ABSTRACT
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-ß) 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-ß 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.
Subject(s)
Diabetes Mellitus, Experimental , Diabetic Nephropathies , Animals , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/metabolism , Diabetic Nephropathies/drug therapy , Diabetic Nephropathies/prevention & control , Kidney , Male , Phosphatidylinositol 3-Kinase/metabolism , Phosphatidylinositol 3-Kinase/pharmacology , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Rats , Rats, Wistar , Sitagliptin Phosphate/metabolism , Sitagliptin Phosphate/pharmacologyABSTRACT
BACKGROUND: We identified and validated novel urinary autophagy markers in diabetic kidney disease (DKD) based on bioinformatics analysis and clinical validation. PATIENTS & METHODS: We retrieved three novel autophagy genes related to DKD from public microarray databases, namely; microtubule-associated protein light chain (MAP1LC3A), WD Repeat Domain, Phosphoinositide Interacting 2 (WIPI2), and RB1-Inducible Coiled-Coil 1 (RB1CC1). Secondly we assessed the expression of the chosen autophagy transcript in urine sediment of 86 patients with DKD and 74 (age and sex matched) controls by reverse transcription quantitative real-time PCR. RESULTS: The urinary expression levels of MAP1LC3A, WIPI, RB1CC1 were significantly lower in DKD than control group (P<0.001).The receiver-operating characteristic curve (ROC) analyses that each urinary autophagy transcript showed high sensitivity and specificity for distinguishing DKD from control (MAP1LC3A, 81.4% and 81.1%; WIPI, 74.4% and 67.6%, and RB1CC1, 81.4%,70.3%, respectively). Notably, a negative correlation was found between these autophagy markers, serum creatinine and urinary albumin creatinine ratio. The sensitivity and specificity of this urinary autophagy based panel reached 90.6% and 60% in diagnosis of DKD. CONCLUSION: We identified and validated a novel diagnostic urinary autophagy based panel with high sensitivity and moderate specificity representing a vital player in the pathogenesis of DKD.
