Metabolic Changes and Oxidative Stress in Diabetic Kidney Disease

Abstract

Diabetic kidney disease (DKD) is a major cause of end-stage kidney disease, and it is crucial to understand the pathophysiology of DKD. The control of blood glucose levels by various glucose-lowering drugs, the common use of inhibitors of the renin–angiotensin system, and the aging of patients with diabetes can alter the disease course of DKD. Moreover, metabolic changes and associated atherosclerosis play a major role in the etiology of DKD. The pathophysiology of DKD is largely attributed to the disruption of various cellular stress responses due to metabolic changes, especially an increase in oxidative stress. Therefore, many antioxidants have been studied as therapeutic agents. Recently, it has been found that NRF2, a master regulator of oxidative stress, plays a major role in the pathogenesis of DKD and bardoxolone methyl, an activator of NRF2, has attracted attention as a drug that increases the estimated glomerular filtration rate in patients with DKD. This review outlines the altered stress responses of cellular organelles in DKD, their involvement in the pathogenesis of DKD, and discusses strategies for developing therapeutic agents, especially bardoxolone methyl.

SGLT2 inhibitors improve kidney function and morphology by regulating renal metabolic reprogramming in mice with diabetic kidney disease

“…The pathogenesis of DKD is multifactorial and still unclear. Accumulating evidence elucidates that various cellular stress responses triggered by metabolic abnormalities contribute to the pathophysiological mechanism of DKD [ 6 ]. The upregulation of sodium-glucose cotransporter 2 (SGLT2), when appearing in diabetes, leads to high transmembrane transport in the proximal tubule and generates a dramatic energy requirement in the renal cortex [ 7 ].…”

Mitochondrial Regulation of Diabetic Kidney Disease

“…The generated ROS is usually carefully balanced to stimulate stress abrogation responses, while not exceeding the cell ability to protect itself from damage through anti-oxidant enzymes. Once the balance is shifted such that the production of ROS exceeds the cells inherent antioxidant protections, an increasing cycle of cell damage is elicited resulting in compromised mitochondrial function, damaged mitochondrial DNA and proteins ( 169 ). If the cell cannot re-establish its balance, the end result is cellular death and kidney dysfunction.…”

Pathophysiologic Mechanisms and Potential Biomarkers in Diabetic Kidney Disease

“…Although the results of animal studies have been promising, therapeutic effects of antioxidants in human studies have been largely unconvincing [ 17 ]. Currently, most therapies mainly target oxidative stress reduction by means of strict glucose control by anti-diabetic agents, as well as use of anti-hypertensive and anti-dyslipidemic agents [ 54 , 55 ]. For example, pioglitazone has been shown to markedly reduce glomerular sclerosis, hypertrophy, tubulointerstitial fibrosis, and albuminuria in a DKD animal model [ 56 ].…”