Top

Diabetology & Metabolic Syndrome

Published in:

Open Access 01-12-2023 | Diabetic Nephropathy | Research

Adipose-derived stem cell exosomes regulate Nrf2/Keap1 in diabetic nephropathy by targeting FAM129B

Authors: Peiyao Ren, Fengmei Qian, Lanjun Fu, Wenfang He, Qiang He, Juan Jin, Danna Zheng

Published in: Diabetology & Metabolic Syndrome | Issue 1/2023

Abstract

Background

Exosomes from adipose-derived stem cells (ADSCs-Exos) have exhibited a therapeutic role in diabetic nephropathy (DN). Further studies are needed to investigate how ADSCs-Exos regulate oxidative stress and inflammation in high glucose-induced podocyte injury.

Methods

An enzyme-linked immunosorbent assay (ELISA) was used to detect cellular inflammation. Reactive oxygen species (ROS) levels were assessed using flow cytometry in podocytes with different treatments. A malondialdehyde (MDA) kit was used to evaluate the lipid peroxidation levels in podocytes and kidney tissues of mice. Western blotting and co-immunoprecipitation were performed to detect protein expression and protein-protein interactions.

Results

ADSCs-Exos reversed oxidative stress and inflammation in podocytes and kidney tissues of DN mice induced by high glucose levels in vitro and in vivo. Interference with heme oxygenase-1 expression could reverse the improvement effect of ADSCs-Exos on oxidative stress induced by high glucose levels. Furthermore, high glucose inhibited nuclear factor erythroid 2-related factor 2 (Nrf2) protein expression and promoted Kelch-like ECH-associated protein 1 (Keap1) protein expression in podocytes, as well as their binding ability. As a potential target for Nrf2/Keap1 pathway regulation, FAM129B expression in podocytes is regulated by high glucose and ADSCs-Exos. Moreover, FAM129B siRNA blocked the inhibitory effect of ADSCs-Exos on intracellular ROS and MDA upregulation induced by high glucose in podocytes.

Conclusion

ADSCs-Exos regulate the Nrf2/Keap1 pathway to alleviate inflammation and oxidative stress in DN by targeting FAM129B, which may provide a potential therapeutic strategy for DN.

Available only for authorised users

Samsu N. (2021) Diabetic nephropathy: Challenges in pathogenesis, diagnosis, and treatment. BioMed Res Int 2021:1497449. https://doi.org/10.1155/2021/1497449.

Umanath K, Lewis JB. Update on diabetic nephropathy: core curriculum 2018. Am J Kidney Dis. 2018;71(6):884–95. https://doi.org/10.1053/j.ajkd.2017.10.026.CrossRefPubMed

Krawczenko A, Klimczak A. Adipose tissue-derived mesenchymal stem/stromal cells and their contribution to angiogenic processes in tissue regeneration. Int J Mol Sci. 2022;23(5). https://doi.org/10.3390/ijms23052425.

Park SJ, Kim JM, Kim J, et al. Molecular mechanisms of biogenesis of apoptotic exosome-like vesicles and their roles as damage-associated molecular patterns. Proc Natl Acad Sci U S A. 2018;115(50):E11721–30. https://doi.org/10.1073/pnas.1811432115.CrossRefPubMedPubMedCentral

Al-Kharboosh R, Perera JJ, Bechtle A, Bu G, Quinones-Hinojosa A. Emerging point-of-care autologous cellular therapy using adipose-derived stromal vascular fraction for neurodegenerative diseases. Clin Transl Med. 2022;12(12):e1093. https://doi.org/10.1002/ctm2.1093.CrossRefPubMedPubMedCentral

Deng H, Chen Y. The role of adipose-derived stem cells-derived extracellular vesicles in the treatment of diabetic foot ulcer: Trends and prospects. Front Endocrinol. 2022;13:902130. https://doi.org/10.3389/fendo.2022.902130.CrossRef

Villata S, Canta M, Cauda v., Evs. (2020) EVs and bioengineering: From cellular products to engineered nanomachines. Int J Mol Sci 21(17). https://doi.org/10.3390/ijms21176048.

Xia X, Wang Y, Zheng JC. Extracellular vesicles, from the pathogenesis to the therapy of neurodegenerative diseases. Transl Neurodegener. 2022;11(1):53. https://doi.org/10.1186/s40035-022-00330-0.CrossRefPubMedPubMedCentral

Thongboonkerd V. Roles for exosome in various kidney diseases and disorders. Front Pharmacol. 2019;10:1655. https://doi.org/10.3389/fphar.2019.01655.CrossRefPubMed

10.

Peng L, Chen Y, Shi S, Wen H. Stem cell-derived and circulating exosomal microRNAs as new potential tools for diabetic nephropathy management. Stem Cell Res Ther. 2022;13(1):25. https://doi.org/10.1186/s13287-021-02696-w.CrossRefPubMedPubMedCentral

11.

Jin J, Shi Y, Gong J, et al. Exosome secreted from adipose-derived stem cells attenuates diabetic nephropathy by promoting autophagy flux and inhibiting apoptosis in podocyte. Stem Cell Res Ther. 2019;10(1):95. https://doi.org/10.1186/s13287-019-1177-1.CrossRefPubMedPubMedCentral

12.

Baum P, Toyka KV, Blüher M, Kosacka J, Nowicki M. Inflammatory mechanisms in the pathophysiology of diabetic peripheral neuropathy (dn)-new aspects. Int J Mol Sci. 2021;22(19):10835. https://doi.org/10.3390/ijms221910835.CrossRefPubMedPubMedCentral

13.

Maiti AK. Development of biomarkers and molecular therapy based on inflammatory genes in diabetic nephropathy. Int J Mol Sci. 2021;22(18):9985. https://doi.org/10.3390/ijms22189985.CrossRefPubMedPubMedCentral

14.

Jianbing H, Xiaotian L, Jie T, et al. The effect of allograft inflammatory factor-1 on inflammation, oxidative stress, and autophagy via mir-34a/atg4b pathway in diabetic kidney disease. Oxid Med Cell Longev. 2022;2022:1668000. https://doi.org/10.1155/2022/1668000.CrossRefPubMedPubMedCentral

15.

Cao Y, Lin JH, Hammes HP, Zhang C. Cellular phenotypic transitions in diabetic nephropathy: an update. Front Pharmacol. 2022;13:1038073. https://doi.org/10.3389/fphar.2022.1038073.CrossRefPubMedPubMedCentral

16.

Nagaishi K, Mizue Y, Chikenji T, et al. Mesenchymal stem cell therapy ameliorates diabetic nephropathy via the paracrine effect of renal trophic factors including exosomes. Sci Rep. 2016;6:34842. https://doi.org/10.1038/srep34842.CrossRefPubMedPubMedCentral

17.

Shen K, Jia Y, Wang X, et al. Exosomes from adipose-derived stem cells alleviate the inflammation and oxidative stress via regulating nrf2/ho-1 axis in macrophages. Free Radical Biol Med. 2021;165:54–66. https://doi.org/10.1016/j.freeradbiomed.2021.01.023.CrossRef

18.

Suzuki T, Yamamoto M. Stress-sensing mechanisms and the physiological roles of the keap1-nrf2 system during cellular stress. J Biol Chem. 2017;292(41):16817–24. https://doi.org/10.1074/jbc.R117.800169.CrossRefPubMedPubMedCentral

19.

Baird L, Yamamoto M. The molecular mechanisms regulating the keap1-nrf2 pathway. Mol Cell Biol. 2020;40(13). https://doi.org/10.1128/MCB.00099-20.

20.

Bellezza I, Giambanco I, Minelli A, Donato R. Nrf2-keap1 signaling in oxidative and reductive stress. Biochim Biophys Acta Mol Cell Res. 2018;1865(5):721–33. https://doi.org/10.1016/j.bbamcr.2018.02.010.CrossRefPubMed

21.

Katsuoka F, Motohashi H, Engel JD, Yamamoto M. Nrf2 transcriptionally activates the mafg gene through an antioxidant response element. J Biol Chem. 2005;280(6):4483–90. https://doi.org/10.1074/jbc.M411451200.CrossRefPubMed

22.

Ortega-Trejo JA, Pérez-Villalva R, Sánchez-Navarro A, et al. Repeated episodes of ischemia/reperfusion induce heme-oxygenase-1 (ho-1) and anti-inflammatory responses and protects against chronic kidney disease. Int J Mol Sci. 2022;23(23):14573. https://doi.org/10.3390/ijms232314573.CrossRefPubMedPubMedCentral

23.

Leal EC, Carvalho E. Heme oxygenase-1 as therapeutic target for diabetic foot ulcers. Int J Mol Sci. 2022;23(19):12043. https://doi.org/10.3390/ijms231912043.CrossRefPubMedPubMedCentral

24.

Jin J, Wang Y, Zhao L, et al. Exosomal mirna-215-5p derived from adipose-derived stem cells attenuates epithelial-mesenchymal transition of podocytes by inhibiting ZEB2. BioMed Res Int. 2020;2020:2685305. https://doi.org/10.1155/2020/2685305.CrossRefPubMedPubMedCentral

25.

Cheng KC, Lin RJ, Cheng JY, et al. Fam129b, an antioxidative protein, reduces chemosensitivity by competing with nrf2 for keap1 binding. EBiomedicine. 2019;45:25–38. https://doi.org/10.1016/j.ebiom.2019.06.022.CrossRefPubMedPubMedCentral

26.

Jiang X, Bao Y, Liu H, et al. Vps34 stimulation of p62 phosphorylation for cancer progression. Oncogene. 2017;36(50):6850–62. https://doi.org/10.1038/onc.2017.295.CrossRefPubMedPubMedCentral

27.

Ge W, Zhao K, Wang X, et al. Ia spp is an antioxidative factor and drives cancer growth and drug resistance by competing with nrf2 for keap1 binding. Cancer Cell. 2017;32(5):561–573e6. https://doi.org/10.1016/j.ccell.2017.09.008.CrossRefPubMed

28.

Cheng HT, Xu X, Lim PS et al. (2021). Worldwide Epidemiology of Diabetes-Related End-Stage Renal Disease, 2000–2015. Diabetes Care. 2021;44(1):89–97. https://doi.org/10.2337/dc20-1913.

29.

Carstens MH, Quintana FJ, Calderwood ST, et al. Treatment of chronic diabetic foot ulcers with adipose-derived stromal vascular fraction cell injections: Safety and evidence of efficacy at 1 year. Stem Cells Transl Med. 2021;10(8):1138–47. https://doi.org/10.1002/sctm.20-0497.CrossRefPubMedPubMedCentral

30.

Liu Y, Lou G, Li A, et al. Amsc-derived exosomes alleviate lipopolysaccharide/d-galactosamine-induced acute liver failure by mir-17-mediated reduction of txnip/nlrp3 inflammasome activation in macrophages. EBiomedicine. 2018;36:140–50. https://doi.org/10.1016/j.ebiom.2018.08.054.CrossRefPubMedPubMedCentral

31.

Bi H, Li H, Zhang C, et al. Stromal vascular fraction promotes migration of fibroblasts and angiogenesis through regulation of extracellular matrix in the skin wound healing process. Stem Cell Res Ther. 2019;10(1):302. https://doi.org/10.1186/s13287-019-1415-6.CrossRefPubMedPubMedCentral

32.

Shin S, Lee J, Kwon Y, et al. Comparative proteomic analysis of the mesenchymal stem cells secretome from adipose, bone marrow, placenta and Wharton’s jelly. Int J Mol Sci. 2021;22(2):20845. https://doi.org/10.3390/ijms22020845.CrossRef

33.

Liu S, Li R, Dou K, et al. Injectable thermo-sensitive hydrogel containing adsc-derived exosomes for the treatment of cavernous nerve injury. Carbohydr Polym. 2023;300:120226. https://doi.org/10.1016/j.carbpol.2022.120226.CrossRefPubMed

34.

Piao C, Sang J, Kou Z, et al. Effects of exosomes derived from adipose-derived mesenchymal stem cells on pyroptosis and regeneration of injured liver. Int J Mol Sci. 2022;23(20):12065. https://doi.org/10.3390/ijms232012065.CrossRefPubMedPubMedCentral

35.

Wang P, Xue Y, Zuo Y, et al. Exosome-encapsulated microrna-140-5p alleviates neuronal injury following subarachnoid hemorrhage by regulating igfbp5-mediated pi3k/akt signaling pathway. Mol Neurobiol. 2022;59(12):7212–28. https://doi.org/10.1007/s12035-022-03007-x.CrossRefPubMed

36.

Liu C, Yang M, Li L, et al. A glimpse of inflammation and anti-inflammation therapy in diabetic kidney disease. Front Physiol. 2022;13:909569. https://doi.org/10.3389/fphys.2022.909569.CrossRefPubMedPubMedCentral

37.

Eshghi F, Tahmasebi S, Alimohammadi M, et al. Study of immunomodulatory effects of mesenchymal stem cell-derived exosomes in a mouse model of lps induced systemic inflammation. Life Sci. 2022;310:120938. https://doi.org/10.1016/j.lfs.2022.120938.CrossRefPubMed

38.

Yuan S, Liang X, He Wet et al. (2021). ATF4-dependent heme-oxygenase-1 attenuates diabetic nephropathy by inducing autophagy and inhibiting apoptosis in podocyte. Ren Fail. 2021;43(1):968–979. https://doi.org/10.1080/0886022X.2021.1936040.

39.

Ding X, Zhao H, Qiao C. (2022). Icariin protects podocytes from NLRP3 activation by Sesn2-induced mitophagy through the Keap1-Nrf2/HO-1 axis in diabetic nephropathy. Phytomedicine. 2022;99:154005. https://doi.org/10.1016/j.phymed.2022.154005.

40.

Antar SA, Abdo W, Taha RS et al. (2022). Telmisartan attenuates diabetic nephropathy by mitigating oxidative stress and inflammation, and upregulating Nrf2/HO-1 signaling in diabetic rats. Life Sci. 2022;291:120260. https://doi.org/10.1016/j.lfs.2021.120260.

41.

Alaofi AL. (2020). Sinapic Acid Ameliorates the Progression of Streptozotocin (STZ)-Induced Diabetic Nephropathy in Rats via NRF2/HO-1 Mediated Pathways. Front Pharmacol. 2020;11:1119. https://doi.org/10.3389/fphar.2020.01119.

42.

Duan Q, Tian L, Feng J et al. (2022). Trametenolic Acid Ameliorates the Progression of Diabetic Nephropathy in db/db Mice via Nrf2/HO-1 and NF-κB-Mediated Pathways. J Immunol Res. 2022;2022:6151847. https://doi.org/10.1155/2022/6151847.

43.

Tu W, Wang H, Li S, Liu Q, Sha H. The anti-inflammatory and antioxidant mechanisms of the keap1/nrf2/are signaling pathway in chronic diseases. Aging Dis. 2019;10(3):637–51. https://doi.org/10.14336/AD.2018.0513.CrossRefPubMedPubMedCentral

44.

Liu Y, Uruno A, Saito R, et al. Nrf2 deficiency deteriorates diabetic kidney disease in akita model mice. Redox Biol. 2022;58:102525. https://doi.org/10.1016/j.redox.2022.102525.CrossRefPubMedPubMedCentral

45.

Kang Y, Song Y, Luo Y, et al. Exosomes derived from human umbilical cord mesenchymal stem cells ameliorate experimental non-alcoholic steatohepatitis via nrf2/nqo-1 pathway. Free Radical Biol Med. 2022;192:25–36. https://doi.org/10.1016/j.freeradbiomed.2022.08.037.CrossRef

46.

Liu J, Huang J, Zhang Z et al. (2022) Mesenchymal stem cell-derived exosomes ameliorate delayed neurocognitive recovery in aged mice by inhibiting hippocampus ferroptosis via activating sirt1/nrf2/ho-1 signaling pathway. Oxidative Med Cell Longevity 2022:3593294 https://doi.org/10.1155/2022/3593294.

47.

Liu S, Pi J, Zhang Q. Signal amplification in the keap1-nrf2-are antioxidant response pathway. Redox Biol. 2022;54:102389. https://doi.org/10.1016/j.redox.2022.102389.CrossRefPubMedPubMedCentral

48.

Ma F, Luo S, Lu C, et al. The role of nrf2 in periodontal disease by regulating lipid peroxidation, inflammation and apoptosis. Front Endocrinol. 2022;13:963451. https://doi.org/10.3389/fendo.2022.963451.CrossRef

49.

Xiang Q, Zhao Y, Lin J, Jiang S, Li W. The nrf2 antioxidant defense system in intervertebral disc degeneration: molecular insights. Exp Mol Med. 2022;54(8):1067–75. https://doi.org/10.1038/s12276-022-00829-6.CrossRefPubMedPubMedCentral

50.

Zeng G, Lian C, Li W, et al. Upregulation of fam129b protects cardiomyocytes from hypoxia/reoxygenation-induced injury by inhibiting apoptosis, oxidative stress, and inflammatory response via enhancing nrf2/are activation. Environ Toxicol. 2022;37(5):1018–31. https://doi.org/10.1002/tox.23461.CrossRef

Title: Adipose-derived stem cell exosomes regulate Nrf2/Keap1 in diabetic nephropathy by targeting FAM129B
Authors: Peiyao Ren
Fengmei Qian
Lanjun Fu
Wenfang He
Qiang He
Juan Jin
Danna Zheng
Publication date: 01-12-2023
Publisher: BioMed Central
Keyword: Diabetic Nephropathy
Published in: Diabetology & Metabolic Syndrome / Issue 1/2023
Electronic ISSN: 1758-5996
DOI: https://doi.org/10.1186/s13098-023-01119-5

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2023

Prevalence of diabetic retinopathy in Brazil: a systematic review with meta-analysis

Levels and correlates of risk factor control in diabetes mellitus –ELSA-Brasil

Effect of peripheral nerve block versus general anesthesia on the hemodynamics and prognosis of diabetic patients undergoing diabetic foot Surgery

Use of continuous glucose monitoring in insulin-treated older adults with type 2 diabetes

Endocan in prediabetes, diabetes, and diabetes-related complications: a systematic review and meta-analysis

Effect of bromocriptine on glycemic control, risk of cardiovascular diseases and weight in patients with type 2 diabetes: a systematic review

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials