activation. This effect is mediated through increased intracellular calcium and can contribute to the pro-coagulant state in diabetes (38). Accordingly, it seems that activation of NHE1 and NHE3 plays a distinguished role in the pathogenesis of heart failure and ESRD in patients with diabetes and that inhibition of these exchangers might have an important influence in their management. Oxidative Stress Increased oxidative stress is one of the metabolic disorders encountered in diabetes. Diabetes patients overproduce free oxygen radicals. Increased production of free oxygen radicals is the sequel to increased activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (39, 40), cyclo-oxygenase (41), and lipoxygenase (42) enzymes in response to hyperglycemia. Proximal convoluted tubular epithelium (PCT) has SGLT2 within its brush border. SGLT2 is another pathway for overproduction of free oxygen radicals. Increased intracellular concentration of uric acid (UA) induces NADPH oxidase (43). Mitochondrial damage results in impaired antioxidant defense (44). Increased free oxygen radicals activate NF-κB (45). Translocation of NF-κB from the cytoplasm to the nucleus occurs when it gets rid of its inhibitor. Within the nucleus, NF-κB triggers the genes encoding transforming growth factor-β1 (TGF-β1), monocyte chemoattractant protein-1 (MCP-1), and intercellular adhesion molecule 1 (ICAM1) (46-48). ROS stimulates overproduction of protein kinase C (PKC) and mitogen-activated protein (MAP) kinase within mesangial cells (MCs) and pericytes with consequent overproduction of extracellular matrix proteins (49). Uric Acid High serum UA is indicated as a strong predictor for proteinuria in T1DM patients. The risk for development of proteinuria increases by 80% with every 1 mg/dL increase in UA (50). There is Figure 2. Consequences of endothelial dysfunction. Endothelial Dysfunction ê NO é Endothelin é ICAM, VCAM Insulin resistance Nephropathy Retinopathy neuropathy Atherosclerosis Ischemia of heart, brain peripheral tissue Systemic Hypertension Microvasculature Conduit arteries Resistance arteries Figure 3. Diabetic state increases the activity of the sodium/hydrogen exchanger on the surface of endothelial cells, vascular smooth muscle cells, cardiomyocytes, and tubular epithelial cells. Consequently, intracellular and mitochondrial calcium increases. Na+ Ca++ Ca++ Na+ Na+ + DM H + + Na+ /Ca++ Exchanger Na+ /H+ Exchanger Figure 4. Consequences of NHE1 activation. NO: nitric oxide; VSMCs: vascular smooth muscle cells; PR: peripheral resistance Consequences of increased intracellular calcim Endothelium Platelets Cardiomyocytes VSMCs Hypertrophy, degeneration, fibrosis é Tone, é PR, atherosclerosis and vascular calcification é adhesiveness and aggregation • • – – – – – – – • • ê NO é Endothelin é Insulin resistance é Microvascular and macrovascular complications Turk J Nephrol 2020; 29(2): 161-73 Sharaf El Din et al. Diabetic Nephropathy Prevention 163 a 2.4-fold risk of decline of GFR in T1DM patients with serum UA >6.6 mg/dL when compared with patients with lower UA level (51). When T1DM patients were followed up for more than 18 years, UA was an independent predictor of overt proteinuria (52); 68% of the hyperuricemic T2DM patients versus 41.5% with normal UA had DN (53). The increased risk for the development of albuminuria and accelerated decline of GFR in hyperuricemic T2DM patients is confirmed by two prospective studies (54, 55). In T2DM patients that have the disease for 15 years or more, UA >7 mg/dL in males and >6 mg/dL in females is associated with a higher rate of DN progression and overall mortality (56). Treatment of T2DM patients suffering from DN and high serum UA with allopurinol decreased UAE and serum creatinine significantly and significantly increased GFR over three years of follow-up (57). In a meta-analysis of 19 randomized controlled trials enrolling 992 patients, the significant favorable effect of urate-lowering therapy on the rate of GFR decline was confirmed (58). Increased level of UA is associated with endothelial dysfunction. In a recent in vitro study, high UA concentration inhibited eNOS expression and NO production in human umbilical vein endothelial cells (HUVECs), activated NF-κB, and increased the level of inflammatory cytokines (59). High UA significantly predicts systemic hypertension (60). Role of Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RA) Glucagon-like peptide-1 (GLP-1) is a polypeptide hormone. Small intestinal mucosal neuro-endocrine cells secrete GLP-1 to activate pancreatic insulin secretion, inhibit glucagon secretion by pancreatic α cells, slow gastric emptying, and control appetite (61). Dipeptidyl peptidase-4 enzyme breakdown of GLP-1 is responsible for the very short plasma half-life of this hormone. Continuous intravenous infusion is thus needed if this agent is used therapeutically (62). GLP-1RA are exogenous GLP-1 analogues with variable sequence similarity to the human GLP-1 (63). This variability involves mainly two sites in the GLP-1 molecule susceptible to cleavage by DPP4; namely, alanine and lysine at positions 8 and 34 respectively. These changes, beside other modifications, have helped to discover many peptides that simulate GLP-1 action but with longer half-life