109
Views
5
CrossRef citations to date
0
Altmetric
Review

The Multiple Roles of Fibroblast Growth Factor in Diabetic Nephropathy

, , , & ORCID Icon
Pages 5273-5290 | Published online: 14 Oct 2021

References

  • Zhang H, Nie X, Shi X, et al. Regulatory mechanisms of the Wnt/beta-catenin pathway in diabetic cutaneous ulcers. Front Pharmacol. 2018;9:1114. doi:10.3389/fphar.2018.01114
  • Gnudi L, Coward RJM, Long DA. Diabetic nephropathy: perspective on novel molecular mechanisms. Trends Endocrinol Metab. 2016;27(11):820–830. doi:10.1016/j.tem.2016.07.002
  • Selby NM, Taal MW. An updated overview of diabetic nephropathy: diagnosis, prognosis, treatment goals and latest guidelines. Diabetes Obes Metab. 2020;22(Suppl 1):3–15. doi:10.1111/dom.14007
  • Giorda CB, Carna P, Salomone M, et al. Ten-year comparative analysis of incidence, prognosis, and associated factors for dialysis and renal transplantation in type 1 and type 2 diabetes versus non-diabetes. Acta Diabetol. 2018;55(7):733–740. doi:10.1007/s00592-018-1142-y
  • Bhattacharjee N, Barma S, Konwar N, Dewanjee S, Manna P. Mechanistic insight of diabetic nephropathy and its pharmacotherapeutic targets: an update. Eur J Pharmacol. 2016;791:8–24. doi:10.1016/j.ejphar.2016.08.022
  • Han Q, Zhu H, Chen X, Liu Z. Non-genetic mechanisms of diabetic nephropathy. Front Med. 2017;11(3):319–332. doi:10.1007/s11684-017-0569-9
  • Umanath K, Lewis JB. Update on diabetic nephropathy: core curriculum 2018. Am J Kidney Dis. 2018;71(6):884–895. doi:10.1053/j.ajkd.2017.10.026
  • Zhang L, Long J, Jiang W, et al. Trends in chronic kidney disease in China. N Engl J Med. 2016;375(9):905–906. doi:10.1056/NEJMc1602469
  • Hui Q, Jin Z, Li X, Liu C, Wang X. FGF family: from drug development to clinical application. Int J Mol Sci. 2018;19(7):1875. doi:10.3390/ijms19071875
  • Zhang X, Yeung DC, Karpisek M, et al. Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans. Diabetes. 2008;57(5):1246–1253. doi:10.2337/db07-1476
  • Li X, Wu D, Tian Y. Fibroblast growth factor 19 protects the heart from oxidative stress-induced diabetic cardiomyopathy via activation of AMPK/Nrf2/HO-1 pathway. Biochem Biophys Res Commun. 2018;502(1):62–68. doi:10.1016/j.bbrc.2018.05.121
  • Wang N, Xu TY, Zhang X, et al. Improving hyperglycemic effect of FGF-21 is associated with alleviating inflammatory state in diabetes. Int Immunopharmacol. 2018;56:301–309. doi:10.1016/j.intimp.2018.01.048
  • Cho JM, Yang EH, Quan W, Nam EH, Cheon HG. Discovery of a novel fibroblast activation protein (FAP) inhibitor, BR103354, with anti-diabetic and anti-steatotic effects. Sci Rep. 2020;10(1):21280. doi:10.1038/s41598-020-77978-z
  • Itoh N, Ornitz DM. Fibroblast growth factors: from molecular evolution to roles in development, metabolism and disease. J Biochem. 2010;149(2):121–130. doi:10.1093/jb/mvq121
  • Beenken A, Mohammadi M. The FGF family: biology, pathophysiology and therapy. Nat Rev Drug Discov. 2009;8(3):235–253.
  • Belov AA, Mohammadi M. Molecular mechanisms of fibroblast growth factor signaling in physiology and pathology. Cold Spring Harb Perspect Biol. 2013;5(6):a015958. doi:10.1101/cshperspect.a015958
  • Ornitz DM, Itoh N. The fibroblast growth factor signaling pathway. Wiley Interdiscip Rev Dev Biol. 2015;4(3):215–266.
  • Dailey L, Ambrosetti D, Mansukhani A, Basilico C. Mechanisms underlying differential responses to FGF signaling. Cytokine Growth Factor Rev. 2005;16(2):233–247. doi:10.1016/j.cytogfr.2005.01.007
  • House SL, Branch K, Newman G, Doetschman T, Schultz Jel J. Cardioprotection induced by cardiac-specific overexpression of fibroblast growth factor-2 is mediated by the MAPK cascade. Am J Physiol Heart Circ Physiol. 2005;289(5):H2167–H2175. doi:10.1152/ajpheart.00392.2005
  • Braun S, Auf Dem Keller U, Steiling H, Werner S, Brockes JP, Martin P. Fibroblast growth factors in epithelial repair and cytoprotection. Philos Trans R Soc Lond B Biol Sci. 2004;359(1445):753–757. doi:10.1098/rstb.2004.1464
  • Gupte VV, Ramasamy SK, Reddy R, et al. Overexpression of fibroblast growth factor-10 during both inflammatory and fibrotic phases attenuates bleomycin-induced pulmonary fibrosis in mice. Am J Respir Crit Care Med. 2009;180(5):424–436. doi:10.1164/rccm.200811-1794OC
  • Zhang X, Ibrahimi OA, Olsen SK, Umemori H, Mohammadi M, Ornitz DM. Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family. J Biol Chem. 2006;281(23):15694–15700. doi:10.1074/jbc.M601252200
  • Eswarakumar VP, Lax I, Schlessinger J. Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Rev. 2005;16(2):139–149. doi:10.1016/j.cytogfr.2005.01.001
  • Lemmon MA, Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2010;141(7):1117–1134. doi:10.1016/j.cell.2010.06.011
  • Schlessinger J, Plotnikov AN, Ibrahimi OA, et al. Crystal structure of a ternary FGF-FGFR-heparin complex reveals a dual role for heparin in FGFR binding and dimerization. Mol Cell. 2000;6(3):743–750. doi:10.1016/S1097-2765(00)00073-3
  • Schlessinger J. Signal transduction. Autoinhibition control. Science. 2003;300(5620):750–752. doi:10.1126/science.1082024
  • Potthoff MJ, Kliewer SA, Mangelsdorf DJ. Endocrine fibroblast growth factors 15/19 and 21: from feast to famine. Genes Dev. 2012;26(4):312–324. doi:10.1101/gad.184788.111
  • Smith ER, McMahon LP, Holt SG. Fibroblast growth factor 23. Ann Clin Biochem. 2013;51(2):203–227. doi:10.1177/0004563213510708
  • Degirolamo C, Sabba C, Moschetta A. Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23. Nat Rev Drug Discov. 2016;15(1):51–69. doi:10.1038/nrd.2015.9
  • Kuro-o M. The Klotho proteins in health and disease. Nat Rev Nephrol. 2019;15(1):27–44. doi:10.1038/s41581-018-0078-3
  • Forbes JM, Cooper ME. Mechanisms of diabetic complications. Physiol Rev. 2013;93(1):137–188. doi:10.1152/physrev.00045.2011
  • Magee C, Grieve DJ, Watson CJ, Brazil DP. Diabetic nephropathy: a tangled web to unweave. Cardiovasc Drugs Ther. 2017;31(5–6):579–592. doi:10.1007/s10557-017-6755-9
  • Zhang L, Wen Z, Han L, et al. Research progress on the pathological mechanisms of podocytes in diabetic nephropathy. J Diabetes Res. 2020;2020:7504798. doi:10.1155/2020/7504798
  • Sifuentes-Franco S, Padilla-Tejeda DE, Carrillo-Ibarra S, Miranda-Díaz AG. Oxidative stress, apoptosis, and mitochondrial function in diabetic nephropathy. Int J Endocrinol. 2018;2018:1875870. doi:10.1155/2018/1875870
  • Tang SCW, Yiu WH. Innate immunity in diabetic kidney disease. Nat Rev Nephrol. 2020;16(4):206–222. doi:10.1038/s41581-019-0234-4
  • Chang -T-T, Chen J-W. The role of chemokines and chemokine receptors in diabetic nephropathy. Int J Mol Sci. 2020;21(9):3172. doi:10.3390/ijms21093172
  • Wada J, Makino H. Inflammation and the pathogenesis of diabetic nephropathy. Clin Sci (Lond). 2013;124(3):139–152. doi:10.1042/CS20120198
  • Luis-Rodriguez D, Martinez-Castelao A, Gorriz JL, De-alvaro F, Navarro-Gonzalez JF. Pathophysiological role and therapeutic implications of inflammation in diabetic nephropathy. World J Diabetes. 2012;3(1):7–18. doi:10.4239/wjd.v3.i1.7
  • Rivero A, Mora C, Muros M, Garcia J, Herrera H, Navarro-Gonzalez JF. Pathogenic perspectives for the role of inflammation in diabetic nephropathy. Clin Sci (Lond). 2009;116(6):479–492. doi:10.1042/CS20080394
  • Navarro-Gonzalez JF, Mora-Fernandez C, Muros de Fuentes M, Garcia-Perez J. Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy. Nat Rev Nephrol. 2011;7(6):327–340. doi:10.1038/nrneph.2011.51
  • Giacco F, Brownlee M, Schmidt AM. Oxidative stress and diabetic complications. Circ Res. 2010;107(9):1058–1070. doi:10.1161/CIRCRESAHA.110.223545
  • Tavafi M. Diabetic nephropathy and antioxidants. J Nephropathol. 2013;2(1):20–27. doi:10.5812/nephropathol.9093
  • Forbes JM, Thorburn DR. Mitochondrial dysfunction in diabetic kidney disease. Nat Rev Nephrol. 2018;14(5):291–312.
  • Stumvoll M, Goldstein BJ, van Haeften TW. Type 2 diabetes: principles of pathogenesis and therapy. Lancet. 2005;365(9467):1333–1346. doi:10.1016/S0140-6736(05)61032-X
  • Orchard TJ, Chang Y-F, Ferrell RE, Petro N, Ellis DE. Nephropathy in type 1 diabetes: a manifestation of insulin resistance and multiple genetic susceptibilities?: further evidence from the Pittsburgh Epidemiology of Diabetes Complication Study. Kidney Int. 2002;62(3):963–970.
  • Dib SA. [Insulin resistance and metabolic syndrome in type 1 diabetes mellitus]. Arq Bras Endocrinol Metabol. 2006;50(2):250–263. Portugese. doi:10.1590/S0004-27302006000200011
  • Noh H, King GL. The role of protein kinase C activation in diabetic nephropathy. Kidney Int Suppl. 2007;72(106):S49–S53. doi:10.1038/sj.ki.5002386
  • Chung SS, Ho EC, Lam KS, Chung SK. Contribution of polyol pathway to diabetes-induced oxidative stress. J Am Soc Nephrol. 2003;14(8 Suppl 3):S233–236. doi:10.1097/01.ASN.0000077408.15865.06
  • Sanajou D, Ghorbani Haghjo A, Argani H, Aslani S. AGE-RAGE axis blockade in diabetic nephropathy: current status and future directions. Eur J Pharmacol. 2018;833:158–164. doi:10.1016/j.ejphar.2018.06.001
  • Kang JS, Lee SJ, Lee JH, et al. Angiotensin II-mediated MYH9 downregulation causes structural and functional podocyte injury in diabetic kidney disease. Sci Rep. 2019;9(1):7679. doi:10.1038/s41598-019-44194-3
  • Kanwar YS, Sun L, Xie P, Liu FY, Chen S. A glimpse of various pathogenetic mechanisms of diabetic nephropathy. Annu Rev Pathol. 2011;6:395–423. doi:10.1146/annurev.pathol.4.110807.092150
  • Kato M, Natarajan R. Epigenetics and epigenomics in diabetic kidney disease and metabolic memory. Nat Rev Nephrol. 2019;15(6):327–345. doi:10.1038/s41581-019-0135-6
  • Callaghan MJ, Chang EI, Seiser N, et al. Pulsed electromagnetic fields accelerate normal and diabetic wound healing by increasing endogenous FGF-2 release. Plast Reconstr Surg. 2008;121(1):130–141. doi:10.1097/01.prs.0000293761.27219.84
  • So WY, Leung PS. Fibroblast growth factor 21 as an emerging therapeutic target for type 2 diabetes mellitus. Med Res Rev. 2016;36(4):672–704. doi:10.1002/med.21390
  • Yang H, Feng A, Lin S, et al. Fibroblast growth factor-21 prevents diabetic cardiomyopathy via AMPK-mediated antioxidation and lipid-lowering effects in the heart. Cell Death Dis. 2018;9(2):1–4.
  • Donate-Correa J, Martín-Núñez E, Ferri C, et al. FGF23 and klotho levels are independently associated with diabetic foot syndrome in type 2 diabetes mellitus. J Clin Med. 2019;8(4):448. doi:10.3390/jcm8040448
  • Katoh M. Therapeutics targeting FGF signaling network in human diseases. Trends Pharmacol Sci. 2016;37(12):1081–1096. doi:10.1016/j.tips.2016.10.003
  • Itoh N, Ornitz DM. Evolution of the Fgf and Fgfr gene families. Trends Genet. 2004;20(11):563–569. doi:10.1016/j.tig.2004.08.007
  • Raju R, Palapetta SM, Sandhya VK, et al. A network map of FGF-1/FGFR signaling system. J Signal Transduct. 2014;2014:962962. doi:10.1155/2014/962962
  • Gasser E, Moutos CP, Downes M, Evans RM. FGF1 - a new weapon to control type 2 diabetes mellitus. Nat Rev Endocrinol. 2017;13(10):599–609. doi:10.1038/nrendo.2017.78
  • Jonker JW, Suh JM, Atkins AR, et al. A PPARγ–FGF1 axis is required for adaptive adipose remodelling and metabolic homeostasis. Nature. 2012;485(7398):391–394. doi:10.1038/nature10998
  • Suh JM, Jonker JW, Ahmadian M, et al. Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer. Nature. 2014;513(7518):436–439. doi:10.1038/nature13540
  • Fan L, Ding L, Lan J, Niu J, He Y, Song L. Fibroblast growth factor-1 improves insulin resistance via repression of JNK-mediated inflammation. Front Pharmacol. 2019;10. doi:10.3389/fphar.2019.01478
  • Li Z, Liu J, Wang W, Zhao Y, Yang D, Geng X. Investigation of hub genes involved in diabetic nephropathy using biological informatics methods. Ann Transl Med. 2020;8(17):1087. doi:10.21037/atm-20-5647
  • Giribabu N, Karim K, Kilari EK, Salleh N. Phyllanthus niruri leaves aqueous extract improves kidney functions, ameliorates kidney oxidative stress, inflammation, fibrosis and apoptosis and enhances kidney cell proliferation in adult male rats with diabetes mellitus. J Ethnopharmacol. 2017;205:123–137. doi:10.1016/j.jep.2017.05.002
  • Liang G, Song L, Chen Z, et al. Fibroblast growth factor 1 ameliorates diabetic nephropathy by an anti-inflammatory mechanism. Kidney Int. 2018;93(1):95–109. doi:10.1016/j.kint.2017.05.013
  • Wang D, Jin M, Zhao X, et al. FGF1(ΔHBS) ameliorates chronic kidney disease via PI3K/AKT mediated suppression of oxidative stress and inflammation. Cell Death Dis. 2019;10(6):464. doi:10.1038/s41419-019-1696-9
  • Wu Y, Li Y, Jiang T, et al. Reduction of cellular stress is essential for Fibroblast growth factor 1 treatment for diabetic nephropathy. J Cell Mol Med. 2018;22(12):6294–6303. doi:10.1111/jcmm.13921
  • Pena AM, Chen S, Feng B, et al. Prevention of diabetic nephropathy by modified acidic fibroblast growth factor. Nephron. 2017;137(3):221–236. doi:10.1159/000478745
  • Perlman AS, Chevalier JM, Wilkinson P, et al. Serum inflammatory and immune mediators are elevated in early stage diabetic nephropathy. Ann Clin Lab Sci. 2015;45(3):256–263.
  • Stephan CC, Chang KC, LeJeune W, et al. Role for heparin-binding growth factors in glucose-induced vascular dysfunction. Diabetes. 1998;47(11):1771–1778. doi:10.2337/diabetes.47.11.1771
  • Strutz F, Zeisberg M, Hemmerlein B, et al. Basic fibroblast growth factor expression is increased in human renal fibrogenesis and may mediate autocrine fibroblast proliferation. Kidney Int. 2000;57(4):1521–1538. doi:10.1046/j.1523-1755.2000.00997.x
  • Strutz F, Zeisberg M, Ziyadeh FN, et al. Role of basic fibroblast growth factor-2 in epithelial-mesenchymal transformation. Kidney Int. 2002;61(5):1714–1728. doi:10.1046/j.1523-1755.2002.00333.x
  • Vasko R, Koziolek M, Ikehata M, et al. Role of basic fibroblast growth factor (FGF-2) in diabetic nephropathy and mechanisms of its induction by hyperglycemia in human renal fibroblasts. Am J Physiol Renal Physiol. 2009;296(6):F1452–F1463. doi:10.1152/ajprenal.90352.2008
  • Masola V, Gambaro G, Tibaldi E, et al. Heparanase and syndecan-1 interplay orchestrates fibroblast growth factor-2-induced epithelial-mesenchymal transition in renal tubular cells. J Biol Chem. 2012;287(2):1478–1488. doi:10.1074/jbc.M111.279836
  • Masola V, Zaza G, Onisto M, Lupo A, Gambaro G. Impact of heparanase on renal fibrosis. J Transl Med. 2015;13:181.
  • Masola V, Zaza G, Gambaro G. Sulodexide and glycosaminoglycans in the progression of renal disease. Nephrol Dial Transplant. 2014;29(Suppl 1):i74–i79. doi:10.1093/ndt/gft389
  • Masola V, Zaza G, Secchi MF, Gambaro G, Lupo A, Onisto M. Heparanase is a key player in renal fibrosis by regulating TGF-β expression and activity. Biochimica et Biophysica Acta. 2014;1843(9):2122–2128. doi:10.1016/j.bbamcr.2014.06.005
  • Floege J, Kriz W, Schulze M, et al. Basic fibroblast growth factor augments podocyte injury and induces glomerulosclerosis in rats with experimental membranous nephropathy. J Clin Invest. 1995;96(6):2809–2819. doi:10.1172/JCI118351
  • Villanueva S, Contreras F, Tapia A, et al. Basic fibroblast growth factor reduces functional and structural damage in chronic kidney disease. Am J Physiol Renal Physiol. 2014;306(4):F430–441. doi:10.1152/ajprenal.00720.2012
  • Okamoto K, Honda K, Doi K, et al. Glypican-5 increases susceptibility to nephrotic damage in diabetic kidney. Am J Pathol. 2015;185(7):1889–1898. doi:10.1016/j.ajpath.2015.03.025
  • Floege J, Hudkins KL, Eitner F, et al. Localization of fibroblast growth factor-2 (basic FGF) and FGF receptor-1 in adult human kidney. Kidney Int. 1999;56(3):883–897. doi:10.1046/j.1523-1755.1999.00637.x
  • Holland WL, Adams AC, Brozinick JT, et al. An FGF21-adiponectin-ceramide axis controls energy expenditure and insulin action in mice. Cell Metab. 2013;17(5):790–797. doi:10.1016/j.cmet.2013.03.019
  • Nakano T, Shiizaki K, Miura Y, et al. Increased fibroblast growth factor-21 in chronic kidney disease is a trade-off between survival benefit and blood pressure dysregulation. Sci Rep. 2019;9(1):19247. doi:10.1038/s41598-019-55643-4
  • Looker HC, Colombo M, Hess S, et al. Biomarkers of rapid chronic kidney disease progression in type 2 diabetes. Kidney Int. 2015;88(4):888–896. doi:10.1038/ki.2015.199
  • Yu W, Zhu H, Chen X, et al. Genetic variants flanking the FGF21 gene were associated with renal function in Chinese patients with type 2 diabetes. J Diabetes Res. 2019;2019:9387358. doi:10.1155/2019/9387358
  • Lin Z, Zhou Z, Liu Y, et al. Circulating FGF21 levels are progressively increased from the early to end stages of chronic kidney diseases and are associated with renal function in Chinese. PLoS One. 2011;6(4):e18398. doi:10.1371/journal.pone.0018398
  • Lee CH, Hui EY, Woo YC, et al. Circulating fibroblast growth factor 21 levels predict progressive kidney disease in subjects with type 2 diabetes and normoalbuminuria. J Clin Endocrinol Metab. 2015;100(4):1368–1375. doi:10.1210/jc.2014-3465
  • Gamrot Z, Adamczyk P, Świętochowska E, Roszkowska-Bjanid D, Gamrot J, Szczepańska M. Fibroblast growth factor 21 (FGF21) in children and adolescents with chronic kidney disease. Physiol Res. 2020;69(3):451–460. doi:10.33549/physiolres.934307
  • Yamamoto S, Koyama D, Igarashi R, et al. Serum endocrine fibroblast growth factors as potential biomarkers for chronic kidney disease and various metabolic dysfunctions in aged patients. Intern Med. 2020;59(3):345–355. doi:10.2169/internalmedicine.3597-19
  • Jian WX, Peng WH, Jin J, et al. Association between serum fibroblast growth factor 21 and diabetic nephropathy. Metabolism. 2012;61(6):853–859. doi:10.1016/j.metabol.2011.10.012
  • Esteghamati A, Khandan A, Momeni A, et al. Circulating levels of fibroblast growth factor 21 in early-stage diabetic kidney disease. Ir J Med Sci. 2017;186(3):785–794. doi:10.1007/s11845-017-1554-7
  • Zhang C, Shao M, Yang H, et al. Attenuation of hyperlipidemia- and diabetes-induced early-stage apoptosis and late-stage renal dysfunction via administration of fibroblast growth factor-21 is associated with suppression of renal inflammation. PLoS One. 2013;8(12):e82275. doi:10.1371/journal.pone.0082275
  • Angel GM, Paola VV, Froylan David MS, et al. Fibroblast growth factor 21 is associated with increased serum total antioxidant capacity and oxidized lipoproteins in humans with different stages of chronic kidney disease. Ther Adv Endocrinol Metab. 2021;12:20420188211001160. doi:10.1177/20420188211001160
  • Iglesias P, Selgas R, Romero S, Diez JJ. Biological role, clinical significance, and therapeutic possibilities of the recently discovered metabolic hormone fibroblastic growth factor 21. Eur J Endocrinol. 2012;167(3):301–309. doi:10.1530/EJE-12-0357
  • Kim HW, Lee JE, Cha JJ, et al. Fibroblast growth factor 21 improves insulin resistance and ameliorates renal injury in db/db mice. Endocrinology. 2013;154(9):3366–3376. doi:10.1210/en.2012-2276
  • Kim KH, Jeong YT, Oh H, et al. Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine. Nat Med. 2013;19(1):83–92. doi:10.1038/nm.3014
  • Wei W, An XR, Jin SJ, Li XX, Xu M. Inhibition of insulin resistance by PGE1 via autophagy-dependent FGF21 pathway in diabetic nephropathy. Sci Rep. 2018;8(1):9. doi:10.1038/s41598-017-18427-2
  • Li S, Guo X, Zhang T, et al. Fibroblast growth factor 21 ameliorates high glucose-induced fibrogenesis in mesangial cells through inhibiting STAT5 signaling pathway. Biomed Pharmacother. 2017;93:695–704. doi:10.1016/j.biopha.2017.06.100
  • Weng W, Ge T, Wang Y, et al. Therapeutic effects of fibroblast growth factor-21 on diabetic nephropathy and the possible mechanism in type 1 diabetes mellitus mice. Diabetes Metab J. 2020;44(4):566–580. doi:10.4093/dmj.2019.0089
  • Liu M-H. FGF-21 alleviates diabetes-associated vascular complications: inhibiting NF-κB/NLRP3 inflammasome-mediated inflammation? Int J Cardiol. 2015;185:320–321. doi:10.1016/j.ijcard.2015.03.165
  • Chen K, Zhang J, Zhang W, et al. ATP-P2X4 signaling mediates NLRP3 inflammasome activation: a novel pathway of diabetic nephropathy. Int J Biochem Cell Biol. 2013;45(5):932–943. doi:10.1016/j.biocel.2013.02.009
  • Lin S, Yu L, Ni Y, et al. Fibroblast growth factor 21 attenuates diabetes-induced renal fibrosis by negatively regulating TGF-beta-p53-Smad2/3-mediated epithelial-to-mesenchymal transition via activation of AKT. Diabetes Metab J. 2020;44(1):158–172. doi:10.4093/dmj.2018.0235
  • Cheng Y, Zhang J, Guo W, et al. Up-regulation of Nrf2 is involved in FGF21-mediated fenofibrate protection against type 1 diabetic nephropathy. Free Radic Biol Med. 2016;93:94–109. doi:10.1016/j.freeradbiomed.2016.02.002
  • Cheng Y, Zhang X, Ma F, et al. The role of Akt2 in the protective effect of fenofibrate against diabetic nephropathy. Int J Biol Sci. 2020;16(4):553–567. doi:10.7150/ijbs.40643
  • Xie Y, Su N, Yang J, et al. FGF/FGFR signaling in health and disease. Signal Transduct Target Ther. 2020;5(1):181.
  • Rodelo-Haad C, Santamaria R, Muñoz-Castañeda JR, Pendón-ruiz de Mier MV, Martin-Malo A, Rodriguez M. FGF23, biomarker or target? Toxins. 2019;11(3):175. doi:10.3390/toxins11030175
  • Muñoz-Castañeda JR, Rodelo-Haad C, Pendon-ruiz de Mier MV, Martin-Malo A, Santamaria R, Rodriguez M. Klotho/FGF23 and Wnt signaling as important players in the comorbidities associated with chronic kidney disease. Toxins. 2020;12(3):185. doi:10.3390/toxins12030185
  • Buchanan S, Combet E, Stenvinkel P, Shiels PG. Klotho, aging, and the failing kidney. Front Endocrinol (Lausanne). 2020;11:560. doi:10.3389/fendo.2020.00560
  • Nowak N. Protective factors as biomarkers and targets for prevention and treatment of diabetic nephropathy: from current human evidence to future possibilities. J Diabetes Investig. 2020;11(5):1085–1096. doi:10.1111/jdi.13257
  • Bouma-de Krijger A, Bots ML, Vervloet MG, et al. Time-averaged level of fibroblast growth factor-23 and clinical events in chronic kidney disease. Nephrol Dial Transplant. 2014;29(1):88–97. doi:10.1093/ndt/gft456
  • Kuro OM. Klotho and endocrine fibroblast growth factors: markers of chronic kidney disease progression and cardiovascular complications? Nephrol Dial Transplant. 2019;34(1):15–21. doi:10.1093/ndt/gfy126
  • Komaba H, Fukagawa M. The role of FGF23 in CKD–with or without Klotho. Nat Rev Nephrol. 2012;8(8):484–490. doi:10.1038/nrneph.2012.116
  • Wahl P, Xie H, Scialla J, et al. Earlier onset and greater severity of disordered mineral metabolism in diabetic patients with chronic kidney disease. Diabetes Care. 2012;35(5):994–1001. doi:10.2337/dc11-2235
  • Garland JS, Holden RM, Ross R, et al. Insulin resistance is associated with fibroblast growth factor-23 in stage 3–5 chronic kidney disease patients. J Diabetes Complications. 2014;28(1):61–65. doi:10.1016/j.jdiacomp.2013.09.004
  • Agarwal R, Duffin KL, Laska DA, Voelker JR, Breyer MD, Mitchell PG. A prospective study of multiple protein biomarkers to predict progression in diabetic chronic kidney disease. Nephrol Dial Transplant. 2014;29(12):2293–2302. doi:10.1093/ndt/gfu255
  • Lu X, Hu MC. Klotho/FGF23 axis in chronic kidney disease and cardiovascular disease. Kidney Dis (Basel). 2017;3(1):15–23. doi:10.1159/000452880
  • David V, Martin A, Isakova T, et al. Inflammation and functional iron deficiency regulate fibroblast growth factor 23 production. Kidney Int. 2016;89(1):135–146. doi:10.1038/ki.2015.290
  • Francis C, David V. Inflammation regulates fibroblast growth factor 23 production. Curr Opin Nephrol Hypertens. 2016;25(4):325–332. doi:10.1097/MNH.0000000000000232
  • Czaya B, Faul C. FGF23 and inflammation-a vicious coalition in CKD. Kidney Int. 2019;96(4):813–815. doi:10.1016/j.kint.2019.05.018
  • Zhang X, Guo K, Xia F, Zhao X, Huang Z, Niu J. FGF23(C-tail) improves diabetic nephropathy by attenuating renal fibrosis and inflammation. BMC Biotechnol. 2018;18(1):33. doi:10.1186/s12896-018-0449-7
  • Farias-Basulto A, Martinez-Ramirez HR, Gomez-Garcia EF, et al. Circulating levels of soluble klotho and fibroblast growth factor 23 in diabetic patients and its association with early nephropathy. Arch Med Res. 2018;49(7):451–455. doi:10.1016/j.arcmed.2019.01.008
  • Titan SM, Zatz R, Graciolli FG, et al. FGF-23 as a predictor of renal outcome in diabetic nephropathy. Clin J Am Soc Nephrol. 2011;6(2):241–247. doi:10.2215/CJN.04250510
  • Silswal N, Touchberry CD, Daniel DR, et al. FGF23 directly impairs endothelium-dependent vasorelaxation by increasing superoxide levels and reducing nitric oxide bioavailability. Am J Physiol Endocrinol Metab. 2014;307(5):E426–E436. doi:10.1152/ajpendo.00264.2014
  • Yilmaz MI, Sonmez A, Saglam M, et al. Ramipril lowers plasma FGF-23 in patients with diabetic nephropathy. Am J Nephrol. 2014;40(3):208–214. doi:10.1159/000366169
  • Zanchi C, Locatelli M, Benigni A, et al. Renal expression of FGF23 in progressive renal disease of diabetes and the effect of ACE inhibitor. PLoS One. 2013;8(8):e70775. doi:10.1371/journal.pone.0070775
  • Dokumacioglu E, Iskender H, Musmul A. Effect of hesperidin treatment on α-Klotho/FGF-23 pathway in rats with experimentally-induced diabetes. Biomed Pharmacother. 2019;109:1206–1210. doi:10.1016/j.biopha.2018.10.192
  • Ge X, Xi L, Wang Q, et al. Circular RNA Circ_0000064 promotes the proliferation and fibrosis of mesangial cells via miR-143 in diabetic nephropathy. Gene. 2020;758:144952. doi:10.1016/j.gene.2020.144952
  • Mou X, Chenv JW, Zhou DY, et al. A novel identified circular RNA, circ_0000491, aggravates the extracellular matrix of diabetic nephropathy glomerular mesangial cells through suppressing miR‑101b by targeting TGFβRI. Mol Med Rep. 2020;22(5):3785–3794.
  • Liu H, Wang X, Wang ZY, Li L. Circ_0080425 inhibits cell proliferation and fibrosis in diabetic nephropathy via sponging miR-24-3p and targeting fibroblast growth factor 11. J Cell Physiol. 2020;235(5):4520–4529. doi:10.1002/jcp.29329
  • Md Dom ZI, Satake E, Skupien J, et al. Circulating proteins protect against renal decline and progression to end-stage renal disease in patients with diabetes. Sci Transl Med. 2021;13:600. doi:10.1126/scitranslmed.abd2699
  • Huh SH, Ha L, Jang HS. Nephron progenitor maintenance is controlled through fibroblast growth factors and sprouty1 interaction. J Am Soc Nephrol. 2020;31(11):2559–2572. doi:10.1681/ASN.2020040401
  • Barak H, Huh SH, Chen S, et al. FGF9 and FGF20 maintain the stemness of nephron progenitors in mice and man. Dev Cell. 2012;22(6):1191–1207. doi:10.1016/j.devcel.2012.04.018
  • Xu W, Yang Z, Lu N. A new role for the PI3K/Akt signaling pathway in the epithelial-mesenchymal transition. Cell Adh Migr. 2015;9(4):317–324. doi:10.1080/19336918.2015.1016686
  • Xuejiao S, Lin C, Zhiyi H. PI3K/Akt-Nrf2 and anti-inflammation effect of macrolides in chronic obstructive pulmonary disease. Curr Drug Metab. 2019;20(4):301–304. doi:10.2174/1389200220666190227224748
  • Yang S, Guo Y, Zhang W, Zhang J, Zhang Y, Xu P. Effect of FGF-21 on implant bone defects through hepatocyte growth factor (HGF)-mediated PI3K/AKT signaling pathway. Biomed Pharmacother. 2019;109:1259–1267. doi:10.1016/j.biopha.2018.10.150
  • Tang QY, Wei JX, Xue SF, Liu GH, Fu LX. Fibrogrowth factor-2 protects against acute lung injury by activating the PI3K/Akt signaling pathway. J Biol Regul Homeost Agents. 2020;34(5):1679–1688.
  • Cantley LC. The phosphoinositide 3-kinase pathway. Science. 2002;296(5573):1655. doi:10.1126/science.296.5573.1655
  • Rizvi F, Shukla S, Kakkar P. Essential role of PH domain and leucine-rich repeat protein phosphatase 2 in Nrf2 suppression via modulation of Akt/GSK3beta/Fyn kinase axis during oxidative hepatocellular toxicity. Cell Death Dis. 2014;5:e1153. doi:10.1038/cddis.2014.118
  • Feng X, Guan W, Zhao Y, et al. Dexmedetomidine ameliorates lipopolysaccharide-induced acute kidney injury in rats by inhibiting inflammation and oxidative stress via the GSK-3beta/Nrf2 signaling pathway. J Cell Physiol. 2019;234(10):18994–19009. doi:10.1002/jcp.28539
  • Kim AH, Khursigara G, Sun X, Franke TF, Chao MV. Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1. Mol Cell Biol. 2001;21(3):893. doi:10.1128/MCB.21.3.893-901.2001
  • Tesch GH, Ma FY, Han Y, Liles JT, Breckenridge DG, Nikolic-Paterson DJ. ASK1 inhibitor halts progression of diabetic nephropathy in nos3-deficient mice. Diabetes. 2015;64(11):3903.
  • Amos LA, Ma FY, Tesch GH, et al. ASK1 inhibitor treatment suppresses p38/JNK signalling with reduced kidney inflammation and fibrosis in rat crescentic glomerulonephritis. J Cell Mol Med. 2018;22(9):4522–4533. doi:10.1111/jcmm.13705
  • Lu Q, Wang -W-W, Zhang M-Z, et al. ROS induces epithelial-mesenchymal transition via the TGF-β1/PI3K/Akt/mTOR pathway in diabetic nephropathy. Exp Ther Med. 2019;17(1):835–846.
  • Fantus D, Rogers NM, Grahammer F, Huber TB, Thomson AW. Roles of mTOR complexes in the kidney: implications for renal disease and transplantation. Nat Rev Nephrol. 2016;12(10):587–609.
  • Kawarada Y, Inoue Y, Kawasaki F, et al. TGF-β induces p53/Smads complex formation in the PAI-1 promoter to activate transcription. Sci Rep. 2016;6:35483. doi:10.1038/srep35483
  • Higgins SP, Tang Y, Higgins CE, et al. TGF-β1/p53 signaling in renal fibrogenesis. Cell Signal. 2018;43:1–10. doi:10.1016/j.cellsig.2017.11.005
  • Mayo LD, Donner DB. The PTEN, Mdm2, p53 tumor suppressor–oncoprotein network. Trends Biochem Sci. 2002;27(9):462–467. doi:10.1016/S0968-0004(02)02166-7
  • Wang Q, Cang Z, Shen L, et al. circ_0037128/miR-17-3p/AKT3 axis promotes the development of diabetic nephropathy. Gene. 2021;765:145076. doi:10.1016/j.gene.2020.145076
  • Yamauchi T, Kamon J, Minokoshi Y, et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med. 2002;8(11):1288–1295. doi:10.1038/nm788
  • Wang W, Sun W, Cheng Y, Xu Z, Cai L. Role of sirtuin-1 in diabetic nephropathy. J Mol Med. 2019;97(3):291–309. doi:10.1007/s00109-019-01743-7
  • Papadimitriou A, Silva KC, Peixoto EBMI, Borges CM, Lopes de faria JM, Lopes de faria JB. Theobromine increases NAD +/Sirt-1 activity and protects the kidney under diabetic conditions. Am J Physiol Renal Physiol. 2014;308(3):F209–F225. doi:10.1152/ajprenal.00252.2014
  • Hasegawa K, Wakino S, Simic P, et al. Renal tubular Sirt1 attenuates diabetic albuminuria by epigenetically suppressing Claudin-1 overexpression in podocytes. Nat Med. 2013;19(11):1496–1504. doi:10.1038/nm.3363
  • Ruderman NB, Xu XJ, Nelson L, et al. AMPK and SIRT1: a long-standing partnership? Am J Physiol Endocrinol Metab. 2010;298(4):E751–E760. doi:10.1152/ajpendo.00745.2009
  • Xue W, Mao J, Chen Q, Ling W, Sun Y. Mogroside IIIE alleviates high glucose-induced inflammation, oxidative stress and apoptosis of podocytes by the activation of AMPK/SIRT1 signaling pathway. Diabetes Metabol Syndr Obes. 2020;13:3821–3830. doi:10.2147/DMSO.S276184
  • Chau MDL, Gao J, Yang Q, Wu Z, Gromada J. Fibroblast growth factor 21 regulates energy metabolism by activating the AMPK-SIRT1-PGC-1alpha pathway. Proc Natl Acad Sci U S A. 2010;107(28):12553–12558. doi:10.1073/pnas.1006962107
  • Cai -Y-Y, Zhang H-B, Fan C-X, et al. Renoprotective effects of brown adipose tissue activation in diabetic mice. J Diabetes. 2019;11(12):958–970. doi:10.1111/1753-0407.12938
  • Papadimitriou A, Peixoto EBMI, Silva KC, Lopes de Faria JM, Lopes de Faria JB. Increase in AMPK brought about by cocoa is renoprotective in experimental diabetes mellitus by reducing NOX4/TGFβ-1 signaling. J Nutr Biochem. 2014;25(7):773–784. doi:10.1016/j.jnutbio.2014.03.010
  • Lin Q, Huang Z, Cai G, et al. Activating AMP-activated protein kinase mediates fibroblast growth factor 1 protection from nonalcoholic fatty liver disease in mice. Hepatology. 2020;73(6):2206.
  • Chen Q, Huang J, Gong W, et al. MRTF-A mediated FN and ICAM-1 expression in AGEs-induced rat glomerular mesangial cells via activating STAT5. Mol Cell Endocrinol. 2018;460:123–133. doi:10.1016/j.mce.2017.07.014
  • Yu J, Zhao L, Wang A, et al. Growth hormone stimulates transcription of the fibroblast growth factor 21 gene in the liver through the signal transducer and activator of transcription 5. Endocrinology. 2012;153(2):750–758. doi:10.1210/en.2011-1591
  • Huang J-S, Chuang L-Y, Guh J-Y, et al. Effect of nitric oxide-cGMP-dependent protein kinase activation on advanced glycation end-product–induced proliferation in renal fibroblasts. J Am Soc Nephrol. 2005;16(8):2318. doi:10.1681/ASN.2005010030
  • Zhou Y, Lv C, Wu C, Chen F, Shao Y, Wang Q. Suppressor of cytokine signaling (SOCS) 2 attenuates renal lesions in rats with diabetic nephropathy. Acta Histochem. 2014;116(5):981–988. doi:10.1016/j.acthis.2014.04.002
  • Kaltenecker D, Mueller KM, Benedikt P, et al. Adipocyte STAT5 deficiency promotes adiposity and impairs lipid mobilisation in mice. Diabetologia. 2017;60(2):296–305. doi:10.1007/s00125-016-4152-8