The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
권호 표지
DOI QR코드

DOI QR Code

Combination of canagliflozin and puerarin alleviates the lipotoxicity to diabetic kidney in mice

  • Qian Zhu (Department of Pharmacy, Hospital of Chengdu University of Traditional Chinese Medicine) ;
  • Qu Zhou (Department of Pharmacy, Hospital of Chengdu University of Traditional Chinese Medicine) ;
  • Xiao-li Luo (Department of Pharmacy, Hospital of Chengdu University of Traditional Chinese Medicine) ;
  • Xu-jie Zhang (Parexel China Co., Ltd.) ;
  • San-yu, Li (Department of Pharmacy, Hospital of Chengdu University of Traditional Chinese Medicine)
  • Received : 2022.06.23
  • Accepted : 2023.02.03
  • Published : 2023.05.01
Download PDF
⟨ Previous Next ⟩

Abstract

Diabetic kidney disease is one of the most serious complications of diabetes. Although diabetic kidney disease can be effectively controlled through strict blood glucose management and corresponding symptomatic treatment, these therapies cannot reduce its incidence in diabetic patients. The sodium-glucose cotransporter 2 (SGLT2) inhibitors and the traditional Chinese herb "Gegen" have been widely used in diabetes-related therapy. However, it remains unclear whether the combined use of these two kinds of medicines contributes to an increased curative effect on diabetic kidney disease. In this study, we examined this issue by evaluating the efficacy of the combination of puerarin, an active ingredient of Gegen, and canagliflozin, an SGLT2 inhibitor for a 12-week intervention using a mouse model of diabetes. The results indicated that the combination of puerarin and canagliflozin was superior to canagliflozin alone in improving the metabolic and renal function parameters of diabetic mice. Our findings suggested that the renoprotective effect of combined puerarin and canagliflozin in diabetic mice was achieved by reducing renal lipid accumulation. This study provides a new strategy for the clinical prevention and treatment of diabetic kidney disease. The puerarin and SGLT2 inhibitor combination therapy at the initial stage of diabetes may effectively delay the occurrence of diabetic kidney injury, and significantly alleviate the burden of renal lipotoxicity.

Keywords

References

  1. Koye DN, Magliano DJ, Nelson RG, Pavkov ME. The global epidemiology of diabetes and kidney disease. Adv Chronic Kidney Dis. 2018;25:121-132. https://doi.org/10.1053/j.ackd.2017.10.011
  2. Li H, Lu W, Wang A, Jiang H, Lyu J. Changing epidemiology of chronic kidney disease as a result of type 2 diabetes mellitus from 1990 to 2017: estimates from Global Burden of Disease 2017. J Diabetes Investig. 2021;12:346-356. https://doi.org/10.1111/jdi.13355
  3. Gregg EW, Williams DE, Geiss L. Changes in diabetes-related complications in the United States. N Engl J Med. 2014;371:286-287.
  4. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117-2128. https://doi.org/10.1056/NEJMoa1504720
  5. Neal B, Perkovic V, Matthews DR. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:2099.
  6. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Silverman MG, Zelniker TA, Kuder JF, Murphy SA, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Ruff CT, Gause-Nilsson IAM, Fredriksson M, Johansson PA, Langkilde AM, Sabatine MS; DECLARE-TIMI 58 Investigators. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380:347-357. https://doi.org/10.1056/NEJMoa1812389
  7. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, Edwards R, Agarwal R, Bakris G, Bull S, Cannon CP, Capuano G, Chu PL, de Zeeuw D, Greene T, Levin A, Pollock C, Wheeler DC, Yavin Y, Zhang H, et al.; CREDENCE Trial Investigators. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380:2295-2306. https://doi.org/10.1056/NEJMoa1811744
  8. Nespoux J, Vallon V. Renal effects of SGLT2 inhibitors: an update. Curr Opin Nephrol Hypertens. 2020;29:190-198. https://doi.org/10.1097/MNH.0000000000000584
  9. Thongnak L, Pongchaidecha A, Lungkaphin A. Renal lipid metabolism and lipotoxicity in diabetes. Am J Med Sci. 2020;359:84-99. https://doi.org/10.1016/j.amjms.2019.11.004
  10. Yuan G, Shi S, Jia Q, Shi J, Shi S, Zhang X, Shou X, Zhu X, Hu Y. Use of network pharmacology to explore the mechanism of gegen (Puerariae lobatae Radix) in the treatment of type 2 diabetes mellitus associated with hyperlipidemia. Evid Based Complement Alternat Med. 2021;2021:6633402.
  11. Wang S, Zhang S, Wang S, Gao P, Dai L. A comprehensive review on Pueraria: insights on its chemistry and medicinal value. Biomed Pharmacother. 2020;131:110734.
  12. Jiang Z, Cui X, Qu P, Shang C, Xiang M, Wang J. Roles and mechanisms of puerarin on cardiovascular disease: a review. Biomed Pharmacother. 2022;147:112655.
  13. Cansby E, Caputo M, Gao L, Kulkarni NM, Nerstedt A, Stahlman M, Boren J, Porosk R, Soomets U, Pedrelli M, Parini P, Marschall HU, Nystrom J, Howell BW, Mahlapuu M. Depletion of protein kinase STK25 ameliorates renal lipotoxicity and protects against diabetic kidney disease. JCI Insight. 2020;5:e140483.
  14. Terami N, Ogawa D, Tachibana H, Hatanaka T, Wada J, Nakatsuka A, Eguchi J, Horiguchi CS, Nishii N, Yamada H, Takei K, Makino H. Long-term treatment with the sodium glucose cotransporter 2 inhibitor, dapagliflozin, ameliorates glucose homeostasis and diabetic nephropathy in db/db mice. PLoS One. 2014;9:e100777.
  15. Hatanaka T, Ogawa D, Tachibana H, Eguchi J, Inoue T, Yamada H, Takei K, Makino H, Wada J. Inhibition of SGLT2 alleviates diabetic nephropathy by suppressing high glucose-induced oxidative stress in type 1 diabetic mice. Pharmacol Res Perspect. 2016;4:e00239.
  16. Nakamichi R, Hayashi K, Itoh H. Effects of high glucose and lipotoxicity on diabetic podocytes. Nutrients. 2021;13:241.
  17. You HS, Shin SJ, Kim J, Kang HT. Statin use and incidence of chronic kidney disease in hypercholesterolemia patients with normal renal function. Am J Nephrol. 2021;52:940-948. https://doi.org/10.1159/000520532
  18. Wan XM, Chen J, Wang M, Zheng C, Zhou XL. Puerarin attenuates cadmium-induced hepatic lipid metabolism disorder by inhibiting oxidative stress and inflammation in mice. J Inorg Biochem. 2021;222:111521.
  19. Noh JW, Yang HK, Jun MS, Lee BC. Puerarin attenuates obesityinduced inflammation and dyslipidemia by regulating macrophages and TNF-alpha in obese mice. Biomedicines. 2022;10:175.
  20. Zhu Q, Yang S, Wei C, Lu G, Lee K, He JC, Liu R, Zhong Y. Puerarin attenuates diabetic kidney injury through interaction with Guanidine nucleotide-binding protein Gi subunit alpha-1 (Gnai1) subunit. J Cell Mol Med. 2022;26:3816-3827. https://doi.org/10.1111/jcmm.17414
  21. Xu X, Chen B, Huang Q, Wu Y, Liang T. The effects of puerarin on autophagy through regulating of the PERK/eIF2α/ATF4 signaling pathway influences renal function in diabetic nephropathy. Diabetes Metab Syndr Obes. 2020;13:2583-2592. https://doi.org/10.2147/DMSO.S256457
  22. Tauber P, Sinha F, Berger RS, Gronwald W, Dettmer K, Kuhn M, Trum M, Maier LS, Wagner S, Schweda F. Empagliflozin reduces renal hyperfiltration in response to uninephrectomy, but is not nephroprotective in UNx/DOCA/Salt mouse models. Front Pharmacol. 2021;12:761855.
  23. Locatelli M, Zoja C, Conti S, Cerullo D, Corna D, Rottoli D, Zanchi C, Tomasoni S, Remuzzi G, Benigni A. Empagliflozin protects glomerular endothelial cell architecture in experimental diabetes through the VEGF-A/caveolin-1/PV-1 signaling pathway. J Pathol. 2022;256:468-479. https://doi.org/10.1002/path.5862
  24. Alkabbani W, Zongo A, Minhas-Sandhu JK, Eurich DT, Shah BR, Alsabbagh MW, Gamble JM. Renal effectiveness and safety of the sodium-glucose cotransporter-2 inhibitors: a population-based cohort study. BMJ Open Diabetes Res Care. 2021;9:e002496.
  25. Yang L, Liang B, Li J, Zhang X, Chen H, Sun J, Zhang Z. Dapagliflozin alleviates advanced glycation end product induced podocyte injury through AMPK/mTOR mediated autophagy pathway. Cell Signal. 2022;90:110206.
  26. Chun KJ, Jung HH. SGLT2 inhibitors and kidney and cardiac outcomes according to estimated GFR and albuminuria levels: a metaanalysis of randomized controlled trials. Kidney Med. 2021;3:732-744.e1. https://doi.org/10.1016/j.xkme.2021.04.009
  27. Jeon YD, Lee JH, Lee YM, Kim DK. Puerarin inhibits inflammation and oxidative stress in dextran sulfate sodium-induced colitis mice model. Biomed Pharmacother. 2020;124:109847.
  28. Li X, Cai W, Lee K, Liu B, Deng Y, Chen Y, Zhang X, He JC, Zhong Y. Puerarin attenuates diabetic kidney injury through the suppression of NOX4 expression in podocytes. Sci Rep. 2017;7:14603.
  29. Zhang Y, Yang X, Ge X, Zhang F. Puerarin attenuates neurological deficits via Bcl-2/Bax/cleaved caspase-3 and Sirt3/SOD2 apoptotic pathways in subarachnoid hemorrhage mice. Biomed Pharmacother. 2019;109:726-733. https://doi.org/10.1016/j.biopha.2018.10.161
  30. Xiao L, Zhong M, Huang Y, Zhu J, Tang W, Li D, Shi J, Lu A, Yang H, Geng D, Li H, Wang Z. Puerarin alleviates osteoporosis in the ovariectomy-induced mice by suppressing osteoclastogenesis via inhibition of TRAF6/ROS-dependent MAPK/NF-κB signaling pathways. Aging (Albany NY). 2020;12:21706-21729.  https://doi.org/10.18632/aging.103976