Klotho gene transfection into mesenchymal stem cells as a potential therapy for kidney disease
DOI:
https://doi.org/10.54361/LJMR.19.2.04Keywords:
Klotho gene, mesenchymal stem cells, kidney therapy, chronic kidney disease, gene transfection, renal regeneration, anti-aging geneAbstract
Purpose: Chronic kidney disease (CKD) is a progressive condition associated with high morbidity and mortality. Traditional therapeutic strategies primarily aim to manage symptoms and slow disease progression, but often fail to reverse kidney damage. The mesenchymal stem cells (MSCs), known for their regenerative and immunomodulatory capacities, have emerged as promising candidates for renal repair. Meanwhile, the Klotho gene, recognized as an anti-aging and nephroprotective gene, is markedly downregulated in CKD. This review conducted the synergistic potential of combining MSC therapy with Klotho gene transfection. By enhancing MSCs with Klotho, their reparative effects, such as anti-fibrotic, anti-inflammatory, and antioxidant properties, can be boosted. Materials and Methods: the search process covered over 50 peer-reviewed articles and research papers, about the Mesenchymal stem cell therapy in kidney repair disease with different transfection protocols, and the same as the klotho gene, with an understanding of the therapeutic role. However, all databases in this review were estimated by PubMed and Google Scholar with keywords. Conclude: the biology of the Klotho gene, MSC-based therapeutic mechanisms, current transfection techniques, preclinical studies, and translational challenges. This approach may offer a novel and more effective therapeutic avenue for kidney disease management.
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References
1. Rastegar F, Shenaq D, Huang J, Zhang W, Zhang BQ, He BC, Chen L, Zuo GW, Luo Q, Shi Q, Wagner ER. Mesenchymal stem cells: Molecular characteristics and clinical applications. World journal of stem cells. 2010 Aug 26;2(4):67.
2. Christoffers S, Seiler L, Wiebe E, Blume C. Possibilities and efficiency of MSC co-transfection for gene therapy. Stem Cell Research & Therapy. 2024 May 23;15(1):150.
3. Franco ML, Beyerstedt S, Rangel ÉB. Klotho and mesenchymal stem cells: a review on cell and gene therapy for chronic kidney disease and acute kidney disease. Pharmaceutics. 2021 Dec 21;14(1):11.
4. Bian A, Neyra JA, Zhan M, Hu MC. Klotho, stem cells, and aging. Clinical Interventions in Aging. 2015 Aug 4:1233-43.
5. Guo Y, Zhuang X, Huang Z, Zou J, Yang D, Hu X, Du Z, Wang L, Liao X. Klotho protects the heart from hyperglycemia-induced injury by inactivating ROS and NF-κB-mediated inflammation both in vitro and in vivo. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease. 2018 Jan 1;1864(1):238-51.
6. Neyra JA, Hu MC. Potential application of klotho in human chronic kidney disease. Bone. 2017 Jul 1;100:41-9.
7. Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. nature. 1997 Nov 6;390(6655):45-51.
8. Gerald LitwackVitamins and Hormones,Chapter Twelve - Aging and FGF23-klotho system,Academic Press.2020.Volume 115,2021,Pages 317-332,ISSN
9. Lim K, Groen A, Molostvov G, Lu T, Lilley KS, Snead D, James S, Wilkinson IB, Ting S, Hsiao LL, Hiemstra TF. α-Klotho expression in human tissues. The Journal of Clinical Endocrinology & Metabolism. 2015 Oct 1;100(10):E1308-18.
10. Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, Fujita T, Fukumoto S, Yamashita T. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature. 2006 Dec 7;444(7120):770-4.
11. Dalton G, An SW, Al-Juboori SI, Nischan N, Yoon J, Dobrinskikh E, Hilgemann DW, Xie J, Luby-Phelps K, Kohler JJ, Birnbaumer L. Soluble klotho binds monosialoganglioside to regulate membrane microdomains and growth factor signaling. Proceedings of the National Academy of Sciences. 2017 Jan 24;114(4):752-7.
12. Wu SE, Chen WL. Soluble klotho as an effective biomarker to characterize inflammatory states. Annals of medicine. 2022 Dec 31;54(1):1520-9.
13. Li SS, Sheng MJ, Sun ZY, Liang Y, Yu LX, Liu QF. Upstream and downstream regulators of Klotho expression in chronic kidney disease. Metabolism. 2023 May 1;142:155530.
14. Kurosu H, Yamamoto M, Clark JD, Pastor JV, Nandi A, Gurnani P, McGuinness OP, Chikuda H, Yamaguchi M, Kawaguchi H, Shimomura I. Suppression of aging in mice by the hormone Klotho. Science. 2005 Sep 16;309(5742):1829-33.
15. Espuch-Oliver A, Vázquez-Lorente H, Jurado-Fasoli L, de Haro-Muñoz T, Díaz-Alberola I, López-Velez MD, de Haro-Romero T, Castillo MJ, Amaro-Gahete FJ. References values of soluble α-klotho serum levels using an enzyme-linked immunosorbent assay in healthy adults aged 18–85 years. Journal of clinical medicine. 2022 Apr 25;11(9):2415.
16. Martin A, David V, Quarles LD. Regulation and function of the FGF23/klotho endocrine pathways. Physiological reviews. 2012 Jan;92(1):131-55.
17. Lin W, Wu X, Wen J, Fei Y, Wu J, Li X, Zhang Q, Dong Y, Xu T, Fan Y, Wang N. Nicotinamide retains Klotho expression and ameliorates rhabdomyolysis-induced acute kidney injury. Nutrition. 2021 Nov 1;91:111376.
18. Shi M, Flores B, Gillings N, Bian A, Cho HJ, Yan S, Liu Y, Levine B, Moe OW, Hu MC. αKlotho mitigates progression of AKI to CKD through activation of autophagy. Journal of the American Society of Nephrology. 2016 Aug 1;27(8):2331-45.
19. Zhu X, Lin Q, Yang Y, Li S, Shao X, Zhang W, Cai H, Li J, Wu J, Zhang K, Qi C. αKlotho modulates BNIP3-mediated mitophagy by regulating FoxO3 to decrease mitochondrial ROS and apoptosis in contrast-induced acute kidney injury. Cellular and Molecular Life Sciences. 2024 Dec;81(1):454.
20. Hajare AD, Dagar N, Gaikwad AB. Klotho antiaging protein: molecular mechanisms and therapeutic potential in diseases. Molecular biomedicine. 2025 Mar 22;6(1):19.
21. 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 Mar 16;12(3):185.
22. Lim K, Groen A, Molostvov G, Lu T, Lilley KS, Snead D, James S, Wilkinson IB, Ting S, Hsiao LL, Hiemstra TF. α-Klotho expression in human tissues. The Journal of Clinical Endocrinology & Metabolism. 2015 Oct 1;100(10):E1308-18.
23. Dalton GD, Xie J, An SW, Huang CL. New insights into the mechanism of action of soluble klotho. Frontiers in endocrinology. 2017 Nov 17;8:323.
24. Prud’homme GJ, Kurt M, Wang Q. Pathobiology of the klotho antiaging protein and therapeutic considerations. Frontiers in Aging. 2022 Jul 12;3:931331.
25. Kim JH, Hwang KH, Park KS, Kong ID, Cha SK. Biological role of anti-aging protein Klotho. Journal of lifestyle medicine. 2015 Mar 30;5(1):1.
26. Zhao X, Han D, Zhao C, Yang F, Wang Z, Gao Y, Jin M, Tao R. New insights into the role of Klotho in inflammation and fibrosis: molecular and cellular mechanisms. Frontiers in Immunology. 2024 Sep 6;15:1454142.
27. Young GH, Wu VC. KLOTHO methylation is linked to uremic toxins and chronic kidney disease. Kidney international. 2012 Apr 1;81(7):611-2.
28. Rubinek T, Shulman M, Israeli S, Bose S, Avraham A, Zundelevich A, Evron E, Nili Gal-Yam E, Kaufman B, Wolf I. Epigenetic silencing of the tumor suppressor klotho in human breast cancer. Breast cancer research and treatment. 2012 Jun;133:649-57.
29. Mencke R, Harms G, Moser J, van Meurs M, Diepstra A, Leuvenink HG, Hillebrands JL. Human alternative Klotho mRNA is a nonsense-mediated mRNA decay target inefficiently spliced in renal disease. JCI insight. 2017 Oct 19;2(20):e94375.
30. Zhao X, Han D, Zhao C, Yang F, Wang Z, Gao Y, Jin M, Tao R. New insights into the role of Klotho in inflammation and fibrosis: molecular and cellular mechanisms. Frontiers in Immunology. 2024 Sep 6;15:1454142.
31. Chen F, Chen N, Xia C, Wang H, Shao L, Zhou C, Wang J. Mesenchymal stem cell therapy in kidney diseases: Potential and challenges. Cell transplantation. 2023 Apr;32:09636897231164251.
32. Wan F, Yang RC, Tang YW, Tang XL, Ye T, Zheng J, Zhang HQ, Lin Y. BMSC-derived exosomes protect against kidney injury through regulating klotho in 5/6 nephrectomy rats. European Journal of Medical Research. 2022 Jul 11;27(1):118.
33. Zhang F, Wan X, Cao YZ, Sun D, Cao CC. Klotho gene‐modified BMSCs showed elevated antifibrotic effects by inhibiting the Wnt/β‐catenin pathway in kidneys after acute injury. Cell biology international. 2018 Dec;42(12):1670-9.
34. Ni W, Zhang Y, Yin Z. The protective mechanism of Klotho gene-modified bone marrow mesenchymal stem cells on acute kidney injury induced by rhabdomyolysis. Regenerative Therapy. 2021 Dec 1;18:255-67.
35. Xie LB, Chen X, Chen B, Wang XD, Jiang R, Lu YP. Protective effect of bone marrow mesenchymal stem cells modified with klotho on renal ischemia-reperfusion injury. Renal Failure. 2019 Jan 1;41(1):175-82.
36. Kim SH, Lee SH, Jin JA, So HJ, Lee JU, Ji MJ, Kwon EJ, Han PS, Lee HK, Kang TW. In vivo safety and biodistribution profile of Klotho-enhanced human urine-derived stem cells for clinical application. Stem Cell Research & Therapy. 2023 Dec 10;14(1):355.
37. Fan J, Sun Z. The antiaging gene klotho regulates proliferation and differentiation of adipose-derived stem cells. Stem Cells. 2016 Jun 1;34(6):1615-25.
38. Kim SH, Jin JA, So HJ, Lee SH, Kang TW, Lee JU, Choi DE, Jeong JY, Chang YK, Choi H, Lee Y. Urine-derived stem
39. cell-secreted Klotho plays a crucial role in the HK-2 fibrosis model by inhibiting the TGF-β signaling pathway. International Journal of Molecular Sciences. 2022 Apr 30;23(9):5012.
1. Rastegar F, Shenaq D, Huang J, Zhang W, Zhang BQ, He BC, Chen L, Zuo GW, Luo Q, Shi Q, Wagner ER. Mesenchymal stem cells: Molecular characteristics and clinical applications. World journal of stem cells. 2010 Aug 26;2(4):67.
2. Christoffers S, Seiler L, Wiebe E, Blume C. Possibilities and efficiency of MSC co-transfection for gene therapy. Stem Cell Research & Therapy. 2024 May 23;15(1):150.
3. Franco ML, Beyerstedt S, Rangel ÉB. Klotho and mesenchymal stem cells: a review on cell and gene therapy for chronic kidney disease and acute kidney disease. Pharmaceutics. 2021 Dec 21;14(1):11.
4. Bian A, Neyra JA, Zhan M, Hu MC. Klotho, stem cells, and aging. Clinical Interventions in Aging. 2015 Aug 4:1233-43.
5. Guo Y, Zhuang X, Huang Z, Zou J, Yang D, Hu X, Du Z, Wang L, Liao X. Klotho protects the heart from hyperglycemia-induced injury by inactivating ROS and NF-κB-mediated inflammation both in vitro and in vivo. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease. 2018 Jan 1;1864(1):238-51.
6. Neyra JA, Hu MC. Potential application of klotho in human chronic kidney disease. Bone. 2017 Jul 1;100:41-9.
7. Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. nature. 1997 Nov 6;390(6655):45-51.
8. Gerald LitwackVitamins and Hormones,Chapter Twelve - Aging and FGF23-klotho system,Academic Press.2020.Volume 115,2021,Pages 317-332,ISSN
9. Lim K, Groen A, Molostvov G, Lu T, Lilley KS, Snead D, James S, Wilkinson IB, Ting S, Hsiao LL, Hiemstra TF. α-Klotho expression in human tissues. The Journal of Clinical Endocrinology & Metabolism. 2015 Oct 1;100(10):E1308-18.
10. Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, Fujita T, Fukumoto S, Yamashita T. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature. 2006 Dec 7;444(7120):770-4.
11. Dalton G, An SW, Al-Juboori SI, Nischan N, Yoon J, Dobrinskikh E, Hilgemann DW, Xie J, Luby-Phelps K, Kohler JJ, Birnbaumer L. Soluble klotho binds monosialoganglioside to regulate membrane microdomains and growth factor signaling. Proceedings of the National Academy of Sciences. 2017 Jan 24;114(4):752-7.
12. Wu SE, Chen WL. Soluble klotho as an effective biomarker to characterize inflammatory states. Annals of medicine. 2022 Dec 31;54(1):1520-9.
13. Li SS, Sheng MJ, Sun ZY, Liang Y, Yu LX, Liu QF. Upstream and downstream regulators of Klotho expression in chronic kidney disease. Metabolism. 2023 May 1;142:155530.
14. Kurosu H, Yamamoto M, Clark JD, Pastor JV, Nandi A, Gurnani P, McGuinness OP, Chikuda H, Yamaguchi M, Kawaguchi H, Shimomura I. Suppression of aging in mice by the hormone Klotho. Science. 2005 Sep 16;309(5742):1829-33.
15. Espuch-Oliver A, Vázquez-Lorente H, Jurado-Fasoli L, de Haro-Muñoz T, Díaz-Alberola I, López-Velez MD, de Haro-Romero T, Castillo MJ, Amaro-Gahete FJ. References values of soluble α-klotho serum levels using an enzyme-linked immunosorbent assay in healthy adults aged 18–85 years. Journal of clinical medicine. 2022 Apr 25;11(9):2415.
16. Martin A, David V, Quarles LD. Regulation and function of the FGF23/klotho endocrine pathways. Physiological reviews. 2012 Jan;92(1):131-55.
17. Lin W, Wu X, Wen J, Fei Y, Wu J, Li X, Zhang Q, Dong Y, Xu T, Fan Y, Wang N. Nicotinamide retains Klotho expression and ameliorates rhabdomyolysis-induced acute kidney injury. Nutrition. 2021 Nov 1;91:111376.
18. Shi M, Flores B, Gillings N, Bian A, Cho HJ, Yan S, Liu Y, Levine B, Moe OW, Hu MC. αKlotho mitigates progression of AKI to CKD through activation of autophagy. Journal of the American Society of Nephrology. 2016 Aug 1;27(8):2331-45.
19. Zhu X, Lin Q, Yang Y, Li S, Shao X, Zhang W, Cai H, Li J, Wu J, Zhang K, Qi C. αKlotho modulates BNIP3-mediated mitophagy by regulating FoxO3 to decrease mitochondrial ROS and apoptosis in contrast-induced acute kidney injury. Cellular and Molecular Life Sciences. 2024 Dec;81(1):454.
20. Hajare AD, Dagar N, Gaikwad AB. Klotho antiaging protein: molecular mechanisms and therapeutic potential in diseases. Molecular biomedicine. 2025 Mar 22;6(1):19.
21. 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 Mar 16;12(3):185.
22. Lim K, Groen A, Molostvov G, Lu T, Lilley KS, Snead D, James S, Wilkinson IB, Ting S, Hsiao LL, Hiemstra TF. α-Klotho expression in human tissues. The Journal of Clinical Endocrinology & Metabolism. 2015 Oct 1;100(10):E1308-18.
23. Dalton GD, Xie J, An SW, Huang CL. New insights into the mechanism of action of soluble klotho. Frontiers in endocrinology. 2017 Nov 17;8:323.
24. Prud’homme GJ, Kurt M, Wang Q. Pathobiology of the klotho antiaging protein and therapeutic considerations. Frontiers in Aging. 2022 Jul 12;3:931331.
25. Kim JH, Hwang KH, Park KS, Kong ID, Cha SK. Biological role of anti-aging protein Klotho. Journal of lifestyle medicine. 2015 Mar 30;5(1):1.
26. Zhao X, Han D, Zhao C, Yang F, Wang Z, Gao Y, Jin M, Tao R. New insights into the role of Klotho in inflammation and fibrosis: molecular and cellular mechanisms. Frontiers in Immunology. 2024 Sep 6;15:1454142.
27. Young GH, Wu VC. KLOTHO methylation is linked to uremic toxins and chronic kidney disease. Kidney international. 2012 Apr 1;81(7):611-2.
28. Rubinek T, Shulman M, Israeli S, Bose S, Avraham A, Zundelevich A, Evron E, Nili Gal-Yam E, Kaufman B, Wolf I. Epigenetic silencing of the tumor suppressor klotho in human breast cancer. Breast cancer research and treatment. 2012 Jun;133:649-57.
29. Mencke R, Harms G, Moser J, van Meurs M, Diepstra A, Leuvenink HG, Hillebrands JL. Human alternative Klotho mRNA is a nonsense-mediated mRNA decay target inefficiently spliced in renal disease. JCI insight. 2017 Oct 19;2(20):e94375.
30. Zhao X, Han D, Zhao C, Yang F, Wang Z, Gao Y, Jin M, Tao R. New insights into the role of Klotho in inflammation and fibrosis: molecular and cellular mechanisms. Frontiers in Immunology. 2024 Sep 6;15:1454142.
31. Chen F, Chen N, Xia C, Wang H, Shao L, Zhou C, Wang J. Mesenchymal stem cell therapy in kidney diseases: Potential and challenges. Cell transplantation. 2023 Apr;32:09636897231164251.
32. Wan F, Yang RC, Tang YW, Tang XL, Ye T, Zheng J, Zhang HQ, Lin Y. BMSC-derived exosomes protect against kidney injury through regulating klotho in 5/6 nephrectomy rats. European Journal of Medical Research. 2022 Jul 11;27(1):118.
33. Zhang F, Wan X, Cao YZ, Sun D, Cao CC. Klotho gene‐modified BMSCs showed elevated antifibrotic effects by inhibiting the Wnt/β‐catenin pathway in kidneys after acute injury. Cell biology international. 2018 Dec;42(12):1670-9.
34. Ni W, Zhang Y, Yin Z. The protective mechanism of Klotho gene-modified bone marrow mesenchymal stem cells on acute kidney injury induced by rhabdomyolysis. Regenerative Therapy. 2021 Dec 1;18:255-67.
35. Xie LB, Chen X, Chen B, Wang XD, Jiang R, Lu YP. Protective effect of bone marrow mesenchymal stem cells modified with klotho on renal ischemia-reperfusion injury. Renal Failure. 2019 Jan 1;41(1):175-82.
36. Kim SH, Lee SH, Jin JA, So HJ, Lee JU, Ji MJ, Kwon EJ, Han PS, Lee HK, Kang TW. In vivo safety and biodistribution profile of Klotho-enhanced human urine-derived stem cells for clinical application. Stem Cell Research & Therapy. 2023 Dec 10;14(1):355.
37. Fan J, Sun Z. The antiaging gene klotho regulates proliferation and differentiation of adipose-derived stem cells. Stem Cells. 2016 Jun 1;34(6):1615-25.
38. Kim SH, Jin JA, So HJ, Lee SH, Kang TW, Lee JU, Choi DE, Jeong JY, Chang YK, Choi H, Lee Y. Urine-derived stem
39. cell-secreted Klotho plays a crucial role in the HK-2 fibrosis model by inhibiting the TGF-β signaling pathway. International Journal of Molecular Sciences. 2022 Apr 30;23(9):5012.
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