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Current Medicinal Chemistry

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ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

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Research Article

The Selective NLRP3-Inflammasome Inhibitor CY-09 Ameliorates Kidney Injury in Diabetic Nephropathy by Inhibiting NLRP3- inflammasome Activation

Author(s): Ming Yang and Li Zhao*

Volume 30, Issue 28, 2023

Published on: 23 November, 2022

Page: [3261 - 3270] Pages: 10

DOI: 10.2174/0929867329666220922104654

Price: $65

Abstract

Background: Diabetic nephropathy (DN) is one of the most serious complications of diabetes mellitus and the main cause of the end-stage renal disease (ESRD). Activation of the NLRP3 inflammasome has been proven to play an important role in the development of DN. Thus, specific and direct targets of NLRP3 inflammasome assembly may have therapeutic potential. CY-09 is a new NLRP3 inflammasome specific inhibitor that has been shown to protect against non-alcoholic fatty liver disease (NAFLD) by inhibiting the activation of the NLRP3 inflammasome. However, its role in kidney disease, especially DN, has not been reported.

Methods: In this study, we used HE staining to assess renal pathological damage in each group, and RT-PCR, immunofluorescence and WB were performed to detect the expression changes in inflammatory and fibrosis proteins. The apoptosis level was detected by TUNEL staining.

Results: Here, we showed increased inflammation, oxidative stress, apoptosis and fibrosis in db/db mice, while CY-09 exerted renoprotection by inhibiting NLRP3 inflammasome activation. In vitro, CY-09 also inhibited NLRP3 and reduced caspase-1, IL-18, IL-1β and apoptosis in a dose-dependent manner.

Conclusion: CY-09 effectively protects the kidney from hyperglycemia induced damage by inhibiting the NLRP3 inflammasome and may be a promising therapeutic strategy to prevent the progression of DKD.

Keywords: NLRP3 inflammasome, CY-09, DN, inflammation

« Previous
[1]
Kato, M.; Natarajan, R. Epigenetics and epigenomics in diabetic kidney disease and metabolic memory. Nat. Rev. Nephrol., 2019, 15(6), 327-345.
[http://dx.doi.org/10.1038/s41581-019-0135-6] [PMID: 30894700]
[2]
Ogurtsova, K.; da Rocha Fernandes, J.D.; Huang, Y.; Linnenkamp, U.; Guariguata, L.; Cho, N.H.; Cavan, D.; Shaw, J.E.; Makaroff, L.E. IDF diabetes atlas: Global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Res. Clin. Pract., 2017, 128, 40-50.
[http://dx.doi.org/10.1016/j.diabres.2017.03.024] [PMID: 28437734]
[3]
Jiao, F.; Wong, C.K.H.; Tang, S.C.W.; Fung, C.S.C.; Tan, K.C.B.; McGhee, S.; Gangwani, R.; Lam, C.L.K. Annual direct medical costs associated with diabetes-related complications in the event year and in subsequent years in Hong Kong. Diabet. Med., 2017, 34(9), 1276-1283.
[http://dx.doi.org/10.1111/dme.13416] [PMID: 28636749]
[4]
Oshima, M.; Shimizu, M.; Yamanouchi, M.; Toyama, T.; Hara, A.; Furuichi, K.; Wada, T. Trajectories of kidney function in diabetes: A clinicopathological update. Nat. Rev. Nephrol., 2021, 17(11), 740-750.
[http://dx.doi.org/10.1038/s41581-021-00462-y] [PMID: 34363037]
[5]
Tang, S.C.W.; Chan, L.Y.Y.; Leung, J.C.K.; Cheng, A.S.; Chan, K.W.; Lan, H.Y.; Lai, K.N. Bradykinin and high glucose promote renal tubular inflammation. Nephrol. Dial. Transplant., 2010, 25(3), 698-710.
[http://dx.doi.org/10.1093/ndt/gfp599] [PMID: 19923143]
[6]
Klessens, C.Q.F.; Zandbergen, M.; Wolterbeek, R.; Bruijn, J.A.; Rabelink, T.J.; Bajema, I.M.; IJpelaar, D.H.T. Macrophages in diabetic nephropathy in patients with type 2 diabetes. Nephrol. Dial. Transplant., 2017, 32(8), 1322-1329.
[PMID: 27416772]
[7]
Tang, P.M.K.; Nikolic-Paterson, D.J.; Lan, H.Y. Macrophages: Versatile players in renal inflammation and fibrosis. Nat. Rev. Nephrol., 2019, 15(3), 144-158.
[http://dx.doi.org/10.1038/s41581-019-0110-2] [PMID: 30692665]
[8]
Meng, X.M.; Nikolic-Paterson, D.J.; Lan, H.Y. Inflammatory processes in renal fibrosis. Nat. Rev. Nephrol., 2014, 10(9), 493-503.
[http://dx.doi.org/10.1038/nrneph.2014.114] [PMID: 24981817]
[9]
Swanson, K.V.; Deng, M.; Ting, J.P.Y. The NLRP3 inflammasome: Molecular activation and regulation to therapeutics. Nat. Rev. Immunol., 2019, 19(8), 477-489.
[http://dx.doi.org/10.1038/s41577-019-0165-0] [PMID: 31036962]
[10]
Li, N.; Zhou, H.; Wu, H.; Wu, Q.; Duan, M.; Deng, W.; Tang, Q. STING-IRF3 contributes to lipopolysaccharide-induced cardiac dys-function, inflammation, apoptosis and pyroptosis by activating NLRP3. Redox Biol., 2019, 24, 101215.
[http://dx.doi.org/10.1016/j.redox.2019.101215] [PMID: 31121492]
[11]
Tang, S.C.W.; Yiu, W.H. Innate immunity in diabetic kidney disease. Nat. Rev. Nephrol., 2020, 16(4), 206-222.
[http://dx.doi.org/10.1038/s41581-019-0234-4] [PMID: 31942046]
[12]
Song, S.; Qiu, D.; Luo, F.; Wei, J.; Wu, M.; Wu, H.; Du, C.; Du, Y.; Ren, Y.; Chen, N.; Duan, H.; Shi, Y. Knockdown of NLRP3 alleviates high glucose or TGFB1-induced EMT in human renal tubular cells. J. Mol. Endocrinol., 2018, 61(3), 101-113.
[http://dx.doi.org/10.1530/JME-18-0069] [PMID: 30307163]
[13]
Ding, H.; Li, J.; Li, Y.; Yang, M.; Nie, S.; Zhou, M.; Zhou, Z.; Yang, X.; Liu, Y.; Hou, F.F. MicroRNA-10 negatively regulates inflammation in diabetic kidney via targeting activation of the NLRP3 inflammasome. Mol. Ther., 2021, 29(7), 2308-2320.
[http://dx.doi.org/10.1016/j.ymthe.2021.03.012] [PMID: 33744467]
[14]
Wu, M.; Han, W.; Song, S.; Du, Y.; Liu, C.; Chen, N.; Wu, H.; Shi, Y.; Duan, H. NLRP3 deficiency ameliorates renal inflammation and fibrosis in diabetic mice. Mol. Cell. Endocrinol., 2018, 478, 115-125.
[http://dx.doi.org/10.1016/j.mce.2018.08.002] [PMID: 30098377]
[15]
Jiang, H.; He, H.; Chen, Y.; Huang, W.; Cheng, J.; Ye, J.; Wang, A.; Tao, J.; Wang, C.; Liu, Q.; Jin, T.; Jiang, W.; Deng, X.; Zhou, R. Identification of a selective and direct NLRP3 inhibitor to treat inflammatory disorders. J. Exp. Med., 2017, 214(11), 3219-3238.
[http://dx.doi.org/10.1084/jem.20171419] [PMID: 29021150]
[16]
Sun, K.; Wang, J.; Lan, Z.; Li, L.; Wang, Y.; Li, A.; Liu, S.; Li, Y. Sleeve gastroplasty combined with the NLRP3 inflammasome inhibitor CY-09 reduces body weight, improves insulin resistance and alleviates hepatic steatosis in mouse model. Obes. Surg., 2020, 30(9), 3435-3443.
[http://dx.doi.org/10.1007/s11695-020-04571-8] [PMID: 32266697]
[17]
Pan, L.L.; Liang, W.; Ren, Z.; Li, C.; Chen, Y.; Niu, W.; Fang, X.; Liu, Y.; Zhang, M.; Diana, J.; Agerberth, B.; Sun, J. Cathelicidin‐related antimicrobial peptide protects against ischaemia reperfusion‐induced acute kidney injury in mice. Br. J. Pharmacol., 2020, 177(12), 2726-2742.
[http://dx.doi.org/10.1111/bph.14998] [PMID: 31976546]
[18]
Forbes, J.M.; Thorburn, D.R. Mitochondrial dysfunction in diabetic kidney disease. Nat. Rev. Nephrol., 2018, 14(5), 291-312.
[http://dx.doi.org/10.1038/nrneph.2018.9] [PMID: 29456246]
[19]
Han, Y.; Xu, X.; Tang, C.; Gao, P.; Chen, X.; Xiong, X.; Yang, M.; Yang, S.; Zhu, X.; Yuan, S.; Liu, F.; Xiao, L.; Kanwar, Y.S.; Sun, L. Reactive oxygen species promote tubular injury in diabetic nephropathy: The role of the mitochondrial ros-txnip-nlrp3 biological axis. Redox Biol., 2018, 16, 32-46.
[http://dx.doi.org/10.1016/j.redox.2018.02.013] [PMID: 29475133]
[20]
Gao, P.; Yang, M.; Chen, X.; Xiong, S.; Liu, J.; Sun, L. DsbA-L deficiency exacerbates mitochondrial dysfunction of tubular cells in diabetic kidney disease. Clin. Sci. (Lond.), 2020, 134(7), 677-694.
[http://dx.doi.org/10.1042/CS20200005] [PMID: 32167139]
[21]
Yang, M.; Zhao, L.; Gao, P.; Zhu, X.; Han, Y.; Chen, X.; Li, L.; Xiao, Y.; Wei, L.; Li, C.; Xiao, L.; Yuan, S.; Liu, F.; Dong, L.Q.; Kanwar, Y.S.; Sun, L. DsbA-L ameliorates high glucose induced tubular damage through maintaining MAM integrity. EBioMedicine, 2019, 43, 607-619.
[http://dx.doi.org/10.1016/j.ebiom.2019.04.044] [PMID: 31060900]
[22]
Chen, X.; Han, Y.; Gao, P.; Yang, M.; Xiao, L.; Xiong, X.; Zhao, H.; Tang, C.; Chen, G.; Zhu, X.; Yuan, S.; Liu, F.; Dong, L.Q.; Liu, F.; Kanwar, Y.S.; Sun, L. Disulfide-bond A oxidoreductase-like protein protects against ectopic fat deposition and lipid-related kidney damage in diabetic nephropathy. Kidney Int., 2019, 95(4), 880-895.
[http://dx.doi.org/10.1016/j.kint.2018.10.038] [PMID: 30791996]
[23]
Afsar, B.; Covic, A.; Ortiz, A.; Afsar, R.E.; Kanbay, M. The future of IL-1 targeting in kidney disease. Drugs, 2018, 78(11), 1073-1083.
[http://dx.doi.org/10.1007/s40265-018-0942-2] [PMID: 29968152]
[24]
Zahid, A.; Li, B.; Kombe, A.J.K.; Jin, T.; Tao, J. Pharmacological inhibitors of the NLRP3 inflammasome. Front. Immunol., 2019, 10, 2538.
[http://dx.doi.org/10.3389/fimmu.2019.02538] [PMID: 31749805]
[25]
Lin, H.B.; Wei, G.S.; Li, F.X.; Guo, W.J.; Hong, P.; Weng, Y.Q.; Zhang, Q.Q.; Xu, S.Y.; Liang, W.B.; You, Z.J.; Zhang, H.F. Macrophage–NLRP3 inflammasome activation exacerbates cardiac dysfunction after ischemic stroke in a mouse model of diabetes. Neurosci. Bull., 2020, 36(9), 1035-1045.
[http://dx.doi.org/10.1007/s12264-020-00544-0] [PMID: 32683554]

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