis in chronic kidney disease by regulating mitochondrial homeostasis through the mediation of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α). European Journal of Histochemistry, 68(2). https://doi.org/10.4081/ejh.2024.3917
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