Sitagliptin's renoprotective effect in a diabetic nephropathy model in rats: The potential role of PI3K/AKT pathway

• Published in: Fundamental & clinical pharmacology 2022-04, Vol.36 (2), p.324-337
• Main Authors: Mohamed, Reham Hussein, Sedky, Amina Ahmed, Hamam, Ghada Galal, Elkhateb, Lobna, Kamar, Sherif A., Adel, Seham, Tawfik, Sherin Shafik
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Actin; AKT protein; Animal models; Animals; Blood; Collagen; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental - complications; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - metabolism; Diabetic Nephropathies - drug therapy; Diabetic Nephropathies - prevention & control; diabetic nephropathy; Growth factors; Kidney; Kidneys; Kinases; Male; Muscles; Nephropathy; Oxidative stress; Pathogenesis; Pharmacology; Phosphatidylinositol 3-Kinase - metabolism; Phosphatidylinositol 3-Kinase - pharmacology; Phosphatidylinositol 3-Kinases - metabolism; phosphatidylinositol 3‐kinase; protein kinase B; Proto-Oncogene Proteins c-akt - metabolism; Rats; Rats, Wistar; Rodents; sitagliptin; Sitagliptin Phosphate - metabolism; Sitagliptin Phosphate - pharmacology; Smooth muscle; Superoxide dismutase; Tissues; Transforming growth factor-b; Tumor necrosis factor; Tumor necrosis factor-TNF; α‐SMA
• ISSN: 0767-3981; 1472-8206
• DOI: 10.1111/fcp.12736

Management of diabetic nephropathy (DN) is far from satisfactory. There is a rising role of the involvement of phosphatidylinositol 3‐kinase (PI3K)/protein kinase B (AKT) pathway in the pathogenesis of DN. This study aimed at investigating the renoprotective effects of PI3K/AKT pathway via sitagliptin in a rat model of DN. Thirty‐two male Wistar rats were divided into four groups (eight rats each): (I) control, (II) sitagliptin, (III) DN, and (IV) DN + sitagliptin. Fasting blood glucose (FBG), kidney index, and kidney function tests in both blood and urine were measured. The levels of superoxide dismutase (SOD), tumor necrosis factor‐alpha (TNF‐α), and transforming growth factor‐beta (TGF‐β) and gene expressions of PI3K, pPI3K, AKT, and pAKT in renal tissue were detected. Renal histopathological and immunohistochemical studies were evaluated. DN + sitagliptin group showed significant decrease in FBG and kidney index, improvement in kidney function tests, and a decrease in levels of TNF‐α and TGF‐β in renal tissues compared with DN group. This was associated with significant increase in SOD and gene expressions of PI3K and AKT and their phosphorylated active forms in renal tissue in DN + sitagliptin group compared with DN group. Moreover, DN + sitagliptin group showed apparent decrease in amount of collagen fibers and expression of alpha‐smooth muscle actin (α‐SMA) compared with DN group. This work shows that sitagliptin improved renal functions and histopathological changes, impeded inflammation, and oxidative stress and upregulated PI3K/AKT pathway which highlights its renoprotective effects in a rat model of DN.