Klotho deficiency aggravates diabetes-induced podocyte injury due to DNA damage caused by mitochondrial dysfunction

Area of Science:

• Nephrology
• Mitochondrial Biology
• Genetics

Background:

• Diabetic nephropathy (DN) is a leading cause of kidney failure, characterized by podocyte injury and proteinuria.
• Mitochondrial dysfunction (MtD) and reactive oxygen species (ROS) are implicated in DN pathogenesis, but the link to DNA damage is unclear.
• Klotho plays a protective role in kidney disease, but its specific influence on DN-related DNA damage requires further investigation.

Purpose of the Study:

• To investigate the role of Klotho deficiency in high glucose (HG)-induced podocyte injury and DNA damage.
• To elucidate the mechanisms by which Klotho deficiency affects mitochondrial function and DNA repair in the context of diabetic nephropathy.

Main Methods:

• In vivo and in vitro models were used to study the effects of Klotho deficiency on diabetic phenotypes.
• Podocyte injury was assessed by measuring urea albumin creatinine ratio (UACR), creatinine, and urea nitrogen.
• DNA damage was evaluated by quantifying 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels and 8-oxoguanine DNA glycosylase (OGG1) expression.

Main Results:

• Klotho deficiency aggravated diabetic phenotypes, including podocyte injury and elevated kidney function markers (UACR, creatinine, urea nitrogen).
• Klotho deficiency significantly increased DNA damage, evidenced by elevated 8-OHdG and reduced OGG1 levels.
• Klotho deficiency was shown to promote mitochondrial dysfunction, contributing to 8-OHdG-induced podocyte injury.

Conclusions:

• Klotho deficiency exacerbates podocyte injury and DNA damage in diabetic nephropathy.
• Klotho deficiency promotes diabetes-induced podocytic mitochondrial dysfunction and impairs DNA repair via affecting OGG1.
• Targeting Klotho may offer a therapeutic strategy for mitigating DNA damage and kidney injury in diabetic nephropathy.