Mitochondrial DNA: A New Predictor of Diabetic Kidney Disease

Yajing Huang,Yangang Wang,Yihai Cao,Jingwei Chi,Fanxiang Wei,Yue Zhou

doi:10.1155/2020/3650937

Abstract

Diabetic kidney disease (DKD) is a common cause of end-stage renal disease, and diagnosis and treatment in time can help delay its progress. At present, there are more and more studies on the pathogenesis of DKD; mitochondrial dysfunction plays an important role in DKD. The occurrence and development of DKD is closely related to epigenetic changes and the interaction between mtDNA, ROS, inflammatory factors, and endothelial damage, which continuously aggravates kidney. The change of mtDNA is both the cause of DKD and the result of DKD. It is of great significance to incorporate the change of mtDNA into the monitoring of patients with diabetes. Existing evidence indicates that changes in mtDNA copy number in blood and urine reflect mitochondrial dysfunction and the severity of DKD. However, large-scale, long-term follow-up clinical trials are still needed to determine the threshold range. By the time, mitochondrial-targeted antioxidants will become a new method for the treatment of DKD and other diabetic complications; mtDNA also can be a therapeutic target for them.

Highlights

Worldwide, the incidence of diabetes mellitus (DM) has increased rapidly and has affected more than 380 million people, of which China has the highest rate of diabetes patients, approximately 98.4 million [1]
Diabetic kidney disease (DKD) is defined as a syndrome that is characterized by leakage of protein, metabolites, and ions into the urine, changes in the glomerular filtration rate (GFR), and an increased risk of cardiovascular disease (CVD) and stroke [3]. e progressive exacerbation of DKD is manifested by the continued exacerbation of albuminuria and the gradual decline of glomerular filtration rate, which eventually leads to complete loss of renal function [4]
Vicious Circle between reactive oxygen species (ROS), mitochondrial DNA (mtDNA), and DKD. e mtDNA changes caused by mitochondrial oxidative stress aggravate the vicious cycle of DKD. e components are as follows: (1) high glucose leads to increased ATP demand, resulting in mitochondrial electron transport chain (mtETC) producing more ROS; (2) excess ROS destroys phospholipids, proteins, and nucleic acids; (3) ROS inhibits mitochondrial germinal growth by downregulating Peroxisome proliferator-activated receptor-c coactivator-1α JNK (PGC-1α), and the amount of mtDNA decreases; (4) decreased synthesis of mtDNA-encoded subunits impairs the electron transport system and further augments the generation of superoxide promoting damage to mtDNA [47]; (5) ROS and damaged mtDNA continue to accumulate, which leads to podocyte and renal tubular cell damage, and aggravate by renal fibrosis

Summary

Introduction

The incidence of diabetes mellitus (DM) has increased rapidly and has affected more than 380 million people, of which China has the highest rate of diabetes patients, approximately 98.4 million [1]. Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) have become the first-line drugs for patient with DKD to control blood pressure and improve the prognosis of DKD. These drugs can only delay the development of DKD, but cannot reverse DKD [4]. Renal fibrosis is the ultimate pathological change of DKD It is caused by a variety of mechanisms including renal hemodynamic changes, oxidative stress, inflammatory response, hypoxia, and activation of the renin-angiotensin-aldosterone system (RAAS) [9, 10]. Impaired mtDNA and disrupted mitochondrial genome integrity play important roles in the development of severe early-onset and chronic aging-related diseases [19]. Chronic hyperglycemia disrupts the bioenergetic balance between the kidney’s energy requirements and the supply of metabolic fuel, which is conducive to the production of ROS [21]. mtDNA in the blood can cross the kidney barrier and is excreted in the urine. erefore, the detection of mtDNA in blood and urine can be used as a metabolic marker of early DKD (Table 1)

Change of mtDNA in DKD

Mitochondrial Oxidative Stress and mtDNA in DKD

Mitochondrial Antioxidants and mtDNA

Findings

Discussion