تقييم SMAD2 و SMAD3 و غلاقتهما بتحويل عامل النموTGF-BETA في مرضى السكري من النوع الثاني المصابين باعتلال الكلية السكري المبكر والمزمن

Assessment of SMAD2, SMAD3 and Their Correlation with TGF-BETA in Type 2 Diabetic Patients with Early and Chronic Diabetic Nephropathy

Diabetes Mellitus (DM) is a metabolic disease characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of different organs, especially the eyes, kidneys, nerves, heart, and blood vessels. Diabetic nephropathy (DN) is one of the most frequent and severe complications of diabetes mellitus and is associated with increased morbidity and mortality in diabetic patients. DN represents the leading cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD). Early detection of DN is critical in improving clinical management and therapeutic intervention progression to ESRD and dialysis. Diabetic kidney disease is characterized by progressive kidney damage reflected by increasing albuminuria (urine albumin-to-creatinine ratio (ACR) exceeding 30 mg/g CR) together with impairment in renal function (decline in glomerular filtration rate (GFR), elevated blood pressure, and excess morbidity and mortality due to cardiovascular complications.
Transforming growth factor (TGF-β) is recognized as a key profibrotic cytokine involved in fibrotic disease, particularly in the vasculature and kidney. The TGF-β signaling pathway is activated in DN. Increased extracellular glucose levels, mesangial cell stretch, activation of renin-angiotensin system, reactive oxidant species (ROS), and advanced glycation end products (AGEs) activate TGF-β synthesis via protein kinase C. TGF-β stimulates its pathway through autocrine or paracrine action. Transcription factor small mothers against decapentaplegic (Smad) family has key roles in cell fate decision in transmitting extracellular signals to the nucleus through transforming growth factor-beta(TGF-β) receptors to activate downstream target gene transcription. For TGF-β signaling, phosphorylation and activation by the active type II and type I receptor complex causes Smad2 and Smad3 to form heterooligomers with Smad4 and translocate the entire complex into the nucleus. There they interact with different cellular partners, bind to DNA, and regulate the transcription of various downstream response genes.
The current study aims to identify the role of SMAD2, and SMAD3 and their Correlation with TGF-β in Type 2 Diabetic Patients with Early and Chronic Diabetic Nephropathy in a sample of the Iraqi population, as well as to study the correlation between these biomarkers with traditional renal function biochemical parameters.
A case-control study was conducted in Hilla city, from October 2021 to May 2022. The samples were collected from Diabetes and Endocrinology Center in Marjan Teaching Hospital in Babylon / Hilla city.
The current study involved 120 individuals, 60 patients with type 2 diabetes mellitus (T2DM) group and 60 participants who are healthy was used as a control group. The patients were subdivided into three equal groups according to their urinary albumin to creatinine ratio (ACR), including patients with normoalbuminuria (n=20)(ACR < 30 mg/g creatinine) and those with microalbuminuria (n=20)(ACR= 30–299 mg/g creatinine) and macroalbuminuria (n=20)(ACR= more than 300 mg/g creatinine). The levels of glucose, HbA1c, blood urea, serum creatinine, TGF-Beta, SMAD2, and SMAD3 were estimated for all participants, in addition to microalbumin in the urine.
The results of the present study found that the mean concentration of FBG and HbA1c levels were significantly increased in T2DM patients with macroalbuminuria, microalbuminuria, and normoalbuminuria compared with the control group, (P-value<0.001).
Serum TGF-β, SMAD2, and SMAD3 levels in T2DM with macroalbuminuria and in T2DM with microalbuminuria were much higher than in T2DM with normoalbuminuria and control groups with highly statistically significant difference (P-value <0.001). On other hand the TGF-β, SMAD2, and SMAD3 was significantly increased in macroalbuminuria as compared with microalbuminuria with a highly statistically significant difference (P-value <0.001). In addition, serum TGF-β, SMAD2, and SMAD3 showed a positive correlation with ACR, Blood Urea, Serum Creatinine, FBG, HbA1c, Diabetic Duration, and a negative correlation with eGFR.
Receiver operating characteristic curves (ROC) revealed that for early detection of DN, A good diagnostic profile of serum TGF-B for early detection of DN, with a sensitivity of 80%, specificity of 95%. Also, the good diagnostic profile of serum SMAD3 for early detection of DN, with a sensitivity of 78.30%, specificity of 95%. So SMAD2 revealed a good diagnostic profile for early detection of DN, with a sensitivity of 66.70 %, specificity of 90 %. all of them are considered independent and reliable biomarkers for the early detection of DN.
In conclusion, this study revealed the importance of these markers in DN pathogenesis which is powered by their correlation with albuminuria and high specificity and sensitivity through ROC analysis, and thus the possibility of their use as biochemical markers in DN was suggested.