Mitochondrial ROS Triggers KIN Pathogenesis in FAN1-Deficient Kidneys.

Area of Science:

• Nephrology
• Genetics
• Molecular Biology

Background:

• Karyomegalic interstitial nephritis (KIN) is a genetic adult-onset chronic kidney disease (CKD) caused by FAN1 mutations, leading to genomic instability.
• The endogenous source of DNA damage in FAN1-deficient kidneys remains unidentified.

Purpose of the Study:

• To investigate the role of reactive oxygen species (ROS) in the pathophysiology of FAN1-deficient kidneys and KIN.
• To explore potential therapeutic strategies targeting oxidative stress in KIN.

Main Methods:

• Utilized FAN1-deficient human renal tubular epithelial cells (hRTECs) and FAN1-null mice as models for KIN.
• Assessed DNA damage, oxidative stress, mitochondrial function, and kidney pathology.
• Administered a mitochondria-targeted ROS scavenger (JP4-039) and low-dose cisplatin.

Main Results:

• FAN1 deficiency causes hypersensitivity to endogenous ROS, leading to chronic oxidative and double-strand DNA damage in kidney tubular cells.
• Oxidative stress in FAN1-deficient cells impairs mitochondrial function, affecting oxidative phosphorylation and fatty acid oxidation.
• ROS scavenger treatment attenuated oxidative stress, DNA damage, and kidney injury in a mouse model of KIN.

Conclusions:

• Endogenous oxidative stress is a key driver of DNA damage and KIN pathogenesis in FAN1-deficient kidneys.
• Therapeutic modulation of kidney oxidative stress presents a promising strategy for mitigating KIN progression.