The Role of Mitochondria in Diabetic Kidney Disease and Potential Therapeutic Targets.

Diabetic kidney disease (DKD) is recognized worldwide as a leading cause of end-stage renal failure. Although therapies that target glomerular hemodynamics and can inhibit disease progression have been developed, there is currently no fundamental cure for the disease. Mitochondria play an important role in cellular respiration, producing adenosine triphosphate (ATP) by oxidative phosphorylation, and are essential for renal function, especially in proximal tubular cells (PTCs). In diabetic conditions, maintaining mitochondrial health is vital for preserving renal function. Under diabetic conditions, excessive reactive oxygen species (ROS) can damage mitochondrial DNA (mtDNA), leading to renal dysfunction. Strategies targeting mitochondrial function, such as AMP-activated protein kinase (AMPK) activation and modulation of nitric oxide (NO) availability, are promising for suppressing diabetic nephropathy. The immune response to DKD, initiated by detecting damage- and pathogen-associated molecular patterns, has a significant impact on the progression of DKD, including leakage of mtDNA and RNA, leading to inflammation through various pathways. This contributes to renal impairment characterized by hyperfiltration, endothelial dysfunction, and albuminuria. Mitochondrial energy metabolism and dynamics induced by hyperglycemia precede the onset of albuminuria and histological changes in the kidneys. The increased mitochondrial fission and decreased fusion that occur under diabetic conditions result in ATP depletion and exacerbate cellular dysfunction. Therapeutic strategies focused on restoring mitochondrial function are promising for slowing the progression of DKD and reduce the adverse effects on renal function. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) and glucagon-like peptide-1 (GLP-1) receptor agonists, already in clinical use, have been shown to be protective for mitochondria, and nuclear factor erythroid 2-related factor 2 (Nrf2) activation and mitochondrial dynamics are promising drug discovery targets for further research.