FNDC5/Irisin Mediates the Protective Effect of Resistance Exercise Against Myocardial Infarction-Induced Renal Injury by Improving Vascular Rarefaction in Mice

Abstract

The rarefaction of renal vessels caused by ischemic heart injury is an important factor leading to the occurrence of type 2 cardiorenal syndrome (CRS type 2), and it will eventually develop into the renal failure. Resistance exercise is an anaerobic form of exercise that can induce local angiogenesis in tissues and organs and improve organ function. However, whether resistance exercise alleviates renal vascular scarcity in myocardial infarction (MI) mice and the potential mechanisms underlying this effect remain incompletely understood. In this study, wild-type and Fndc5 knockout mice were subjected to MI modeling and subsequently underwent resistance exercise training. Our findings demonstrate that MI induced renal oxidative stress, apoptosis, and microvascular rarefaction, whereas resistance exercise significantly attenuated these pathological changes. Notably, Fndc5 knockout diminished the protective effects of resistance exercise. Human umbilical vein endothelial cells (HUVECs) were cultured and treated to investigate the molecular mechanisms. Both recombinant Irisin and AICAR effectively inhibited H₂O₂-induced oxidative stress and apoptosis, promoted cell migration, and enhanced renal tubule formation. Importantly, Irisin-mediated improvements in cell migration and tubulogenesis were dependent on activation of both AMPK and Akt-eNOS signaling pathways. The resistance exercise promotes renal angiogenesis through the AMPK and Akt-eNOS signaling pathway mediated by FNDC5/Irisin, thereby alleviating MI-induced renal oxidative stress and cell apoptosis.

Keywords

Myocardial infarction / Resistance exercise / FNDC5/Irisin / Kidney / Angiogenesis

References

[1] Ambrosetti M, Abreu A, Corrà U, Davos CH, Hansen D, Frederix I, Iliou MC, Pedretti RFE, Schmid JP, Vigorito C, Voller H, Wilhelm M, Piepoli MF, Bjarnason-Wehrens B, Berger T, Cohen-Solal A, Cornelissen V, Dendale P, Doehner W, Gaita D, Gevaert AB, Kemps H, Kraenkel N, Laukkanen J, Mendes M, Niebauer J, Simonenko M, Zwisler AO. Secondary prevention through comprehensive cardiovascular rehabilitation: from knowledge to implementation. 2020 update. A position paper from the Secondary Prevention and Rehabilitation Section of the European Association of Preventive Cardiology. Eur J Prev Cardiol, 2021, 28(5): 460-495

[2] Arcidiacono T, Magni G, Macrina L, Sirtori M, Belloni C, Premaschi S, Lanzani C, Simonini M, Citterio L, Locatelli M, Rubinacci A, Vezzoli G. Serum Irisin may predict cardiovascular events in elderly patients with chronic kidney disease stage 3–5. J Ren Nutr., 2022, 32(3): 282-91

[3] Askari H, Rajani SF, Poorebrahim M, Haghi-Aminjan H, Raeis-Abdollahi E, Abdollahi M. A glance at the therapeutic potential of Irisin against diseases involving inflammation, oxidative stress, and apoptosis: an introductory review. Pharmacol Res, 2018, 129: 44-55

[4] Banerjee D, Ali MA, Wang AY, Jha V. Acute kidney injury in acute heart failure-when to worry and when not to worry?. Nephrol Dial Transplant, 2024, 40(1): 10-8

[5] Bao JF, She QY, Hu PP, Jia N, Li A. Irisin, a fascinating field in our times. Trends Endocrinol Metab, 2022, 33(9): 601-13

[6] Bi J, Zhang J, Ren Y, Du Z, Zhang Y, Liu C, Wang Y, Zhang L, Shi Z, Wu Z, Lv Y, Wu R. Exercise hormone Irisin mitigates endothelial barrier dysfunction and microvascular leakage-related diseases. JCI Insight, 2020, 5(13): e136277

[7] Boström P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, Rasbach KA, Boström EA, Choi JH, Long JZ, Kajimura S, Zingaretti MC, Vind BF, Tu H, Cinti S, Højlund K, Gygi SP, Spiegelman BM. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature, 2012, 4817382463-8

[8] Chen JF, Liu F, Qiao MM, Shu HZ, Li XC, Peng C, Xiong L. Vasorelaxant effect of curcubisabolanin A isolated from curcuma longa through the PI3K/Akt/eNOS signaling pathway. J Ethnopharmacol., 2022, 294 115332

[9] Chi C, Fu H, Li YH, Zhang GY, Zeng FY, Ji QX, Shen QR, Wang XJ, Li ZC, Zhou CC, Sun DY, Fu JT, Wu WB, Zhang PP, Zhang JB, Liu J, Shen FM, Li DJ, Wang P. Exerkine fibronectin type-III domain-containing protein 5/irisin-enriched extracellular vesicles delay vascular ageing by increasing SIRT6 stability. Eur Heart J, 2022, 43(43): 4579-95

[10] Cui Y, Yu L, Cong W, Jiang S, Qiu X, Wei C, Zheng G, Mao J, Liu R, Patzak A, Persson PB, Chen J, Zhao L, Lai EY. Irisin preserves mitochondrial integrity and function in tubular epithelial cells after ischemia-reperfusion-induced acute kidney injury. Acta Physiol Oxf, 2024, 240(9 e14211

[11] Deus LA, Corrêa HL, Neves RVP, Reis AL, Honorato FS, Araújo TB, Souza MK, Haro AS, Silva VL, Barbosa JMDS, Padula IA, Andrade RV, Simões HG, Prestes J, Stone WJ, Melo GF, Rosa TS. Metabolic and hormonal responses to chronic blood-flow restricted resistance training in chronic kidney disease: a randomized trial. Appl Physiol Nutr Metab, 2022, 472): 183-94

[12] Ebert T, Focke D, Petroff D, Wurst U, Richter J, Bachmann A, Lössner U, Kralisch S, Kratzsch J, Beige J, Bast I, Anders M, Blüher M, Stumvoll M, Fasshauer M. Serum levels of the myokine Irisin in relation to metabolic and renal function. Eur J Endocrinol, 2014, 170(4): 501-6

[13] Faleiros CM, Francescato HD, Papoti M, Chaves L, Silva CG, Costa RS, Coimbra TM. Effects of previous physical training on adriamycin nephropathy and its relationship with endothelial lesions and angiogenesis in the renal cortex. Life Sci, 2017, 169: 43-51

[14] Fan X, Zhang X, Liu LC, Kim AY, Curley SP, Chen X, Dworkin LD, Cooper CJ, Gupta R. Interleukin-10 attenuates renal injury after myocardial infarction in diabetes. J Investig Med, 2022, 70(5): 1233-42

[15] Franscescon F, Bianchini MC, Gheller E, Pomianowsky CE, Puhle JG, Lima LZM, Bizuti MR, Marafon F, Haag FB, de Resende E, Silva DT. Resistance physical exercise modulates metabolic adipokines, decreases body weight, and improves glomerular filtration in patients with chronic kidney disease in hemodialysis. Mol Cell Biochem, 2025, 480(4): 2525-38

[16] Honda T, Hirakawa Y, Nangaku M. The role of oxidative stress and hypoxia in renal disease. Kidney Res Clin Pract, 2019, 38(4): 414-26

[17] Horii N, Uchida M, Hasegawa N, Fujie S, Oyanagi E, Yano H, Hashimoto T, Iemitsu M. Resistance training prevents muscle fibrosis and atrophy via down-regulation of C1q-induced Wnt signaling in senescent mice. FASEB J, 2018, 32(7): 3547-59

[18] Kim JH, Lee S, Jang H, Jung S, Jung MH, Yun JW, Jeon H, Kim HJ, Chang SH, Lee EJ, Kim HS. Transcriptional intermediary factor 1γ-induced irisin in skeletal muscle attenuates renal fibrosis in diabetic nephropathy. J Cachexia Sarcopenia Muscle., 2025, 16(2 e13810

[19] Li H, Qin S, Liang Q, Xi Y, Bo W, Cai M, Tian Z. Exercise training enhances myocardial mitophagy and improves cardiac function via Irisin/FNDC5-PINK1/Parkin pathway in MI mice. Biomedicines, 2021, 96): 701

[20] Liang J, Qiu Y, Fu T, Li J, Xiao F, Xing G, Cai H, Tong Y. Mitochondrial oxidative stress and vascular remodeling in uric acid nephropathy: mechanistic insights and therapeutic implications. Int J Nephrol Renovasc Dis, 2025, 18: 281-301

[21] Liao Q, Qu S, Tang LX, Li LP, He DF, Zeng CY, Wang WE. Irisin exerts a therapeutic effect against myocardial infarction via promoting angiogenesis. Acta Pharmacol Sin, 2019, 40(10): 1314-21

[22] Liao L, Gong L, Zhou M, Xue X, Li Y, Peng C. Leonurine ameliorates oxidative stress and insufficient angiogenesis by regulating the PI3K/Akt-eNOS signaling pathway in H₂O₂-induced HUVECs. Oxid Med Cell Longev, 2021, 2021 9919466

[23] Liu Y, Fu Y, Liu Z, Shu S, Wang Y, Cai J, Tang C, Dong Z. Irisin is induced in renal ischemia-reperfusion to protect against tubular cell injury via suppressing p53. Biochimica et Biophysica Acta (BBA), 2020, 1866(7 165792

[24] Lu J, Xiang G, Liu M, Mei W, Xiang L, Dong J. Irisin protects against endothelial injury and ameliorates atherosclerosis in Apolipoprotein E-Null diabetic mice. Atherosclerosis, 2015, 432): 438-48

[25] Luo M, Luo S, Xue Y, Chang Q, Yang H, Dong W, Zhang T, Cao S. Aerobic exercise inhibits renal EMT by promoting Irisin expression in SHR. iScience, 2023, 26(2): 105990

[26] Matsushita K, Saritas T, Eiwaz MB, McClellan N, Coe I, Zhu W, Ferdaus MZ, Sakai LY, McCormick JA, Hutchens MP. The acute kidney injury to chronic kidney disease transition in a mouse model of acute cardiorenal syndrome emphasizes the role of inflammation. Kidney Int, 2020, 97195-105

[27] Minuti A, Raffaele I, Scuruchi M, Lui M, Muscarà C, Calabrò M. Role and functions of Irisin: a perspective on recent developments and neurodegenerative diseases. Antioxidants (Basel), 2025, 14(5 554

[28] Miyaji T, Hu X, Yuen PS, Muramatsu Y, Iyer S, Hewitt SM, Star RA. Ethyl pyruvate decreases sepsis-induced acute renal failure and multiple organ damage in aged mice. Kidney Int, 2003, 645): 1620-31

[29] Molitoris BA. Therapeutic translation in acute kidney injury: the epithelial/endothelial axis. J Clin Invest, 2014, 124(6): 2355-63

[30] Ozer JS, Dieterle F, Troth S, Perentes E, Cordier A, Verdes P, Staedtler F, Mahl A, Grenet O, Roth DR, Wahl D, Legay F, Holder D, Erdos Z, Vlasakova K, Jin H, Yu Y, Muniappa N, Forest T, Clouse HK, Reynolds S, Bailey WJ, Thudium DT, Topper MJ, Skopek TR, Sina JF, Glaab WE, Vonderscher J, Maurer G, Chibout SD, Sistare FD, Gerhold DL. A panel of urinary biomarkers to monitor reversibility of renal injury and a serum marker with improved potential to assess renal function. Nat Biotechnol, 2010, 28(5): 486-94

[31] Podkowińska A, Formanowicz D. Chronic kidney disease as oxidative stress- and inflammatory-mediated cardiovascular disease. Antioxid (Basel), 2020, 9(8): 752

[32] Pontremoli R, Borghi C, Perrone Filardi P. Renal protection in chronic heart failure: focus on sacubitril/valsartan. Eur Heart J Cardiovasc Pharmacother, 2021, 75445-52

[33] Rabadi MM, Verde MR, Camilliere M, Vecchio N, Kandhi S, Sekulic M, Wolin MS, Ratliff BB. Renal and vascular functional decline in aged low birth weight murine adults. Kidney Blood Press Res, 2024, 49(1): 1075-90

[34] Rangel Silvares R, da Nunes Goulart Silva Pereira E, Eduardo Ilaquita Flores E, Lino Rodrigues K, Ribeiro Silva A, Gonçalves-de-Albuquerque CF, Daliry A. High-fat diet-induced kidney alterations in rats with metabolic syndrome: endothelial dysfunction and decreased antioxidant defense. Diabetes Metab Syndr Obes, 2019, 12: 1773-1781

[35] Rodríguez C, Sánchez A, Sáenz-Medina J, Muñoz M, Hernández M, López M, Rivera L, Contreras C, Prieto D. Activation of AMP kinase ameliorates kidney vascular dysfunction, oxidative stress and inflammation in rodent models of obesity. Br J Pharmacol, 2021, 178(20): 4085-103

[36] Savira F, Magaye R, Liew D, Reid C, Kelly DJ, Kompa AR, Sangaralingham SJ, Burnett JCJr, Kaye D, Wang BH. Cardiorenal syndrome: multi-organ dysfunction involving the heart, kidney and vasculature. Br J Pharmacol, 2020, 177(13): 2906-2922

[37] Song S, Shi C, Bian Y, Yang Z, Mu L, Wu H, Duan H, Shi Y. Sestrin2 remedies podocyte injury via orchestrating TSP-1/TGF-β1/Smad3 axis in diabetic kidney disease. Cell Death Dis, 2022, 13(7): 663

[38] Souza MK, Neves RVP, Rosa TS, Cenedeze MA, Arias SCA, Fujihara CK, Bacurau RFP, Câmara NOS, Moraes MR, Pacheco E Silva Filho A. Resistance training attenuates inflammation and the progression of renal fibrosis in chronic renal disease. Life Sci, 2018, 206: 93-97

[39] Sueyoshi M, Fukunaga M, Mei M, Nakajima A, Tanaka G, Murase T, Narita Y, Hirata S, Kadowaki D. Effects of lactulose on renal function and gut microbiota in adenine-induced chronic kidney disease rats. Clin Exp Nephrol, 2019, 23(7): 908-19

[40] Tanaka T, Nangaku M. Angiogenesis and hypoxia in the kidney. Nat Rev Nephrol, 2013, 9(4): 211-22

[41] Thanapongsatorn P, Tanomchartchai A, Assavahanrit J. Long-term outcomes of acute kidney injury in acute decompensated heart failure: identifying true cardiorenal syndrome and unveiling prognostic significance. Kidney Res Clin Pract, 2024, 43(4): 480-91

[42] Virzì GM, Zhang J, Nalesso F, Ronco C, McCullough PA. The role of dendritic and endothelial cells in cardiorenal syndrome. Cardiorenal Med, 2018, 8(2): 92-104

[43] Volterrani M, Caminiti G, Perrone MA, Cerrito A, Franchini A, Manzi V, Iellamo F. Effects of concurrent, within-session, aerobic and resistance exercise training on functional capacity and muscle performance in elderly male patients with chronic heart failure. J Clin Med., 2023, 12(3): 750

[44] Wang LX, Zhu XM, Yao YM. Sestrin2: its potential role and regulatory mechanism in host immune response in diseases. Front Immunol, 2019, 10: 2797

[45] Wang Y, Tian M, Tan J, Pei X, Lu C, Xin Y, Deng S, Zhao F, Gao Y, Gong Y. Irisin ameliorates neuroinflammation and neuronal apoptosis through integrin αVβ5/AMPK signaling pathway after intracerebral hemorrhage in mice. J Neuroinflammation, 2022, 19182

[46] Xi Y, Hao M, Liang Q, Li Y, Gong DW, Tian Z. Dynamic resistance exercise increases skeletal muscle-derived FSTL1 inducing cardiac angiogenesis via DIP2A-Smad2/3 in rats following myocardial infarction. J Sport Health Sci, 2021, 105594-603

[47] Xi Y, Gong DW, Tian Z. FSTL1 as a potential mediator of exercise-induced cardioprotection in post-myocardial infarction rats. Sci Rep, 2016, 6: 32424

[48] Xie J, Yuan Y, Yao G, Chen Z, Yu W, Zhu Q. Nucleoporin 160 (NUP160) inhibition alleviates diabetic nephropathy by activating autophagy. Bioengineered, 2021, 12(1): 6390-402

[49] Xu X, Zhang B, Wang Y, Shi S, Lv J, Fu Z, Gao X, Li Y, Wu H, Song Q. Renal fibrosis in type 2 cardiorenal syndrome: an update on mechanisms and therapeutic opportunities. Biomed Pharmacother., 2023, 164: 114901

[50] Yang Z, Wei J, Wang Y, Du Y, Song S, Li J, Su Z, Shi Y, Wu H. Irisin ameliorates renal tubulointerstitial fibrosis by regulating the Smad4/β-Catenin pathway in diabetic mice. Diabetes Metab Syndr Obes, 2023, 16: 1577-93

[51] Zhang Y, Nakano D, Guan Y, Hitomi H, Uemura A, Masaki T, Kobara H, Sugaya T, Nishiyama A. A sodium-glucose cotransporter 2 inhibitor attenuates renal capillary injury and fibrosis by a vascular endothelial growth factor-dependent pathway after renal injury in mice. Kidney Int, 2018, 94(3): 524-35

[52] Zhang J, Bi J, Ren Y, Du Z, Li T, Wang T, Zhang L, Wang M, Wei S, Lv Y, Wu R. Involvement of GPX4 in irisin’s protection against ischemia reperfusion-induced acute kidney injury. J Cell Physiol, 2021, 236(2): 931-45

[53] Zhao L, Zhang T, Zhao Z, Ren X, Huang X, Hao Y, Zhou X. Irisin improves acute kidney injury induced by ischemia-reperfusion through targeting energy metabolism reprogramming. Int J Biol Macromol, 2025, 323(Pt 2): 147073

[54] Zheng Z, Wang M, Cheng C, Liu D, Wu L, Zhu J, Qian X. Ginsenoside Rb1 reduces H₂O₂-induced HUVEC dysfunction by stimulating the sirtuin-1/AMP-activated protein kinase pathway. Mol Med Rep., 2020, 221247-56

[55] Zhong X, Tang TT, Shen AR, Cao JY, Jing J, Wang C, Zhu XX, Wen Y, Li ZL, Wang B, Qin SF, Liu BC, Lv LL. Tubular epithelial cells-derived small extracellular vesicle-VEGF-A promotes peritubular capillary repair in ischemic kidney injury. NPJ Regen Med., 2022, 7173

Funding

National Natural Science Foundation of China(32171128)

Fundamental Research Funds for the Central Universities(GK202301013)

RIGHTS & PERMISSIONS

Beijing Sport University