Nephroprotective effect of dapagliflozin in type 2 diabetes mellitus: A potential role of Klotho protein

DOI: https://doi.org/10.31450/ukrjnd.3(71).2021.02
Keywords: diabetic nephropathy, Klotho, dapagliflozin, sodium-glucose cotransporter 2 inhibitors

Abstract

Abstract. The present study aimed to investigate the dynamics of clinical and laboratory parameters and serum Klotho protein level in patients with diabetic kidney disease using nephroprotective therapy combined with an inhibitor of the sodium-glucose cotransporter 2 (SGLT2) dapagliflozin.

Methods. A total of 76 type 2 diabetic patients with diabetic nephropathy (DN) were examined in this prospective study. Control group - 20 healthy subjects. 53 patients received a standard course of treatment, which included metformin, renin-angiotensin-aldosterone system blockers and statins. In addition to standard therapy, 23 patients have been prescribed the SGLT2 inhibitor dapagliflozin 10 mg per day. The treatment follow-up period was six months. Klotho concentration was determined by an enzyme-linked immunosorbent assay.

Results. The development of DN in type 2 diabetic patients was accompanied by a significant decrease in soluble Klotho protein in comparison with controls and patients without nephropathy. During follow-up, Klotho protein level was changed significantly in the group of DN patients with albuminuria. Standard therapy resulted in Klotho concentration increase by 14% compared to pre-treatment values; a more demonstrative increase in the Klotho level was found in the dapagliflozin group (almost 23%).

Conclusions. SGLT2 inhibitor treatment resulted in a significant increase of pleiotropic serum protein Klotho in patients with type 2 diabetes and diabetic kidney disease.

Downloads

Download data is not yet available.

References

IDF Diabetes Atlas. 9th ed. International Diabetes Federation. 2019. Available from: https://www.diabetesatlas.org/en.

Wu B, Bell K, Stanford A, Kern DM, Tunceli O, Vupputuri S, et al. Understanding CKD among patients with T2DM: prevalence, temporal trends, and treatment patterns –  NHANES 2007–2012. Article and supplementary tables. BMJ Open Diabetes Res. Care. 2016; 4(1): e000154.  doi:10.1136/bmjdrc-2015-000154.

Topchii I, Semenovykh P, Galchinskaya V, Yakimenko Yu, Shcherban T. Association of fibroblast growth factor 23 with markers of inflammation and fibrosis in diabetic nephropathy. Georgian Medical News. 2019; 292-293 (7-8): 44-49. Available from: https://cdn.website-editor.net/480918712df344a4a77508d4cd7815ab/files/uploaded/V292-293_N7-8_July-August_2019.pdf [In Russian].

Topchii I, Semenovykh P, Shcherban T, Galchinska V, Savicheva K. Serum Klotho protein level in type 2 diabetic patients depending on the renal function. Ukrainian Journal of Nephrology and Dialysis. 2020; 3(67): 60-66. doi: 10.31450/ukrjnd.3(67).2020.08. [In Ukrainian].

Kuro-o M. Klotho in chronic kidney disease — what’s new? Nephrol. Dial. Transplant. 2009; 24(6): 1705–8. doi: 10.1093/ndt/gfp069.

Jiang W, Xiao T, Han W, Xiong J, He T, Liu Y, et al. Klotho inhibits PKCα/p66SHC-mediated podocyte injury in diabetic nephropathy. Mol. Cell Endocrinol. 2019; 494 :110490. doi: 10.1016/j.mce.2019.110490.

Hu CM, Kuro-o M, Moe OW. The emerging role of Klotho in clinical nephrology. Nephrol. Dial. Transplant. 2012; 27: 2650–7. doi: 10.1093/ndt/gfs160.

Nie F, Wu D, Du H, Yang X, Yang M, Pang X, et al. Serum klotho protein levels and their correlations with the progression of type 2 diabetes mellitus. J. Diabetes Complications. 2017; 31(3): 594-8. doi: 10.1016/j.jdiacomp.2016.11.008.

Donate-Correa J, Mora-Fernández C, Martínez-Sanz R. Expression of FGF23/KLOTHO system in human vascular tissue. Int. J. Cardiol. 2013; 165(1): 179–83. doi: 10.1016/j.ijcard.2011.08.850.

Haiming Z, Yuexian S, Fukang M, Wang L, Hou Y, Zhu Z. Association of Klotho single nucleotide polymorphisms with cardiovascular diseases: a systematic review and meta-analysis. Int. J. Clin. Exp. Med. 2017; 10(3): 5721-41. Available from:  http://www.ijcem.com/files/ijcem0036293.pdf. 

Fadeev VV. Mesto ingibitora natrij-gljukoznogo kotransportera 2-go tipa dapagliflozina v profilaktike serdechno-sosudistyh oslozhnenij u pacientov s saharnym diabetom 2 tipa. Jendokrinologija: novosti, mnenija, obuchenie. 2020; 9(2): 59–69. doi: 10.33029/2304-9529-2020-9-2-59-69. [In Russian].

2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur. Heart J. 2020; 41(2): 255–323. doi: 10.1093/eurheartj/ehz486.

Sharonova LA, Verbovoj AF. Mesto gliflozinov v upravlenii saharnym diabetom 2 tipa. Farmateka. 2019; 26 (4): 105–10. doi: https://dx.doi.org/10.18565/pharmateca.2019.4.105-110. [In Russian].

Lim SC, Liu J-J, Subramaniam T, Sum CF. Elevated circulating alpha-klotho by angiotensin II receptor blocker losartan is associated with reduction of albuminuria in type 2 diabetic patients. J. of the Renin-Angiotensin-Aldosterone System. 2014; 15(4): 487 –90. doi: 10.1177/1470320313475905.

Zhou L, Mo H, Miao J, Zhou D, Tan RJ, Hou FF, et al. Klotho Ameliorates Kidney Injury and Fibrosisand Normalizes Blood Pressure by Targeting the Renin-Angiotensin System. Am. J. Pathol. 2015;185: 3211-23. doi: 10.1016/j.ajpath.2015.08.004.

Santos P, Krieger J-E, Pereira AC. Renin–Angiotensin System, Hypertension, and Chronic Kidney Disease: Pharmacogenetic Implications Journal of Pharmacological Sciences. 2012; 120(2): 77-88. doi: 10.1254/jphs.12R03CR.

Burns WC, Thomas MC. Angiotensin II and its role in tubular epithelial to mesenchymal transition associated with chronic kidney disease. Cells Tissues Organs. 2011; 193:74 – 84. doi: 10.1159/000320359.

Morgunov LJu., Bondarenko TV, Mager AA. Dapagliflozin pri hronicheskoj bolezni pochek: real'naja klinicheskaja praktika. Lechenie i profilaktika. 2019;9(2): 50-55. Available from: https://readera.org/143167402. [In Russian].

Nespoux J, Vallon V. SGLT2 inhibition and kidney protection. Clin. Sci. (Lond.). 2018;132(12):1329-39. doi: 10.1042/CS20171298.

Shestakova MV. Issledovanie DECLARE-TIMI 58 v kontekste EMPA-REG OUTCOME i CANVAS. Saharnyj diabet. 2019; 22(6): 592–601. doi: 10.14341/DM10289. [In Russian].

Zinman B, Inzucchi SE, Lachin JM, Wanner C, Ferrari R, Fitchett D, et al. Rationale, design, and baseline characteristics of a randomized, placebo-controlled cardiovascular outcome trial of empaglifl ozin (EMPA-REG OUTCOME™). Cardiovasc. Diabetol. 2014; 13:102. doi: 10.1186/1475–2840–13–102.

Neal MB, Perkovic V, Mahaffey KW, Zeeuw deD, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N. Engl. J. Med. 2017;377: 644–57. doi: 10.1056/NEJMoa1611925.


Abstract views: 481
PDF Downloads: 18030
Published
2021-06-07
How to Cite
Topchii, I., Semenovykh, P., Galchiskaya, V., & Savicheva, K. (2021). Nephroprotective effect of dapagliflozin in type 2 diabetes mellitus: A potential role of Klotho protein. Ukrainian Journal of Nephrology and Dialysis, (3(71), 11-18. https://doi.org/10.31450/ukrjnd.3(71).2021.02
Issue
No 3(71) (2021): Ukrainian Journal of Nephrology and Dialysis
Section
Original Papers