Mitochondrial dysfunction and chronic sterile inflammation are common features of type 2 diabetes. Therefore, we aimed to investigate whether mitochondrial DNA (mtDNA) could be a biomarker implicated in the progression of type 2 diabetes and diabetic nephropathy and explore the underlying mechanism.

We developed a method for relative quantification of mtDNA content in clinical practice. qRT‐PCR was used to measure the mtDNA content both in vivo in CD‐1 mice with diabetes induction by streptozotocin and in vitro in murine endothelial cells and conditionally immortalized mouse podocytes. By pumping mtDNA into the mouse circulation, the effect of mtDNA on the kidney was assessed in mice. In patients with type 2 diabetes (n = 42; 24 males; mean age 57.9 ± 12.00 years), plasma mtDNA was evaluated.

Plasma mtDNA content was significantly decreased in patients with type 2 diabetes, particularly those with significant proteinuria. In vitro, high glucose treatment suppressed intracellular mtDNA content and facilitated the extracellular release of mtDNA, so excessive circulatory mtDNA induced by high glucose might be filtered through the kidney and then into urine. Indeed, urinary mtDNA content was significantly increased in both diabetic patients and mice. Moreover, by pumping excess mtDNA into circulation in mice, filtered mtDNA could trigger inflammation and induce kidney injury.

Excessive mtDNA filtered through the kidney under diabetic conditions may be involved in chronic renal inflammation. Reduced plasma mtDNA content and increased urinary mtDNA/creatinine ratio might play a potential role as an early biomarker of diabetic nephropathy.