Korean J Physiol Pharmacol.  2023 May;27(3):221-230. 10.4196/kjpp.2023.27.3.221.

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

• Zhu Q
• Zhou Q
• Luo Xl
• Zhang Xj
• Li Sy

• KMID: 2541634
• DOI: http://doi.org/10.4196/kjpp.2023.27.3.221

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.

Keyword

Canagliflozin; Diabetes mellitus; Diabetic nephropathies; Lipotoxicity; Puerarin

Figure

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  Fig. 1 Effect of canagliflozin and puerarin on body weight and hyperglycemia. (A) Body weight in control and diabetic mice with different treatments at the end of the 22nd week. (B) Blood glucose in control mice and diabetic mice with different treatments at the end of the 22nd week. (C) Body weight time course in control mice and diabetic mice with different treatments. (D) Blood glucose time course in control mice and diabetic mice with different treatments. Data are shown as mean ± SD (n = 6). #p < 0.05, ##p < 0.01 vs. control group; *p < 0.05, **p < 0.01 vs. diabetes group; ^p < 0.05, ^^p < 0.01 vs. canagliflozin group.

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  Fig. 2 Effect of canagliflozin and puerarin on functional and structural parameters of kidneys. (A) Effect of canagliflozin and puerarin on urinary albumin excretion. (B) Representative image of HE (100×), PAS (400×), and picrosirius red (100×) staining of kidney sections. (C) PAS-positive area in glomeruli. (D) Percentages of picrosirius red-positive areas. Data are shown as mean ± SD (n = 6). HE, hematoxylin and eosin; PAS, periodic acid-Schiff. ##p < 0.01 vs. control group; **p < 0.01 vs. diabetes group; ^^p < 0.01 vs. canagliflozin group.

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  Fig. 3 Effect of canagliflozin and puerarin on lipid homeostasis of kidneys. (A) Representative image of oil red O staining (100×) of kidney sections. (B) Oil red O-positive area in the kidney. (C) Western blot of CD36, adipophilin, and PPARα in the kidney. (D) Relative expression of CD36. (E) Relative expression of adipophilin. (F) Relative expression of PPARα. Data are shown as mean ± SD (n = 6). #p < 0.05, ##p < 0.01 vs. control group; **p < 0.01 vs. diabetes group; ^^p < 0.01 vs. canagliflozin group.

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  Fig. 4 Effect of puerarin in combination with canagliflozin on oxidative stress and the inflammatory response of kidneys. (A) MDA level in the kidney. (B) GPx activity in the kidney. (C) SOD activity in the kidney. (D) CAT activity in the kidney. (E) GSH levels in the kidney. (F) Western blot of TNFα, IFNγ, IL6, and IL1β in the kidney. (G) Relative expression of TNFα. (H) Relative expression of IFNγ. (I) Relative expression of IL6. (J) Relative expression of IL1β. Data are shown as mean ± SD (n = 6). MDA, malondialdehyde; GPx, glutathione peroxidase; SOD, superoxide dismutase; CAT, catalase; GSH, glutathione; TNFα, tumor necrosis factor α; IFNγ, interferon γ; IL, interleukin. #p < 0.05, ##p < 0.01 vs. control group; *p < 0.05, **p < 0.01 vs. diabetes group.

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