Renal, Electrolyte, and Hypertension Division, Department of Medicine.
Institute for Diabetes, Obesity, and Metabolism.
J Clin Invest. 2023 Feb 15;133(4):e165654. doi: 10.1172/JCI165654.
Kidney disease is a major driver of mortality among patients with diabetes and diabetic kidney disease (DKD) is responsible for close to half of all chronic kidney disease cases. DKD usually develops in a genetically susceptible individual as a result of poor metabolic (glycemic) control. Molecular and genetic studies indicate the key role of podocytes and endothelial cells in driving albuminuria and early kidney disease in diabetes. Proximal tubule changes show a strong association with the glomerular filtration rate. Hyperglycemia represents a key cellular stress in the kidney by altering cellular metabolism in endothelial cells and podocytes and by imposing an excess workload requiring energy and oxygen for proximal tubule cells. Changes in metabolism induce early adaptive cellular hypertrophy and reorganization of the actin cytoskeleton. Later, mitochondrial defects contribute to increased oxidative stress and activation of inflammatory pathways, causing progressive kidney function decline and fibrosis. Blockade of the renin-angiotensin system or the sodium-glucose cotransporter is associated with cellular protection and slowing kidney function decline. Newly identified molecular pathways could provide the basis for the development of much-needed novel therapeutics.
肾脏疾病是糖尿病患者死亡的主要原因，而糖尿病肾病（DKD）导致了近一半的慢性肾病病例。DKD 通常在遗传易感个体中由于代谢（血糖）控制不佳而发展。分子和遗传研究表明，足细胞和内皮细胞在驱动糖尿病中的白蛋白尿和早期肾脏疾病方面起着关键作用。近端肾小管的变化与肾小球滤过率密切相关。高血糖通过改变内皮细胞和足细胞的细胞代谢，并对近端肾小管细胞施加需要能量和氧气的过量工作负荷，从而对肾脏造成关键的细胞应激。代谢变化诱导早期适应性细胞肥大和肌动蛋白细胞骨架的重组。随后，线粒体缺陷导致氧化应激增加和炎症途径激活，导致肾功能进行性下降和纤维化。肾素-血管紧张素系统或钠-葡萄糖共转运蛋白的阻断与细胞保护和减缓肾功能下降有关。新发现的分子途径可能为急需的新型治疗方法提供基础。
