Farber Evgeny, Hanut Anaam, Tadmor Hagar, Ruth Ana, Nakhoul Farid, Nakhoul Nakhoul
Nephrology and Hypertension Division, The Medical Center in Galilee, Nahariya.
Metabolism and Diabetes Lab, The Medical Center in Galilee, Nahariya.
Harefuah. 2021 Nov;160(11):740-745.
Diabetes mellitus (DM) is the leading cause of end stage renal disease; 40% of the patients worldwide will require replacement therapy after 20 years of DM. Early-stage diabetic nephropathy is characterized by hyper filtration with micro-and macro albuminuria. Later on end-stage renal disease (ESRD) can appear; 40% of diabetic patients develop micro-and macrovascular complications, with increased risk among patients with genetic predisposition, such as Haptoglobin 2-2 phenotype. The most frequent complications are diabetic kidney disease, diabetic retinopathy and coronary artery disease. Chronic systemic inflammation and the inflammatory response, such as increased circulating cytokines have been recognized as main players in the development and progression of diabetic nephropathy. DM is also associated with increased oxidative stress, and alterations in carbohydrate, lipid and protein metabolism. Blocking the renin- angiotensin- aldosterone system (RAAS) is not sufficient to delay the progression of DM. Autophagy may be involved in the pathogenesis of diabetic nephropathy. Under normal blood glucose level, autophagy is an important protective mechanism in renal epithelial cells, including podocytes, proximal tubular, mesangial and endothelial cells. Down regulation of the autophagy mechanism, as in hyperglycemic condition, can contribute to the development and progression of DM. The recently used new family of drugs SGL2Tis (sodium-glucose cotransporter-2 inhibitors) reduces the typical glomerular hyper-filtration. Preclinical and clinical studies focusing on SGLT2I treatment have consistently demonstrated a reduction in albuminuria and maintenance of renal function. SGLT2 inhibition may lead to positive molecular changes in podocyte cells and proximal tubule cells by directly affect basal autophagy.
糖尿病（DM）是终末期肾病的主要病因；全球40%的糖尿病患者在患病20年后将需要替代治疗。早期糖尿病肾病的特征是伴有微量和大量蛋白尿的高滤过。随后可能会出现终末期肾病（ESRD）；40%的糖尿病患者会发生微血管和大血管并发症，在具有遗传易感性的患者中风险增加，例如触珠蛋白2-2表型的患者。最常见的并发症是糖尿病肾病、糖尿病视网膜病变和冠状动脉疾病。慢性全身炎症和炎症反应，如循环细胞因子增加，已被认为是糖尿病肾病发生和发展的主要因素。糖尿病还与氧化应激增加以及碳水化合物、脂质和蛋白质代谢改变有关。阻断肾素-血管紧张素-醛固酮系统（RAAS）不足以延缓糖尿病的进展。自噬可能参与糖尿病肾病的发病机制。在正常血糖水平下，自噬是肾上皮细胞（包括足细胞、近端肾小管、系膜细胞和内皮细胞）中的一种重要保护机制。自噬机制的下调，如在高血糖状态下，可促进糖尿病的发生和发展。最近使用的新型药物钠-葡萄糖协同转运蛋白2抑制剂（SGL2Tis）可降低典型的肾小球高滤过。聚焦于SGLT2I治疗的临床前和临床研究一致表明可减少蛋白尿并维持肾功能。抑制SGLT2可能通过直接影响基础自噬而导致足细胞和近端小管细胞发生积极的分子变化。
