Modulation of Intrarenal eNOS and p47phox Expression by Galangin Attenuates Kidney Injury in Diabetic Rats
DOI:
https://doi.org/10.64960/srimedj.v40i6.269232Keywords:
eNOS, p47phox, galangin, kidney injury, diabetic ratsAbstract
Background and Objective: Diabetic nephropathy (DN) develops as a consequence of chronic hyperglycemia, which triggers the overexpression of p47phox while simultaneously suppressing endothelial nitric oxide synthase (eNOS) expression. This dual mechanism promotes oxidative stress, inflammation, and disrupts renal function, leading to kidney injury that represents the initial pathological step in DN progression. The objective of this study was to investigate the therapeutic potential of galangin (GA) in addressing kidney injury in diabetic rats.
Methods: Male Wistar rats were divided into two main groups: non-diabetic and diabetic. The non-diabetic group comprised a vehicle-treated control and a GA-treated (50 mg/kg) subgroup. The diabetic group comprised a vehicle-treated control, a GA 25 mg/kg subgroup, and a GA 50 mg/kg subgroup (n = 6-8 per group). Type 2 diabetes was induced in male Wistar rats by a single intraperitoneal injection of nicotinamide (110 mg/kg/day), followed by a single intraperitoneal injection of streptozotocin (55 mg/kg/day). After eight weeks of diabetes induction, rats received GA supplementation at doses 25 or 50 mg/kg/day for four weeks. Metabolic parameters and renal functions, kidney tissue of p47phox and eNOS proteins, oxidative stress markers, and glomerular morphology by light microscopy and ultrastructure by transmission electron microscopy were evaluated.
Results: GA supplementation significantly reduced elevated fasting blood glucose and insulin resistance while improving kidney function compared to diabetic controls (p < 0.05). Excessive superoxide production and oxidative stress in diabetic kidneys were markedly attenuated following GA treatment (p < 0.05). GA administration, particularly at 50 mg/kg/day, significantly inhibited glomerular hypertrophy and ultrastructural kidney changes. Additionally, GA suppressed renal p47phox expression while upregulating eNOS expression in diabetic kidney tissues.
Conclusions: GA provides renoprotection in diabetic rats through glucose-lowering and antioxidant mechanisms that suppress p47phox-mediated reactive oxygen species generation, restore eNOS expression, normalize renal function, and preserve glomerular architecture. These findings support GA's therapeutic potential for preventing or delaying early diabetic nephropathy.
References
Shen Y, Cai R, Sun J, Dong X, Huang R, Tian S, et al. Diabetes mellitus as a risk factor for incident chronic kidney disease and end-stage renal disease in women compared with men: a systematic review and meta-analysis. Endocrine 2017;55(1):66-76. doi:10.1007/s12020-016-1014-6.
Afkarian M, Sachs MC, Kestenbaum B, Hirsch IB, Tuttle KR, Himmelfarb J, et al. Kidney disease and increased mortality risk in type 2 diabetes. J Am Soc Nephrol 2013;24(2):302-8. doi:10.1681/ASN.2012070718.
Jerums G, Premaratne E, Panagiotopoulos S, MacIsaac RJ. The clinical significance of hyperfiltration in diabetes. Diabetologia 2010;53(10):2093-104. doi:10.1007/s00125-010-1794-9.
Ma L, Liu D, Yu Y, Li Z, Wang Q. Immune-mediated renal injury in diabetic kidney disease: from mechanisms to therapy. Front Immunol 2025;16:1587806. doi:10.3389/fimmu.2025.1587806.
Sedeek M, Nasrallah R, Touyz RM, Hebert RL. NADPH oxidases, reactive oxygen species, and the kidney: friend and foe. J Am Soc Nephrol 2013;24(10):1512-8. doi:10.1681/ASN.2012111112.
Wang W, Jittikanont S, Falk SA, Li P, Feng L, Gengaro PE, et al. Interaction among nitric oxide, reactive oxygen species, and antioxidants during endotoxemia-related acute renal failure. Am J Physiol Renal Physiol 2003;284(3):F532-7. doi:10.1152/ajprenal.00323.2002.
Araujo M, Welch WJ. Oxidative stress and nitric oxide in kidney function. Curr Opin Nephrol Hypertens 2006;15(1):72-7. doi:10.1097/01.mnh.0000191912.65281.e9.
Reddy YS, Kiranmayi VS, Bitla AR, Krishna GS, Rao PV, Sivakumar V. Nitric oxide status in patients with chronic kidney disease. Indian J Nephrol 2015;25(5):287-91. doi:10.4103/0971-4065.147376.
Lieberthal W, Nigam SK. Acute renal failure II. Experimental models of acute renal failure: imperfect but indispensable. Am J Physiol Renal Physiol 2000;278(1):F1-12. doi:10.1152/ajprenal.2000.278.1.F1.
Liu H, Feng J, Tang L. Early renal structural changes and potential biomarkers in diabetic nephropathy. Front Physiol 2022;13:1020443. doi:10.3389/fphys.2022.1020443.
Aloud AA, Chinnadurai V, Govindasamy C, Alsaif MA, Al-Numair KS. Galangin, a dietary flavonoid, ameliorates hyperglycaemia and lipid abnormalities in rats with streptozotocin-induced hyperglycaemia. Pharm Biol 2018;56(1):302-8. doi:10.1080/13880209.2018.1474931.
Heidari H, Khalaj A, Khani S, Abdollahi M, Farahani H, Khani S. Hypoglycemic, hypolipidemic and hepatoprotective effects of Alpinia officinarum on nicotinamide/streptozotocin induced type II diabetic rats. Horm Mol Biol Clin Investig 2022;43(3):289-96. doi:10.1515/hmbci-2021-0050.
Zhang X, Zhang Y, Zhou M, Xie Y, Dong X, Bai F, et al. DPHC from Alpinia officinarum ameliorates oxidative stress and insulin resistance via activation of Nrf2/ARE pathway in db/db mice and high glucose-treated HepG2 cells. Front Pharmacol 2021;12:792977. doi:10.3389/fphar.2021.792977.
Sangartit W, Pakdeechote P, Kukongviriyapan V, Donpunha W, Shibahara S, Kukongviriyapan U. Tetrahydrocurcumin in combination with deferiprone attenuates hypertension, vascular dysfunction, baroreflex dysfunction, and oxidative stress in iron-overloaded mice. Vascul Pharmacol 2016;87:199-208. doi:10.1016/j.vph.2016.10.001.
Sangartit W, Ha KB, Lee ES, Kim HM, Kukongviriyapan U, Lee EY, et al. Tetrahydrocurcumin ameliorates kidney injury and high systolic blood pressure in high-fat diet-induced type 2 diabetic mice. Endocrinol Metab (Seoul) 2021;36(4):810-22. doi:10.3803/EnM.2021.988.
Ha KB, Sangartit W, Jeong AR, Lee ES, Kim HM, Shim S, et al. EW-7197 attenuates the progression of diabetic nephropathy in db/db mice through suppression of fibrogenesis and inflammation. Endocrinol Metab (Seoul) 2022;37(1):96-111. doi:10.3803/EnM.2021.1305.
Hahn M, van Krieken PP, Nord C, Alanentalo T, Morini F, Xiong Y, et al. Topologically selective islet vulnerability and self-sustained downregulation of markers for beta-cell maturity in streptozotocin-induced diabetes. Commun Biol 2020;3(1):541. doi:10.1038/s42003-020-01243-2.
Aloud AA, Veeramani C, Govindasamy C, Alsaif MA, El Newehy AS, Al-Numair KS. Galangin, a dietary flavonoid, improves antioxidant status and reduces hyperglycemia-mediated oxidative stress in streptozotocin-induced diabetic rats. Redox Rep 2017;22(6):290-300. doi:10.1080/13510002.2016.1273437.
Kalhotra P, Chittepu V, Osorio-Revilla G, Gallardo-Velazquez T. Discovery of galangin as a potential DPP-4 inhibitor that improves insulin-stimulated skeletal muscle glucose uptake: a combinational therapy for diabetes. Int J Mol Sci 2019;20(5):1228. doi:10.3390/ijms20051228.
Yoshida Y, Shibata H. A new mechanism of diabetic kidney disease progression by Piezo proteins: mediators between mechanical stimuli and fibrosis. Hypertens Res 2025;48(4):1619-20. doi:10.1038/s41440-025-02162-7.
Zhang H, Wang K, Zhao H, Qin B, Cai X, Wu M, et al. Diabetic kidney disease: from pathogenesis to multimodal therapy-current evidence and future directions. Front Med (Lausanne) 2025;12:1631053. doi:10.3389/fmed.2025.1631053.
Shi XY, Hou FF, Niu HX, Wang GB, Xie D, Guo ZJ, et al. Advanced oxidation protein products promote inflammation in diabetic kidney through activation of renal nicotinamide adenine dinucleotide phosphate oxidase. Endocrinology 2008;149(4):1829-39. doi:10.1210/en.2007-1544.
Lee HE, Shim S, Choi Y, Bae YS. NADPH oxidase inhibitor development for diabetic nephropathy through water tank model. Kidney Res Clin Pract 2022;41(Suppl 2):S89-98. doi:10.23876/j.krcp.21.269.
Zou Y, Dai J, Li J, Liu M, Li R, Li G, et al. Role of the TGF‑beta/Smad signaling pathway in the transition from acute kidney injury to chronic kidney disease (review). Int J Mol Med 2025;56(4):162. doi:10.3892/ijmm.2025.5603.
Hong L, Li M, Fan Y. Oxidative stress and programmed cell death in diabetic wounds: a comprehensive review. Sci Prog 2025;108(3):3685042513706746. doi:10.1177/00368504251370676.
Youn JY, Gao L, Cai H. The p47phox- and NADPH oxidase organiser 1 (NOXO1)-dependent activation of NADPH oxidase 1 (NOX1) mediates endothelial nitric oxide synthase (eNOS) uncoupling and endothelial dysfunction in a streptozotocin-induced murine model of diabetes. Diabetologia 2012;55(7):2069-79. doi:10.1007/s00125-012-2557-6.
Elumalai S, Karunakaran U, Moon JS, Won KC. NADPH oxidase (NOX) targeting diabetes: a special emphasis on pancreatic beta-cell dysfunction. Cells 2021;10(7):1573. doi:10.3390/cells10071573.
Roy B. Pathophysiological mechanisms of diabetes-induced macrovascular and microvascular complications: the role of oxidative stress. Med Sci (Basel) 2025;13(3):87. doi:10.3390/medsci13030087.
Luczak A, Madej M, Kasprzyk A, Doroszko A. Role of the eNOS uncoupling and the nitric oxide metabolic pathway in the pathogenesis of autoimmune rheumatic diseases. Oxid Med Cell Longev 2020;2020:1417981. doi:10.1155/2020/1417981.
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