Mitochondrial DNA‐Mediated Inflammation in Acute Kidney Injury and Chronic Kidney Disease

Abstract

The integrity and function of mitochondria are essential for normal kidney physiology. Mitochondrial DNA (mtDNA) has been widely a concern in recent years because its abnormalities may result in disruption of aerobic respiration, cellular dysfunction, and even cell death. Particularly, aberrant mtDNA copy number (mtDNA-CN) is associated with the development of acute kidney injury and chronic kidney disease, and urinary mtDNA-CN shows the potential to be a promising indicator for clinical diagnosis and evaluation of kidney function. Several lines of evidence suggest that mtDNA may also trigger innate immunity, leading to kidney inflammation and fibrosis. In mechanism, mtDNA can be released into the cytoplasm under cell stress and recognized by multiple DNA-sensing mechanisms, including Toll-like receptor 9 (TLR9), cytosolic cGAS-stimulator of interferon genes (STING) signaling, and inflammasome activation, which then mediate downstream inflammatory cascades. In this review, we summarize the characteristics of these mtDNA-sensing pathways mediating inflammatory responses and their role in the pathogenesis of acute kidney injury, nondiabetic chronic kidney disease, and diabetic kidney disease. In addition, we highlight targeting of mtDNA-mediated inflammatory pathways as a novel therapeutic target for these kidney diseases.

Antioxidant Roles of SGLT2 Inhibitors in the Kidney

“…Interestingly, release of mtDNA under cellular stress has been previously considered as a damage-associated molecular pattern (DAMP) [ 85 ]. mtDNA can be recognized by Toll-like receptor 9 (TLR9) and cystosolic Cgas-stimulator of interferon genes (STING) and activate the inflammasome, leading to kidney inflammation and fibrosis [ 86 ]. In this line, recent evidence showed an increase in macrophage infiltration in a mouse model of type 2 diabetes [ 87 ] and in human progressive DKD [ 88 ], which correlates with the disease state and renal injury.…”

Therapeutic Potential of Photobiomodulation for Chronic Kidney Disease

“…Hence, the kidney is susceptible to mitochondrial dysfunction, which is increasingly recognized to play a pivotal role in the progression of CKD [ 21 ]. Mitochondrial defects, including a decrease in the quality and quantity of mtDNA, have been documented in experimental models and in patients with CKD [ 22 , 23 , 24 , 25 ]. In addition, the accumulation of damaged mtDNA and fragmented mitochondria leads to mitochondrial dysfunction, which is a hallmark of tubular injury, particularly in patients with diabetic kidney disease (DKD) [ 26 ].…”

“…Inflammation is triggered by injury during a complex biological preventive and reparative process. Many studies have elucidated that inflammatory molecules and signaling pathways are directly involved in the development and progression of CKD [ 24 , 35 ].…”

A Glimpse of Inflammation and Anti-Inflammation Therapy in Diabetic Kidney Disease

“…As we know that proximal tubular cells of the kidney are rich in mitochondria and mitochondrial dysfunction and mtDNA release have been recognized in various kidney disease ( Forbes and Thorburn, 2018 ; Ahmad et al, 2021 ). A large amount of mtDNA was detected in the blood and urine of patients with DKD, which is also related to the severity of interstitial fibrosis ( Malik et al, 2009 ; Huang Y. et al, 2020 ; Jin et al, 2021 ). The level of mtDNA was increased in primary mesangial cells treated with high glucose, which is accompanied with enhanced TLR9 activation ( Czajka et al, 2015 ).…”