Yi Hsuan Ku

Introduction. Kidney disease (KD) represents the ninth leading cause of death in the United States, and a key risk factor is diabetes¹. There is currently no cure for chronic KD (CKD), and CKD patients can only receive supportive therapy². CKD patients are more likely to die from cardiovascular complications before their condition progresses to end-stage KD^3,4. Microvascular rarefaction (reduced capillary density) is prevalent and considered a hallmark of CKD, but its underlying mechanisms are unclear^5,6. Studies have found that mitochondria serve a fundamental role in tubular injury in patients with diabetic KD (DKD)⁴. Other studies have revealed that mitochondria-derived reactive oxygen species (mtROS) result in microvascular dysfunction in CKD patients^3,4,7. Methods. After administration of mtRNOS scavenger MitoTempo into healthy controls and CKD patients, local heating was applied to dilate vessels and determine the effect of mtROS on cutaneous blood flow³. Immunohistochemistry and mass spectrometry analyses were utilized to determine expression of cellular components involved in progression of CKD^4,5. Sodium-glucose cotransporter (SGLT)-2 inhibitor treatment in mice was analyzed for vascular endothelial growth factor (VEGF) expression to determine the level of angiogenesis in proximal tubular cells⁸. Results. Local heating caused a greater increase in cutaneous blood flow in healthy subjects than CKD patients. However, this response in CKD patients was comparable to the level in healthy subjects after administration of MitoTempo. Mitochondrial DNA amplification was significantly lower in patients with DKD compared to healthy subjects and diabetic patients without KD⁴. This finding was associated with increased expression of mitochondrial fission proteins, decreased expression of fusion proteins, and increased mtROS release^4,7. Prolonged elevation of oxidative stress led to decreased mtDNA and further accumulation of damaged mtDNA⁴. There was also an elevated expression of fibrillin-1 in endothelial cells of patients with KD, and this was associated with lower percentages of cells in the S-phase of the cell cycle and higher expression of proteins related to apoptosis pathways⁵. SGLT-2 inhibitors induced an increase in VEGF-2 mRNA expression and was associated with decreased endothelial rarefaction and renal fibrosis by promoting angiogenesis in the proximal tubule⁸. Conclusion. Studies found that accumulation of mtDNA damage and increased fission activity led to mitochondrial dysfunction, activation of apoptosis, and increase in ROS release^3,4,7. MtROS was a major source of oxidative stress that prompted microvascular dysfunction^3,4,7. However, SGLT inhibitors are a potential treatment alternative for preventing endothelial rarefaction and the progression of CKD by reducing renal fibrosis and promoting VEGF-induced angiogenesis^2,8.

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