Exosomes on the development and progression of renal fibrosis

Abstract

Renal fibrosis is a prevalent pathological alteration that occurs throughout the progression of primary and secondary renal disorders towards end-stage renal disease. As a complex and irreversible pathophysiological phenomenon, it includes a sequence of intricate regulatory processes at the molecular and cellular levels. Exosomes are a distinct category of extracellular vesicles that play a crucial role in facilitating intercellular communication. Multiple pathways are regulated by exosomes produced by various cell types, including tubular epithelial cells and mesenchymal stem cells, in the context of renal fibrosis. Furthermore, research has shown that exosomes present in bodily fluids, including urine and blood, may be indicators of renal fibrosis. However, the regulatory mechanism of exosomes in renal fibrosis has not been fully elucidated. This article reviewed and analysed the various mechanisms by which exosomes regulate renal fibrosis, which may provide new ideas for further study of the pathophysiological process of renal fibrosis and targeted treatment of renal fibrosis with exosomes.

References

[1] NastaseMV, Zeng-Brouwers J, WygreckaM, SchaeferL. Targeting renal fibrosis: mechanisms and drug delivery systems. Adv Drug Deliv Rev. 2018;129:295-307.

[2] HumphreysBD. Mechanisms of renal fibrosis. Annu Rev Physiol. 2018;80:309-326.

[3] DrewDA, WeinerDE, SarnakMJ. Cognitive impairment in CKD: pathophysiology, management, and prevention. Am J Kidney Dis. 2019;74(6):782-790.

[4] TuttleKR, JonesCR, DarathaKB, et al. Incidence of chronic kidney disease among adults with diabetes, 2015-2020. N Engl J Med. 2022;387(15):1430-1431.

[5] WuR, LiJ, TuG, et al. Comprehensive molecular and cellular characterization of acute kidney injury progression to renal fibrosis. Front Immunol. 2021;12:699192.

[6] NeyraJA, ChawlaLS. Acute kidney disease to chronic kidney disease. Crit Care Clin. 2021;37(2):453-474.

[7] GuoY, CenK, HongK, Mai Y, JiangM. Construction of a neural network diagnostic model for renal fibrosis and investigation of immune infiltration characteristics. Front Immunol. 2023;14:1183088.

[8] KalluriR, LeBleuVS. The biology, function, and biomedical applications of exosomes. Science. 2020;367(6478):eaau6977.

[9] DaiJ, SuY, ZhongS, et al. Exosomes: key players in cancer and potential therapeutic strategy. Signal Transduct Target Ther. 2020;5(1):145.

[10] ZhangJ, LiS, LiL, et al. Exosome and exosomal microRNA: trafficking, sorting, and function. Genomics Proteomics Bioinformatics. 2015;13(1):17-24.

[11] PegtelDM, GouldSJ. Exosomes. Annu Rev Biochem. 2019;88:487-514.

[12] NooninC, Thongboonkerd V. Exosome-inflammasome crosstalk and their roles in inflammatory responses. Theranostics. 2021;11(9):4436-4451.

[13] CullyM. Exosome-based candidates move into the clinic. Nat Rev Drug Discov. 2021;20(1):6-7.

[14] LiangY, DuanL, LuJ, XiaJ. Engineering exosomes for targeted drug delivery. Theranostics. 2021;11(7):3183-3195.

[15] StahlAL, Johansson K, MossbergM, KahnR, Karpman D. Exosomes and microvesicles in normal physiology, pathophysiology, and renal diseases. Pediatr Nephrol. 2019;34(1):11-30.

[16] WangC, LiZ, LiuY, YuanL. Exosomes in atherosclerosis: performers, bystanders, biomarkers, and therapeutic targets. Theranostics. 2021;11(8):3996-4010.

[17] YuD, LiY, WangM, et al. Exosomes as a new frontier of cancer liquid biopsy. Mol Cancer. 2022;21(1):56.

[18] KhanNU, LinJ, LiuX, et al. Insights into predicting diabetic nephropathy using urinary biomarkers. Biochim Biophys Acta Proteins Proteom. 2020;1868(10):140475.

[19] ValadiH, Ekström K, BossiosA, SjöstrandM, LeeJJ, LötvallJO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9(6):654-659.

[20] DoyleLM, WangMZ. Overview of extracellular vesicles, their origin, composition, purpose, and methods for exosome isolation and analysis. Cells. 2019;8(7):727.

[21] KrylovaSV, FengD. The machinery of exosomes: biogenesis, release, and uptake. Int J Mol Sci. 2023;24(2):1337.

[22] MulcahyLA, PinkRC, CarterDR. Routes and mechanisms of extracellular vesicle uptake. J Extracell Vesicles. 2014;3(1):24641.

[23] AryaSB, CollieSP, ParentCA. The ins-and-outs of exosome biogenesis, secretion, and internalization. Trends Cell Biol. 2024;34(2):90-108.

[24] WangY, ZhouCJ, LiuY. Wnt signaling in kidney development and disease. Prog Mol Biol Transl Sci. 2018;153:181-207.

[25] ChiabottoG, BrunoS, CollinoF, Camussi G. Mesenchymal stromal cells epithelial transition induced by renal tubular cells-derived extracellular vesicles. PLoS One. 2016;11(7):e0159163.

[26] YinS, ZhouS, RenD, et al. Mesenchymal stem cell-derived exosomes attenuate epithelial-mesenchymal transition of HK-2 cells. Tissue Eng Part A. 2022;28(13–14):651-659.

[27] RigalliJP, BarrosER, SommersV, Bindels RJM, HoenderopJGJ. Novel aspects of extracellular vesicles in the regulation of renal physiological and pathophysiological processes. Front Cell Dev Biol. 2020;8:244.

[28] AbbasianN, Herbert KE, PawluczykI, BurtonJO, Bevington A. Vesicles bearing gifts: the functional importance of micro-RNA transfer in extracellular vesicles in chronic kidney disease. Am J Physiol Renal Physiol. 2018;315(5):F1430-F1443.

[29] GildeaJJ, SeatonJE, VictorKG, et al. Exosomal transfer from human renal proximal tubule cells to distal tubule and collecting duct cells. Clin Biochem. 2014;47(15):89-94.

[30] PomattoMAC, GaiC, BussolatiB, Camussi G. Extracellular vesicles in renal pathophysiology. Front Mol Biosci. 2017;4:37.

[31] GaoC, Higgins PJ, ZhangW. AQP2:mutations associated with congenital nephrogenic diabetes insipidus and regulation by post-translational modifications and protein-protein interactions. Cells. 2020;9(10):2172.

[32] IidaK, Whitlow MB, NussenzweigV. Membrane vesiculation protects erythrocytes from destruction by complement. J Immunol. 1991;147(8):2638-2642.

[33] ZhangZ, ZhangH, LiD, ZhouX, QinQ, ZhangQ. Caspase-3-mediated GSDME induced pyroptosis in breast cancer cells through the ROS/JNK signalling pathway. J Cell Mol Med. 2021;25(17):8159-8168.

[34] DongHQ, LiangSJ, XuYL, et al. Liproxstatin-1 induces cell cycle arrest, apoptosis, and caspase-3/GSDME-dependent secondary pyroptosis in K562 cells. Int J Oncol. 2022;61(4):119.

[35] BussolatiB, Camussi G. Renal injury: early apoptotic extracellular vesicles in injury and repair. Nat Rev Nephrol. 2017;13(9):523-524.

[36] Feigerlova E etal. Extracellular vesicles as immune mediators in response to kidney injury. Am J Physiol Renal Physiol. 2018;314(1):F9-F21.

[37] ThongboonkerdV, Kanlaya R. The divergent roles of exosomes in kidney diseases: pathogenesis, diagnostics, prognostics and therapeutics. Int J Biochem Cell Biol. 2022;149:106262.

[38] ShenK, JiaY, WangX, et al. Exosomes from adipose-derived stem cells alleviate the inflammation and oxidative stress via regulating Nrf2/HO-1 axis in macrophages. Free Radic Biol Med. 2021;165:54-66.

[39] YuanS, LiG, ZhangJ, Chen X, SuJ, ZhouF. Mesenchymal stromal cells-derived extracellular vesicles as potential treatments for osteoarthritis. Pharmaceutics. 2023;15(7):1814.

[40] HarrellCR, Jovicic N, DjonovV, ArsenijevicN, Volarevic V. Mesenchymal stem cell-derived exosomes and other extracellular vesicles as new remedies in the therapy of inflammatory diseases. Cells. 2019;8(12):1605.

[41] AngHL, MohanCD, ShanmugamMK, et al. Mechanism of epithelial-mesenchymal transition in cancer and its regulation by natural compounds. Med Res Rev. 2023;43(4):1141-1200.

[42] CuiJ, ZhangC, LeeJE, et al. MLL3 loss drives metastasis by promoting a hybrid epithelial-mesenchymal transition state. Nat Cell Biol. 2023;25(1):145-158.

[43] MayAM, BatoonL, McCauleyLK, Keller ET. The role of tumor epithelial-mesenchymal transition and macrophage crosstalk in cancer progression. Curr Osteoporos Rep. 2023;21(2):117-127.

[44] MahmoudianRA, Akhlaghipour I, LotfiM, ShahidsalesS, Moghbeli M. Circular RNAs as the pivotal regulators of epithelial-mesenchymal transition in gastrointestinal tumor cells. Pathol Res Pract. 2023;245:154472.

[45] TsubakiharaY, Moustakas A. Epithelial-mesenchymal transition and metastasis under the control of transforming growth factor beta. Int J Mol Sci. 2018;19(11):3672.

[46] ManfiolettiG, FedeleM. Epithelial-mesenchymal transition (EMT). Int J Mol Sci. 2023;24(14):11386.

[47] PengD, FuM, WangM, Wei Y, WeiX. Targeting TGF-beta signal transduction for fibrosis and cancer therapy. Mol Cancer. 2022;21(1):104.

[48] MarconiGD, Fonticoli L, RajanTS, et al. Epithelial-mesenchymal transition (EMT):the type-2 EMT in wound healing. Tissue Regeneration and Organ Fibrosis. Cells. 2021;10(7):1587.

[49] SistoM, Ribatti D, LisiS. Organ fibrosis and autoimmunity: the role of inflammation in TGFbeta-dependent EMT. Biomolecules. 2021;11(2):310.

[50] AndugulapatiSB, Gourishetti K, TirunavalliSK, ShaikhTB, SistlaR. Biochanin-a ameliorates pulmonary fibrosis by suppressing the TGF-beta mediated EMT, myofibroblasts differentiation and collagen deposition in in vitro and in vivo systems. Phytomedicine. 2020;78:153298.

[51] PanY, WangJ, HeL, ZhangF. MicroRNA-34a promotes EMT and liver fibrosis in primary biliary cholangitis by regulating TGF-beta1/smad pathway. J Immunol Res. 2021;2021:6890423.

[52] IwanoM. EMT and TGF-beta in renal fibrosis. Front Biosci. 2010;2(1):229-238.

[53] LovisaS, LeBleuVS, TampeB, et al. Epithelial-to-mesenchymal transition induces cell cycle arrest and parenchymal damage in renal fibrosis. Nat Med. 2015;21(9):998-1009.

[54] ZouJ, ZhouX, MaY, YuR. Losartan ameliorates renal interstitial fibrosis through metabolic pathway and Smurfs-TGF-beta/Smad. Biomed Pharmacother. 2022;149:112931.

[55] NagaishiK, MizueY, ChikenjiT, et al. Mesenchymal stem cell therapy ameliorates diabetic nephropathy via the paracrine effect of renal trophic factors including exosomes. Sci Rep. 2016;6:34842.

[56] ZhuF, Chong Lee Shin OLS, PeiG, et al. Adipose-derived mesenchymal stem cells employed exosomes to attenuate AKI-CKD transition through tubular epithelial cell dependent Sox9 activation. Oncotarget. 2017;8(41):70707-70726.

[57] Chun-YanL, Zi-YiZ, Tian-LinY, et al. Liquid biopsy biomarkers of renal interstitial fibrosis based on urinary exosome. Exp Mol Pathol. 2018;105(2):223-228.

[58] HuangH, HuangX, LuoS, et al. The MicroRNA MiR-29c alleviates renal fibrosis via TPM1-mediated suppression of the Wnt/beta-catenin pathway. Front Physiol. 2020;11:331.

[59] YangY, WangJ, ZhangY, Hu X, LiL, ChenP. Exosomes derived from mesenchymal stem cells ameliorate renal fibrosis via delivery of miR-186-5p. Hum Cell. 2022;35(1):83-97.

[60] QiuZ, ZhongZ, ZhangY, Tan H, DengB, MengG. Human umbilical cord mesenchymal stem cell-derived exosomal miR-335-5p attenuates the inflammation and tubular epithelial-myofibroblast transdifferentiation of renal tubular epithelial cells by reducing ADAM19 protein levels. Stem Cell Res Ther. 2022;13(1):373.

[61] LiuY, GuoW, GuoY, ChenX, LiuW. Bone marrow mesenchymal stem cell-derived exosomes improve renal fibrosis via regulating Smurf 2/Smad 7. Front Biosci. 2022;27(1):17.

[62] LiuL, LiuL, LiuR, LiuJ, ChengQ. Exosomal miR-21-5p derived from multiple myeloma cells promote renal epithelial-mesenchymal transition through targeting TGF-beta/SMAD7 signalling pathway. Clin Exp Pharmacol Physiol. 2023;50(9):711-718.

[63] FinchNC, NealCR, WelshGI, Foster RR, SatchellSC. The unique structural and functional characteristics of glomerular endothelial cell fenestrations and their potential as a therapeutic target in kidney disease. Am J Physiol Renal Physiol. 2023;325:F465-F478.

[64] XiangH, XuZ, ZhangC, Xiong J. Macrophage-derived exosomes mediate glomerular endothelial cell dysfunction in sepsis-associated acute kidney injury. Cell Biosci. 2023;13(1):46.

[65] Cruz-SolbesAS, YoukerK. Epithelial to mesenchymal transition (EMT) and endothelial to mesenchymal transition (EndMT):role and implications in kidney fibrosis. Results Probl Cell Differ. 2017;60:345-372.

[66] XuY, Kovacic JC. Endothelial to mesenchymal transition in health and disease. Annu Rev Physiol. 2023;85:245-267.

[67] XuH, HuoR, LiH, et al. KRAS mutation-induced EndMT of brain arteriovenous malformation is mediated through the TGF-beta/BMP-SMAD4 pathway. Stroke Vasc Neurol. 2023;8(3):197-206.

[68] YangS, WangSS, ChenL, et al. Neutrophil extracellular traps delay diabetic wound healing by inducing endothelial-to-mesenchymal transition via the hippo pathway. Int J Biol Sci. 2023;19(1):347-361.

[69] DongR, ZhangX, LiuY, et al. Rutin alleviates EndMT by restoring autophagy through inhibiting HDAC1 via PI3K/AKT/mTOR pathway in diabetic kidney disease. Phytomedicine. 2023;112:154700.

[70] DuftonNP, Peghaire CR, Osuna-AlmagroL, et al. Dynamic regulation of canonical TGFbeta signalling by endothelial transcription factor ERG protects from liver fibrogenesis. Nat Commun. 2017;8(1):895.

[71] LiZ, ChenB, DongW, et al. MKL1 promotes endothelial-to-mesenchymal transition and liver fibrosis by activating TWIST1 transcription. Cell Death Dis. 2019;10(12):899.

[72] ZhangH, FengCH, HeS, et al. Leech-centipede granules suppress EndMT to improve erectile dysfunction in rats with diabetes mellitus via TGF-beta/Smad pathway. Chin J Integr Med. 2023;29(1):28-36.

[73] HulshoffMS, Schellinger IN, XuX, et al. miR-132-3p and KLF7 as novel regulators of aortic stiffening-associated EndMT in type 2 diabetes mellitus. Diabetol Metab Syndr. 2023;15(1):11.

[74] HeQ, HuoR, WangJ, et al. Exosomal miR-3131 derived from endothelial cells with KRAS mutation promotes EndMT by targeting PICK1 in brain arteriovenous malformations. CNS Neurosci Ther. 2023;29(5):1312-1324.

[75] LovisaS, Fletcher-Sananikone E, SugimotoH, et al. Endothelial-to-mesenchymal transition compromises vascular integrity to induce Myc-mediated metabolic reprogramming in kidney fibrosis. Sci Signal. 2020;13(635):eaaz2597.

[76] WuX, GaoY, XuL, et al. Exosomes from high glucose-treated glomerular endothelial cells trigger the epithelial-mesenchymal transition and dysfunction of podocytes. Sci Rep. 2017;7(1):9371.

[77] FranzinR, StasiA, SallustioF, et al. Extracellular vesicles derived from patients with antibody-mediated rejection induce tubular senescence and endothelial to mesenchymal transition in renal cells. Am J Transplant. 2022;22(9):2139-2157.

[78] SablikKA, Clahsen-van Groningen MC, DammanJ, RoelenDL, BetjesMGH. Banff lesions and renal allograft survival in chronic-active antibody mediated rejection. Transpl Immunol. 2019;56:101213.

[79] MontgomeryRA, LoupyA, SegevDL. Antibody-mediated rejection: new approaches in prevention and management. Am J Transplant. 2018;18(Suppl 3):3-17.

[80] WangP, ChenW, ZhaoS, Cheng F. The role of LncRNA-regulated autophagy in AKI. Biofactors. 2023;49:1010-1021.

[81] KaushalGP, ShahSV. Autophagy in acute kidney injury. Kidney Int. 2016;89(4):779-791.

[82] TangC, Livingston MJ, LiuZ, DongZ. Autophagy in kidney homeostasis and disease. Nat Rev Nephrol. 2020;16(9):489-508.

[83] LivingstonMJ, ShuS, FanY, et al. Tubular cells produce FGF2 via autophagy after acute kidney injury leading to fibroblast activation and renal fibrosis. Autophagy. 2023;19(1):256-277.

[84] LiuC, WangX, WangX, et al. A new LKB1 activator, piericidin analogue S14, retards renal fibrosis through promoting autophagy and mitochondrial homeostasis in renal tubular epithelial cells. Theranostics. 2022;12(16):7158-7179.

[85] HanYC, TangSQ, LiuYT, et al. AMPK agonist alleviate renal tubulointerstitial fibrosis via activating mitophagy in high fat and streptozotocin induced diabetic mice. Cell Death Dis. 2021;12(10):925.

[86] CaiY, FengZ, JiaQ, et al. Cordyceps cicadae ameliorates renal hypertensive injury and fibrosis through the regulation of SIRT1-mediated autophagy. Front Pharmacol. 2021;12:801094.

[87] KimKH, LeeMS. Autophagy—a key player in cellular and body metabolism. Nat Rev Endocrinol. 2014;10(6):322-337.

[88] TranS, Fairlie WD, LeeEF. BECLIN1:protein structure, function and regulation. Cells. 2021;10(6):1522.

[89] KimYC, GuanKL. mTOR: a pharmacologic target for autophagy regulation. J Clin Invest. 2015;125(1):25-32.

[90] HuaT, YangM, SongH, et al. Huc-MSCs-derived exosomes attenuate inflammatory pain by regulating microglia pyroptosis and autophagy via the miR-146a-5p/TRAF6 axis. J Nanobiotechnol. 2022;20(1):324.

[91] EbrahimN, AhmedI, HussienN, et al. Mesenchymal stem cell-derived exosomes ameliorated diabetic nephropathy by autophagy induction through the mTOR signaling pathway. Cells. 2018;7(12):226.

[92] ZhaoP, ZhuY, SunL, et al. Circulating exosomal miR-1-3p from rats with myocardial infarction plays a protective effect on contrast-induced nephropathy via targeting ATG13 and activating the AKT signaling pathway. Int J Biol Sci. 2021;17(4):972-985.

[93] LiD, QuJ, YuanX, et al. Mesenchymal stem cells alleviate renal fibrosis and inhibit autophagy via exosome transfer of miRNA-122a. Stem Cells Int. 2022;2022:1981798.

[94] HuenSC, Cantley LG. Macrophages in renal injury and repair. Annu Rev Physiol. 2017;79:449-469.

[95] MosserDM, Hamidzadeh K, GoncalvesR. Macrophages and the maintenance of homeostasis. Cell Mol Immunol. 2021;18(3):579-587.

[96] WangY, HarrisDC. Macrophages in renal disease. J Am Soc Nephrol. 2011;22(1):21-27.

[97] Shapouri-MoghaddamA, Mohammadian S, VaziniH, et al. Macrophage plasticity, polarization, and function in health and disease. J Cell Physiol. 2018;233(9):6425-6440.

[98] TariqueAA, LoganJ, ThomasE, Holt PG, SlyPD, FantinoE. Phenotypic, functional, and plasticity features of classical and alternatively activated human macrophages. Am J Respir Cell Mol Biol. 2015;53(5):676-688.

[99] ZhouX, ChenH, HuY, et al. Enhancer of zeste homolog 2 promotes renal fibrosis after acute kidney injury by inducing epithelial-mesenchymal transition and activation of M2 macrophage polarization. Cell Death Dis. 2023;14(4):253.

[100] HuX, XuY, ZhangZ, et al. TSC1 affects the process of renal ischemia-reperfusion injury by controlling macrophage polarization. Front Immunol. 2021;12:637335.

[101] LuY, YangL, ChenX, Liu J, NieA, ChenX. Bone marrow mesenchymal stem cell-derived exosomes improve renal fibrosis by reducing the polarisation of M1 and M2 macrophages through the activation of EP2 receptors. IET Nanobiotechnol. 2022;16(1):14-24.

[102] XieX, YangX, WuJ, et al. Exosome from indoleamine 2, 3-dioxygenase-overexpressing bone marrow mesenchymal stem cells accelerates repair process of ischemia/reperfusion-induced acute kidney injury by regulating macrophages polarization. Stem Cell Res Ther. 2022;13(1):367.

[103] LuY, ZhangR, GuX, WangX, XiP, ChenX. Exosomes from tubular epithelial cells undergoing epithelial-to-mesenchymal transition promote renal fibrosis by M1 macrophage activation. FASEB Bioadv. 2023;5(3):101-113.

[104] LvLL, FengY, WuM, et al. Exosomal miRNA-19b-3p of tubular epithelial cells promotes M1 macrophage activation in kidney injury. Cell Death Differ. 2020;27(1):210-226.

[105] WenY, LuX, RenJ, et al. KLF4 in macrophages attenuates TNFalpha-mediated kidney injury and fibrosis. J Am Soc Nephrol. 2019;30(10):1925-1938.

[106] Nikolic-PatersonDJ, Wang S, LanHY. Macrophages promote renal fibrosis through direct and indirect mechanisms. Kidney Int Suppl. 2011;4(1):34-38.

[107] LiuY. Cellular and molecular mechanisms of renal fibrosis. Nat Rev Nephrol. 2011;7(12):684-696.

[108] TanRJ, ZhouD, LiuY. Signaling crosstalk between tubular epithelial cells and interstitial fibroblasts after kidney injury. Kidney Dis. 2016;2(3):136-144.

[109] ZhangY, QinX, YangY, et al. Ginkgo biloba extract attenuates cisplatin-induced renal interstitial fibrosis by inhibiting the activation of renal fibroblasts through down-regulating the HIF-1alpha/STAT3/IL-6 pathway in renal tubular epithelial cells. Phytomedicine. 2023;115:154809.

[110] LiuX, MiaoJ, WangC, et al. Tubule-derived exosomes play a central role in fibroblast activation and kidney fibrosis. Kidney Int. 2020;97(6):1181-1195.

[111] ZhaoS, LiW, YuW, et al. Exosomal miR-21 from tubular cells contributes to renal fibrosis by activating fibroblasts via targeting PTEN in obstructed kidneys. Theranostics. 2021;11(18):8660-8673.

[112] ZhouX, ZhaoS, LiW, et al. Tubular cell-derived exosomal miR-150-5p contributes to renal fibrosis following unilateral ischemia-reperfusion injury by activating fibroblast in vitro and in vivo. Int J Biol Sci. 2021;17(14):4021-4033.

[113] GuanH, PengR, MaoL, FangF, XuB, ChenM. Injured tubular epithelial cells activate fibroblasts to promote kidney fibrosis through miR-150-containing exosomes. Exp Cell Res. 2020;392(2):112007.

[114] ChenS, ZhangM, LiJ, et al. Beta-catenin-controlled tubular cell-derived exosomes play a key role in fibroblast activation via the OPN-CD44 axis. J Extracell Vesicles. 2022;11(3):e12203.

[115] HewitsonTD, SmithER. A metabolic reprogramming of glycolysis and glutamine metabolism is a requisite for renal fibrogenesis-why and how? Front Physiol. 2021;12:645857.

[116] UngCY, Onoufriadis A, ParsonsM, McGrathJA, ShawTJ. Metabolic perturbations in fibrosis disease. Int J Biochem Cell Biol. 2021;139:106073.

[117] YangQ, HuoE, CaiY, et al. PFKFB3-mediated glycolysis boosts fibroblast activation and subsequent kidney fibrosis. Cells. 2023;12(16):2081.

[118] WeiQ, SuJ, DongG, Zhang M, HuoY, DongZ. Glycolysis inhibitors suppress renal interstitial fibrosis via divergent effects on fibroblasts and tubular cells. Am J Physiol Renal Physiol. 2019;316(6):F1162-F1172.

[119] SongC, WangS, FuZ, et al. IGFBP5 promotes diabetic kidney disease progression by enhancing PFKFB3-mediated endothelial glycolysis. Cell Death Dis. 2022;13(4):340.

[120] XuS, CheukYC, JiaY, et al. Bone marrow mesenchymal stem cell-derived exosomal miR-21a-5p alleviates renal fibrosis by attenuating glycolysis by targeting PFKM. Cell Death Dis. 2022;13(10):876.

[121] KuriharaH, SakaiT. Cell biology of mesangial cells: the third cell that maintains the glomerular capillary. Anat Sci Int. 2017;92(2):173-186.

[122] ZhaoJH. Mesangial cells and renal fibrosis. Adv Exp Med Biol. 2019;1165:165-194.

[123] WuXM, GaoYB, CuiFQ, Zhang N. Exosomes from high glucose-treated glomerular endothelial cells activate mesangial cells to promote renal fibrosis. Biol Open. 2016;5(4):484-491.

[124] LiH, RongP, MaX, et al. Mouse umbilical cord mesenchymal stem cell paracrine alleviates renal fibrosis in diabetic nephropathy by reducing myofibroblast transdifferentiation and cell proliferation and upregulating MMPs in mesangial cells. J Diabetes Res. 2020;2020:3847171.

[125] LiL, ShenN, WangN, et al. Inhibiting core fucosylation attenuates glucose-induced peritoneal fibrosis in rats. Kidney Int. 2018;93(6):1384-1396.

[126] FangM, KangL, WangX, et al. Inhibition of core fucosylation limits progression of diabetic kidney disease. Biochem Biophys Res Commun. 2019;520(3):612-618.

[127] LiuA, WangX, HuX, et al. Core fucosylation involvement in the paracrine regulation of proteinuria-induced renal interstitial fibrosis evaluated with the use of a microfluidic chip. Acta Biomater. 2022;142:99-112.

[128] HuX, ShenN, LiuA, et al. Bone marrow mesenchymal stem cell-derived exosomal miR-34c-5p ameliorates RIF by inhibiting the core fucosylation of multiple proteins. Mol Ther. 2022;30(2):763-781.

[129] ThongboonkerdV. Roles for exosome in various kidney diseases and disorders. Front Pharmacol. 2019;10:1655.

[130] JinJ, SunH, ShiC, et al. Circular RNA in renal diseases. J Cell Mol Med. 2020;24(12):6523-6533.

[131] FuriniG, Schroeder N, HuangL, et al. Proteomic profiling reveals the transglutaminase-2 externalization pathway in kidneys after unilateral ureteric obstruction. J Am Soc Nephrol. 2018;29(3):880-905.

[132] SaejongS, Townamchai N, SomparnP, et al. MicroRNA-21 in plasma exosome, but not from whole plasma, as a biomarker for the severe interstitial fibrosis and tubular atrophy (IF/TA) in post-renal transplantation. Asian Pac J Allergy Immunol. 2022;40(1):94-102.

[133] LvLL, CaoYH, NiHF, et al. MicroRNA-29c in urinary exosome/microvesicle as a biomarker of renal fibrosis. Am J Physiol Renal Physiol. 2013;305(8):F1220-F1227.

[134] LvCY, DingWJ, WangYL, et al. A PEG-based method for the isolation of urinary exosomes and its application in renal fibrosis diagnostics using cargo miR-29c and miR-21 analysis. Int Urol Nephrol. 2018;50(5):973-982.

[135] SoleC, Cortes-Hernandez J, FelipML, VidalM, Ordi-Ros J. miR-29c in urinary exosomes as predictor of early renal fibrosis in lupus nephritis. Nephrol Dial Transplant. 2015;30(9):1488-1496.

[136] YuY, BaiF, QinN, et al. Non-proximal renal tubule-derived urinary exosomal miR-200b as a biomarker of renal fibrosis. Nephron. 2018;139(3):269-282.

[137] CaoY, ShiY, YangY, et al. Urinary exosomes derived circRNAs as biomarkers for chronic renal fibrosis. Ann Med. 2022;54(1):1966-1976.

[138] CaoY, ShiY, WangY, et al. Exosomal hsa_circ_0008925 from urine is related to chronic renal fibrosis. Dis Markers. 2022;2022:1899282.

[139] LvLL, CaoYH, PanMM, et al. CD2AP mRNA in urinary exosome as biomarker of kidney disease. Clin Chim Acta. 2014;428:26-31.

[140] SoleC, MolineT, VidalM, Ordi-Ros J, Cortes-HernandezJ. An exosomal urinary miRNA signature for early diagnosis of renal fibrosis in lupus nephritis. Cells. 2019;8(8):773.

[141] MohanA, SinghRS, KumariM, et al. Urinary exosomal microRNA-451-5p is a potential early biomarker of diabetic nephropathy in rats. PLoS One. 2016;11(4):e0154055.

[142] Perez-HernandezJ, Martinez-Arroyo O, OrtegaA, et al. Urinary exosomal miR-146a as a marker of albuminuria, activity changes and disease flares in lupus nephritis. J Nephrol. 2021;34(4):1157-1167.

[143] SongJ, QinX, LiH, HuangG, BiH. Clinical and pathological correlation between urinary exosome miR-223 and IgAN patients. Clin Nephrol. 2023;100:209-215.

[144] BarileL, Vassalli G. Exosomes: therapy delivery tools and biomarkers of diseases. Pharmacol Ther. 2017;174:63-78.

[145] WanT, ZhongJ, PanQ, ZhouT, PingY, Liu X. Exosome-mediated delivery of Cas9 ribonucleoprotein complexes for tissue-specific gene therapy of liver diseases. Sci Adv. 2022;8(37):eabp9435.

[146] GaoL, QiuF, CaoH, et al. Therapeutic delivery of microRNA-125a-5p oligonucleotides improves recovery from myocardial ischemia/reperfusion injury in mice and swine. Theranostics. 2023;13(2):685-703.

[147] JiangYY, LiJD, XueX, YinZF, XuK, SuJC. Engineered extracellular vesicles for bone therapy. Nano Today. 2022;44:101487.

[148] DingDC, ShyuWC, LinSZ. Mesenchymal stem cells. Cell Transplant. 2011;20(1):5-14.

[149] SamsonrajRM, Raghunath M, NurcombeV, HuiJH, van Wijnen AJ, CoolSM. Concise review: multifaceted characterization of human mesenchymal stem cells for use in regenerative medicine. Stem Cells Transl Med. 2017;6(12):2173-2185.

[150] NajiA, EitokuM, FavierB, Deschaseaux F, Rouas-FreissN, SuganumaN. Biological functions of mesenchymal stem cells and clinical implications. Cell Mol Life Sci. 2019;76(17):3323-3348.

[151] HerisRM, Shirvaliloo M, Abbaspour-AghdamS, et al. The potential use of mesenchymal stem cells and their exosomes in Parkinson’s disease treatment. Stem Cell Res Ther. 2022;13(1):371.

[152] ZengZL, XieH. Mesenchymal stem cell-derived extracellular vesicles: a possible therapeutic strategy for orthopaedic diseases: a narrative review. Biomater Transl. 2022;3(3):175-187.

[153] DengS, ZhuF, DaiK, WangJ, LiuC. Harvest of functional mesenchymal stem cells derived from in vivo osteo-organoids. Biomater Transl. 2023;4(4):270-279.

[154] GyorgyB, HungME, BreakefieldXO, LeonardJN. Therapeutic applications of extracellular vesicles: clinical promise and open questions. Annu Rev Pharmacol Toxicol. 2015;55:439-464.

[155] WangJ, LiX, WangS, Cui J, RenX, SuJ. Bone-targeted exosomes: strategies and applications. Adv Healthc Mater. 2023;12(18):e2203361.

[156] JiJL, ShiHM, LiZL, et al. Satellite cell-derived exosome-mediated delivery of microRNA-23a/27a/26a cluster ameliorates the renal tubulointerstitial fibrosis in mouse diabetic nephropathy. Acta Pharmacol Sin. 2023;44(12):2455-2468.

[157] ZhangA, WangH, WangB, Yuan Y, KleinJD, WangXH. Exogenous miR-26a suppresses muscle wasting and renal fibrosis in obstructive kidney disease. FASEB J. 2019;33(12):13590-13601.

[158] ZhengH, JiJ, ZhaoT, Wang E, ZhangA. Exosome-encapsulated miR-26a attenuates aldosterone-induced tubulointerstitial fibrosis by inhibiting the CTGF/SMAD3 signaling pathway. Int J Mol Med. 2023;51(2):11.

[159] KimS, JeongCH, SongSH, et al. Micellized protein transduction domain-bone morphogenetic protein-7 efficiently blocks renal fibrosis via inhibition of transforming growth factor-beta-mediated epithelial-mesenchymal transition. Front Pharmacol. 2020;11:591275.

[160] SadeghiS, Tehrani FR, TahmasebiS, ShafieeA, Hashemi SM. Exosome engineering in cell therapy and drug delivery. Inflammopharmacology. 2023;31(1):145-169.

[161] MalekianF, Shamsian A, KodamSP, UllahM. Exosome engineering for efficient and targeted drug delivery: current status and future perspective. J Physiol. 2023;601(22):4853-4872.

[162] Alvarez-ErvitiL, SeowY, YinHF, Betts C, LakhalS, WoodMJA. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol. 2011;29(4):341-345.

[163] GuoJ, WangF, HuY, et al. Exosome-based bone-targeting drug delivery alleviates impaired osteoblastic bone formation and bone loss in inflammatory bowel diseases. Cell Rep Med. 2023;4(1):100881.

[164] LiYJ, WuJY, LiuJ, et al. Artificial exosomes for translational nanomedicine. J Nanobiotechnol. 2021;19(1):242.

[165] Garcia-ManriqueP, Gutierrez G, Blanco-LopezMC. Fully artificial exosomes: towards new theranostic biomaterials. Trends Biotechnol. 2018;36(1):10-14.

[166] GoG, LeeJ, ChoiDS, Kim SS, GhoYS. Extracellular vesicle-mimetic ghost nanovesicles for delivering anti-inflammatory drugs to mitigate gram-negative bacterial outer membrane vesicle-induced systemic inflammatory response syndrome. Adv Healthc Mater. 2019;8(4):e1801082.

[167] PattyPJ, Frisken BJ. The pressure-dependence of the size of extruded vesicles. Biophys J. 2003;85(2):996-1004.

[168] JeongD, JoW, YoonJ, et al. Nanovesicles engineered from ES cells for enhanced cell proliferation. Biomaterials. 2014;35(34):9302-9310.

[169] Martinez-LostaoL, García-Alvarez F, BasáñezG, et al. Liposome-bound APO2L/TRAIL is an effective treatment in a rabbit model of rheumatoid arthritis. Arthritis Rheum. 2010;62(8):2272-2282.

[170] GuH, LiJ, NiY. Sinomenine improves renal fibrosis by regulating mesenchymal stem cell-derived exosomes and affecting autophagy levels. Environ Toxicol. 2023;38(10):2524-2537.

[171] LiuD, LiuFX, LiZY, et al. HNRNPA1-mediated exosomal sorting of miR-483-5p out of renal tubular epithelial cells promotes the progression of diabetic nephropathy-induced renal interstitial fibrosis. Cell Death Dis. 2021;12(3):255.

[172] XuD, YuanL, CheM, et al. Molecular mechanism of Gan-song Yin inhibiting the proliferation of renal tubular epithelial cells by regulating miR-21-5p in adipocyte exosomes. J Ethnopharmacol. 2024;321:117530.

[173] ZhaoM, YangB, LiL, et al. Efficacy of modified Huangqi Chifeng decoction in alleviating renal fibrosis in rats with IgA nephropathy by inhibiting the TGF-beta1/Smad3 signaling pathway through exosome regulation. J Ethnopharmacol. 2022;285:114795.

RIGHTS & PERMISSIONS

2024 The Author(s). Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.