Mechanism of progression of diabetic kidney disease mediated by podocyte mitochondrial injury

Abstract

Diabetic kidney disease (DKD) is an important diabetic microvascular complication, which has become the main cause of end-stage renal disease (ESRD) all over the world. It is of great significance to find effective therapeutic targets and improve the prognosis of the disease. Traditionally, it is believed that the activation of the renin-angiotensin-aldosterone system (RAAS) is the main reason for the progression of DKD, but with the progress of research, it is known that the production of proteinuria in patients with DKD is also related to podocyte injury and loss. Many studies have shown that mitochondrial dysfunction in podocytes plays an important role in the occurrence and development of DKD, and oxidative stress is also the main pathway and common hub of diabetes to the occurrence and development of microvascular and macrovascular complications. Thus, the occurrence and progression of DKD is correlated with not only the activation of the RAAS, but also the damage of mitochondria, oxidative stress, and inflammatory mediators. Besides, diabetes-related metabolic disorders can also cause abnormalities in mitochondrial dynamics, autophagy and cellular signal transduction, which are intertwined in a complex way. Therefore, in this review, we mainly explore the mechanism and the latest research progress of podocyte mitochondria in DKD and summarize the main signal pathways involved in them. Thus, it provides feasible clinical application and future research suggestions for the prevention and treatment of DKD, which has important practical significance for the later treatment of patients with DKD.

The Pathogenesis of End-Stage Renal Disease from the Standpoint of the Theory of General Pathological Processes of Inflammation

“…Metabolic variables such as hyperglycemia, AGE buildup, and highly saturated FFA concentrations influence the negative dynamics of proinflammatory tissue stress, leading to damage to proximal tubule cells and glomerular podocytes in DKD [ 153 ]. All these are associated with the development of mitochondrial and oxidative stress and with the proinflammatory secretory phenotype of kidney cells [ 154 , 155 ]. Hypoxia is another important factor in the development of tissue stress in the kidneys, as it triggers a vicious cycle of capillary injury, inflammation, extracellular matrix deposition, and, eventually, fibrosis and nephron loss [ 27 , 103 ].…”

NADH/NAD+ Redox Imbalance and Diabetic Kidney Disease

“…The hallmark of diabetes is a persistent high blood glucose content (hyperglycemia) that can damage a variety of tissues and cells [ 15 , 21 , 22 , 23 ]. In the kidney, renal microvascular structures are the major targets of high blood glucose [ 24 , 25 , 26 , 27 ]. Additionally, given the facts that the kidney is the organ where mature or active form of vitamin D is made [ 28 , 29 , 30 ] and erythropoiesis erythropoietin is produced [ 31 , 32 , 33 ], DKD can also lead to vitamin D deficiency and anemia [ 34 , 35 , 36 , 37 , 38 , 39 , 40 ].…”

Role of Albuminuria in Detecting Cardio-Renal Risk and Outcome in Diabetic Subjects

“…These mechanisms involve an alteration of intracellular homeostasis with consequent cell death. Several signaling pathways seem entangled in the genesis of damage to podocytes' mitochondria and consequent proteinuria in Diabetic Kidney Disease (DKD), particularly the mammalian target of rapamycin (mTOR), Wnt/βcatenin and AMPK signaling pathways [37,38].…”