Saxagliptin attenuates glomerular podocyte injury by increasing the expression of renal nephrin and podocin in type 2 diabetic rats
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To observe the effects of saxagliptin on the expression of mitogen-activated protein kinase 38 (p38MAPK), nephrin and podocin in renal tissue in type 2 diabetic (T2DM) rats, and to explore the possible mechanism of its renal protection.
Forty-eight male Sprague–Dawley rats were used for the study and divided into four different groups: normal controls (Group NC), DM controls (Group DM), DM + glibenclamide (Group Su) and DM + saxagliptin (Group Sa). The day drug administration started was defined as week 0. After 12 weeks, hemoglobin A1c (HbA1c), total cholesterol (TC), triglyceride (TG), urea nitrogen (BUN) and creatinine (Cr) in serum were detected, simultaneously albumin and creatinine in urine were measured, respectively, and then urinary albumin/creatinine ratio (UACR) was calculated. The pathological morphology of kidney tissue in different groups was observed, and the expression of nephrin and podocin mRNA and protein in kidney tissue were detected.
(1) After 12 weeks, FBG and HbA1c in Group Su and Group Sa were significantly lower than those in Group DM (both P < 0.05), while there was no significant difference between Group Su and Group Sa. TC, TG and UACR in Group Sa were significantly decreased than those in Group DM. (2) When compared with Group DM, the kidney weight/body weight ratios, the average width of glomerular basement membrane and foot process fusion ratio were all improved in Group Sa after 12 weeks. (3) The expression of p38MAPK mRNA and protein was significantly decreased, while nephrin and podocin mRNA and protein were significantly higher in Group Sa than those in Group DM after 12 weeks. (4) A significant negative correlation was detected between p38MAPK mRNA and nephrin (r = − 0.421, P = 0.009) and podocin mRNA (r = − 0.570, P = 0.000), respectively.
Saxagliptin can reduce urinary albumin excretion and exert renal protective effect, especially on podocytes in T2DM rats. The mechanism may be related to its inhibition of renal p38MAPK signaling pathway and the increase in the expression of nephrin and podocin in renal tissue, which is independent of its hypoglycemic effect.
KeywordsDiabetes mellitus Saxagliptin DPP-4 Nephrin Podocin p38MAPK
This study was supported by the National Natural Science Foundation of China (81800731) and Local Scientific and Technological Development Project guided by Central Government of China (No: 2017070802D147).
compliance with ethical standards
Conflict of interest
All the authors declare that they have no conflict of interest.
The study protocol was approved by the Ethics Committee of Anhui provincial hospital, Medical Institution Animal Care and Research Advisory Committee (Hefei, China).