Skip to content
2000
Volume 20, Issue 9
  • ISSN: 1574-888X
  • E-ISSN: 2212-3946

Abstract

Objectives

This study aims to explore the therapeutic potential of mesenchymal stem cells (MSC) in treating diabetic nephropathy (DN) by investigating their effect on IL-11 modulation in a mouse model.

Methods

The effects of MSC therapy on DN were examined both and . Sixty adult male C57BL/6 mice were divided into the streptozotocin (STZ) diabetes (T1D) and the high-fat diet diabetes (T2D) models, with both groups receiving MSC treatment or saline for 4 or 8 weeks. Blood glucose, serum urea, interleukin-11 (IL-11), and kidney fibrosis markers were measured. Additionally, western blotting was used to assess levels of Type I and III collagen, E-Cadherin, α-smooth muscle actin (α-SMA), Vimentin, and ferroptosis suppressor protein 1 (FSP-1).

Results

MSC-treated T1D and T2D mice showed reduced blood glucose, serum urea, IL-11, TGF-β, and fibrosis markers (type I and III collagen, α-SMA, Vimentin, FSP-1), alongside increased E-Cadherin expression. Similar effects were observed using mouse glomerular epithelial cells, confirming MSC-mediated suppression of fibrosis pathways.

Conclusion

MSC therapy improves nephropathy, likely by inhibiting IL-11 and reducing fibrosis-related markers, making it a promising treatment for DN.

Loading

Article metrics loading...

/content/journals/cscr/10.2174/011574888X348254241216171655
2024-12-27
2025-12-08
Loading full text...

Full text loading...

References

  1. LeiL. MaoY. MengD. ZhangX. CuiL. HuoY. WangY. Percentage of circulating cd8+ t lymphocytes is associated with albuminuria in type 2 diabetes mellitus.Exp. Clin. Endocrinol. Diabetes20131221273010.1055/s‑0033‑135866624203650
    [Google Scholar]
  2. ZhengZ. ZhengF. Immune cells and inflammation in diabetic nephropathy.J. Diabetes Res.2016201611010.1155/2016/184169026824038
    [Google Scholar]
  3. ZhangL. LongJ. JiangW. ShiY. HeX. ZhouZ. LiY. YeungR.O. WangJ. MatsushitaK. CoreshJ. ZhaoM.H. WangH. Trends in chronic kidney disease in china.N. Engl. J. Med.2016375990590610.1056/NEJMc160246927579659
    [Google Scholar]
  4. BetzB. ConwayB.R. Recent advances in animal models of diabetic nephropathy.Nephron, Exp. Nephrol.2014126419119510.1159/00036330025034792
    [Google Scholar]
  5. MarshallS.M. Recent advances in diabetic nephropathy.Clin. Med.2004a4327728210.7861/clinmedicine.4‑3‑27715244365
    [Google Scholar]
  6. MarshallS.M. Recent advances in diabetic nephropathy.Postgrad. Med. J.2004b8094962463310.1136/pgmj.2004.02128715537844
    [Google Scholar]
  7. GaoM.J. YuG. DongJ. Comparison of therapeutic effects of calcium dobesilate and perlndopril in treatment of early diabetic nephropathy.Diabetes Res. Clin. Pract.2014106S30S3010.1016/S0168‑8227(14)70265‑7
    [Google Scholar]
  8. GaoX.Y. LiuY. ZhouL.P. JiangJ.J. ChenY. ShenZ.X. SunS.Z. Clinical study of renal glucose kang mixture combined with western medicine in the treatment of early diabetic nephropathy.J. Am. Geriatr. Soc.201462S335S336
    [Google Scholar]
  9. MassotoT.B. SantosA.C.R. RamalhoB.S. AlmeidaF.M. MartinezA.M.B. MarquesS.A. Mesenchymal stem cells and treadmill training enhance function and promote tissue preservation after spinal cord injury.Brain Res.2020172614649410.1016/j.brainres.2019.14649431586628
    [Google Scholar]
  10. XingX. HanS. ChengG. NiY. LiZ. LiZ. Proteomic analysis of exosomes from adipose-derived mesenchymal stem cells: A novel therapeutic strategy for tissue injury.BioMed Res. Int.2020202011010.1155/2020/609456232190672
    [Google Scholar]
  11. ArenaS. SalatiM. SorgentoniG. BarbisanF. OrcianiM. Characterization of tumor-derived mesenchymal stem cells potentially differentiating into cancer-associated fibroblasts in lung cancer.Clin. Transl. Oncol.201820121582159110.1007/s12094‑018‑1894‑429796998
    [Google Scholar]
  12. D’AngeloW. ChenB. GurungC. GuoY.L. Characterization of embryonic stem cell-differentiated fibroblasts as mesenchymal stem cells with robust expansion capacity and attenuated innate immunity.Stem Cell Res. Ther.20189127810.1186/s13287‑018‑1033‑830359317
    [Google Scholar]
  13. ShimadaM. FengR. IkemotoT. MorineY. ImuraS. IwahashiS. SaitoY. TakasuC. Establishment of insulin-producing cells differentiated from human adipose-derived mesenchymal stem cells using a 3d-culture system with xeno-antigen free reagents.Transplantation2018102Suppl. 7S235S23510.1097/01.tp.0000542909.28600.e6
    [Google Scholar]
  14. PittengerM.F. MackayA.M. BeckS.C. JaiswalR.K. DouglasR. MoscaJ.D. MoormanM.A. SimonettiD.W. CraigS. MarshakD.R. Multilineage potential of adult human mesenchymal stem cells.Science1999284541114314710.1126/science.284.5411.14310102814
    [Google Scholar]
  15. TsaiT.L. LiW.J. Identification of bone marrow-derived soluble factors regulating human mesenchymal stem cells for bone regeneration.Stem Cell Reports20178238740010.1016/j.stemcr.2017.01.00428162996
    [Google Scholar]
  16. SeifrtováM. HavelekR. ĆmielováJ. JiroutováA. SoukupT. BrůčkováL. MokrýJ. EnglishD. ŘezáčováM. The response of human ectomesenchymal dental pulp stem cells to cisplatin treatment.Int. Endod. J.201245540141210.1111/j.1365‑2591.2011.01990.x22142405
    [Google Scholar]
  17. MennanC. BrownS. McCarthyH. MavrogonatouE. KletsasD. GarciaJ. BalainB. RichardsonJ. RobertsS. Mesenchymal stromal cells derived from whole human umbilical cord exhibit similar properties to those derived from wharton’s jelly and bone marrow.FEBS Open Bio20166111054106610.1002/2211‑5463.1210427833846
    [Google Scholar]
  18. BouhtitF. NajarM. AghaD.M. MelkiR. NajimiM. SadkiK. LewalleP. HamalA. LagneauxL. MerimiM. The biological response of mesenchymal stromal cells to thymol and carvacrol in comparison to their essential oil: An innovative new study.Food Chem. Toxicol.201913411084410.1016/j.fct.2019.11084431562950
    [Google Scholar]
  19. DamalaM. SwiokloS. KoduriM.A. MitragotriN.S. BasuS. ConnonC.J. SinghV. Encapsulation of human limbus-derived stromal/mesenchymal stem cells for biological preservation and transportation in extreme indian conditions for clinical use.Sci. Rep.2019911695010.1038/s41598‑019‑53315‑x31740778
    [Google Scholar]
  20. PickenA. HarrimanJ. Iftimia-ManderA. JohnsonL. ProsserA. QuirkR. ThomasR. A monte carlo framework for managing biological variability in manufacture of autologous cell therapy from mesenchymal stromal cells therapies.Cytotherapy202022422723810.1016/j.jcyt.2020.01.00632113873
    [Google Scholar]
  21. YoonY.M. LeeJ.H. SongK.H. NohH. LeeS.H. Melatonin-stimulated exosomes enhance the regenerative potential of chronic kidney disease-derived mesenchymal stem/stromal cells via cellular prion proteins.J. Pineal Res.2020683e1263210.1111/jpi.1263231989677
    [Google Scholar]
  22. PackhamD.K. FraserI.R. KerrP.G. SegalK.R. Allogeneic mesenchymal precursor cells (MPC) in diabetic nephropathy: A randomized, placebo-controlled, dose escalation study.EBioMedicine20161226326910.1016/j.ebiom.2016.09.01127743903
    [Google Scholar]
  23. TögelF. WeissK. YangY. HuZ. ZhangP. WestenfelderC. Vasculotropic, paracrine actions of infused mesenchymal stem cells are important to the recovery from acute kidney injury.Am. J. Physiol. Renal Physiol.20072925F1626F163510.1152/ajprenal.00339.200617213465
    [Google Scholar]
  24. ZhangM. MalN. KiedrowskiM. ChackoM. AskariA.T. PopovicZ.B. KocO.N. PennM.S. Sdf-1 expression by mesenchymal stem cells results in trophic support of cardiac myocytes after myocardial infarction.FASEB J.200721123197320710.1096/fj.06‑6558com17496162
    [Google Scholar]
  25. WuY. ZhangC. GuoR. WuD. ShiJ. LiL. ChuY. YuanX. GaoJ. Mesenchymal stem cells: An overview of their potential in cell-based therapy for diabetic nephropathy.Stem Cells Int.2021202111210.1155/2021/662081133815509
    [Google Scholar]
  26. BiB. SchmittR. IsrailovaM. NishioH. CantleyL.G. Stromal cells protect against acute tubular injury via an endocrine effect.J. Am. Soc. Nephrol.20071892486249610.1681/ASN.200702014017656474
    [Google Scholar]
  27. NagaishiK. MizueY. ChikenjiT. OtaniM. NakanoM. KonariN. FujimiyaM. Mesenchymal stem cell therapy ameliorates diabetic nephropathy via the paracrine effect of renal trophic factors including exosomes.Sci. Rep.2016613484210.1038/srep3484227721418
    [Google Scholar]
  28. LivakK.J. SchmittgenT.D. Analysis of relative gene expression data using real-time quantitative pcr and the 2(-delta delta c(t)) method.Methods200125440240810.1006/meth.2001.126211846609
    [Google Scholar]
  29. MagalhãesD.A. KumeW.T. CorreiaF.S. QueirozT.S. Allebrandt NetoE.W. SantosM.P.D. KawashitaN.H. FrançaS.A. High-fat diet and streptozotocin in the induction of type 2 diabetes mellitus: A new proposal. an acad bras cienc.2019
  30. GhafarzadehM. NamdariP. TarhaniM. TarhaniF. A review of application of stem cell therapy in the management of congenital heart disease.J. Matern. Fetal Neonatal Med.20203391607161510.1080/14767058.2018.152082930185081
    [Google Scholar]
  31. ZhaoR.C. Stem cell–based therapy for coronavirus disease 2019.Stem Cells Dev.2020291167968110.1089/scd.2020.007132292113
    [Google Scholar]
  32. BoyleS.C. KimM. ValeriusM.T. McMahonA.P. KopanR. Notch pathway activation can replace the requirement for wnt4 and wnt9b in mesenchymal-to-epithelial transition of nephron stem cells.Development2011138194245425410.1242/dev.07043321852398
    [Google Scholar]
  33. MachiguchiT. NakamuraT. Cellular interactions via conditioned media induce in vivo nephron generation from tubular epithelial cells or mesenchymal stem cells.Biochem. Biophys. Res. Commun.2013435332733310.1016/j.bbrc.2013.04.05023618853
    [Google Scholar]
  34. MachiguchiT. NakamuraT. Nephron generation in kidney cortices through injection of pretreated mesenchymal stem cell-differentiated tubular epithelial cells.Biochem. Biophys. Res. Commun.2019518114114710.1016/j.bbrc.2019.08.02231420163
    [Google Scholar]
  35. CohrsC.M. PanzerJ.K. DrotarD.M. EnosS.J. KipkeN. ChenC. BozsakR. SchönigerE. EhehaltF. DistlerM. BrennandA. BornsteinS.R. WeitzJ. SolimenaM. SpeierS. Dysfunction of persisting β cells is a key feature of early type 2 diabetes pathogenesis.Cell Rep.202031110746910.1016/j.celrep.2020.03.03332268101
    [Google Scholar]
  36. MarchettiP. SuleimanM. De LucaC. BarontiW. BosiE. TesiM. MarselliL. A direct look at the dysfunction and pathology of the β cells in human type 2 diabetes.Semin. Cell Dev. Biol.2020103839310.1016/j.semcdb.2020.04.00532417220
    [Google Scholar]
  37. LeeH. LeeY.S. HarendaQ. PietrzakS. OktayH.Z. SchreiberS. LiaoY. SonthaliaS. CieckoA.E. ChenY.G. KelesS. SridharanR. EnginF. Beta cell dedifferentiation induced by ire1α deletion prevents type 1 diabetes.Cell Metab.2020314822836.e510.1016/j.cmet.2020.03.00232220307
    [Google Scholar]
  38. TandayN. IrwinN. FlattP.R. MoffettR.C. Dapagliflozin exerts positive effects on beta cells, decreases glucagon and does not alter beta- to alpha-cell transdifferentiation in mouse models of diabetes and insulin resistance.Biochem. Pharmacol.202017711400910.1016/j.bcp.2020.11400932360307
    [Google Scholar]
  39. CransD. YangL. AlfanoJ.A. ChiL.H. JinW. (4-hydroxypyridine-2,6-dicarboxylato)oxovanadate(v)—a new insulin-like compound: Chemistry, effects on myoblast and yeast cell growth and effects on hyperglycemia in rats with stz-induced diabetes.Coord. Chem. Rev.20032371-2132210.1016/S0010‑8545(02)00292‑8
    [Google Scholar]
  40. GoyalS.N. ReddyN.M. PatilK.R. NakhateK.T. OjhaS. PatilC.R. AgrawalY.O. Challenges and issues with streptozotocin-induced diabetes – a clinically relevant animal model to understand the diabetes pathogenesis and evaluate therapeutics.Chem. Biol. Interact.2016244496310.1016/j.cbi.2015.11.03226656244
    [Google Scholar]
  41. HerathC. JayasumanaC. De SilvaP.M.C.S. De SilvaP.H.C. SiribaddanaS. De BroeM.E. Kidney diseases in agricultural communities: A case against heat-stress nephropathy.Kidney Int. Rep.20183227128010.1016/j.ekir.2017.10.00629725631
    [Google Scholar]
  42. LionakiS. PanagiotellisK. MelexopoulouC. BoletisJ.N. The clinical course of IGA nephropathy after kidney transplantation and its management.Transplant. Rev.201731210611410.1016/j.trre.2017.01.00528209246
    [Google Scholar]
  43. VargheseS. Gowtham KumarS. Prevalence of micro albuminuria and diagnostic accuracy of urine dipstick for the screening of diabetic nephropathy in type 2 diabetes patients.Biocatal. Agric. Biotechnol.20192110131610.1016/j.bcab.2019.101316
    [Google Scholar]
  44. CappelliC. TellezA. JaraC. AlarcónS. TorresA. MendozaP. PodestáL. FloresC. QuezadaC. OyarzúnC. San MartínR. The tgf-β profibrotic cascade targets ecto-5′-nucleotidase gene in proximal tubule epithelial cells and is a traceable marker of progressive diabetic kidney disease.Biochim. Biophys. Acta Mol. Basis Dis.20201866716579610.1016/j.bbadis.2020.16579632289379
    [Google Scholar]
  45. RauchmanM. GriggsD. Emerging strategies to disrupt the central tgf-β axis in kidney fibrosis.Transl. Res.20192099010410.1016/j.trsl.2019.04.00331085163
    [Google Scholar]
  46. ZhangL. SuS. ZhuY. GuoJ. GuoS. QianD. OuyangZ. DuanJ. Mulberry leaf active components alleviate type 2 diabetes and its liver and kidney injury in db/db mice through insulin receptor and tgf-β/smads signaling pathway.Biomed. Pharmacother.201911210867510.1016/j.biopha.2019.10867530780108
    [Google Scholar]
  47. AlyM.H. ArafatM.A. HusseinO.A. ElsaidH.H. Abdel-HammedA.R. Study of angiopoietin-2 and vascular endothelial growth factor as markers of diabetic nephropathy onset in egyptians diabetic patients with non-albuminuric state.Diabetes Metab. Syndr.20191321623162710.1016/j.dsx.2019.03.01631336531
    [Google Scholar]
  48. LiangG. SongL. ChenZ. QianY. XieJ. ZhaoL. LinQ. ZhuG. TanY. LiX. MohammadiM. HuangZ. Fibroblast growth factor 1 ameliorates diabetic nephropathy by an anti-inflammatory mechanism.Kidney Int.20189319510910.1016/j.kint.2017.05.01328750927
    [Google Scholar]
  49. BetzB.B. JenksS.J. CronshawA.D. LamontD.J. CairnsC. ManningJ.R. GoddardJ. WebbD.J. MullinsJ.J. HughesJ. McLachlanS. StrachanM.W.J. PriceJ.F. ConwayB.R. Urinary peptidomics in a rodent model of diabetic nephropathy highlights epidermal growth factor as a biomarker for renal deterioration in patients with type 2 diabetes.Kidney Int.20168951125113510.1016/j.kint.2016.01.01527083286
    [Google Scholar]
  50. RenX. LiH. FengP. WangJ. MengZ. ZhengW. YangH. XuK. Synergistic effects of combining anti-midkine and hepatocyte growth factor therapies against diabetic nephropathy in rats.Am. J. Med. Sci.20153501475410.1097/MAJ.000000000000051026086153
    [Google Scholar]
  51. MoritaT. YamamotoT. ChurgJ. Mesangiolysis: An update.Am. J. Kidney Dis.199831455957310.1053/ajkd.1998.v31.pm95311719531171
    [Google Scholar]
  52. SilbigerS. CrowleyS. ShanZ. BrownleeM. SatrianoJ. SchlondorffD. Nonenzymatic glycation of mesangial matrix and prolonged exposure of mesangial matrix to elevated glucose reduces collagen synthesis and proteoglycan charge.Kidney Int.199343485386410.1038/ki.1993.1208479121
    [Google Scholar]
  53. Clarke StoutL. KumarS. WhortonE.B. Focal mesangiolysis and the pathogenesis of the kimmelstiel-wilson nodule.Hum. Pathol.1993241778910.1016/0046‑8177(93)90066‑P8418016
    [Google Scholar]
  54. DeconteS.R. OliveiraR.J.S. CalábriaL.K. OliveiraV.N. GouveiaN.M. MoraesA.S. EspindolaF.S. Alterations of antioxidant biomarkers and type I collagen deposition in the parotid gland of streptozotocin-induced diabetic rats.Arch. Oral Biol.201156874475110.1016/j.archoralbio.2011.01.00521310393
    [Google Scholar]
  55. HopferU. HopferH. Meyer-SchwesingerC. LoefflerI. FukaiN. OlsenB.R. StahlR.A.K. WolfG. Lack of type viii collagen in mice ameliorates diabetic nephropathy.Diabetes20095871672168110.2337/db08‑018319401424
    [Google Scholar]
  56. HornigoldN. JohnsonT.S. HuangL. HaylorJ.L. GriffinM. MooneyA. Inhibition of collagen I accumulation reduces glomerulosclerosis by a hic-5-dependent mechanism in experimental diabetic nephropathy.Lab. Invest.201393555356510.1038/labinvest.2013.4223508044
    [Google Scholar]
  57. JakopinE. BevcS. EkartR. HojsR. Collagen type III nephropathy as a systemic disease? - A case report.Nefrologia202040110610810.1016/j.nefro.2019.04.00831377028
    [Google Scholar]
/content/journals/cscr/10.2174/011574888X348254241216171655
Loading
/content/journals/cscr/10.2174/011574888X348254241216171655
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher's website along with the published article.

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test