Glomerular Endothelial Mitochondrial Dysfunction Is Essential and Characteristic of Diabetic Kidney Disease Susceptibility

Abstract

The molecular signaling mechanisms between glomerular cell types during initiation/progression of diabetic kidney disease (DKD) remain poorly understood. We compared the early transcriptome profile between DKD-resistant C57BL/6J and DKD-susceptible DBA/2J (D2) glomeruli and demonstrated a significant downregulation of essential mitochondrial genes in glomeruli from diabetic D2 mice, but not in C57BL/6J, with comparable hyperglycemia. Diabetic D2 mice manifested increased mitochondrial DNA lesions (8-oxoguanine) exclusively localized to glomerular endothelial cells after 3 weeks of diabetes, and these accumulated over time in addition to increased urine secretion of 8-oxo-deoxyguanosine. Detailed assessment of glomerular capillaries from diabetic D2 mice demonstrated early signs of endothelial injury and loss of fenestrae. Glomerular endothelial mitochondrial dysfunction was associated with increased glomerular endothelin-1 receptor type A (Ednra) expression and increased circulating endothelin-1 (Edn1). Selective Ednra blockade or mitochondrial-targeted reactive oxygen species scavenging prevented mitochondrial oxidative stress of endothelial cells and ameliorated diabetes-induced endothelial injury, podocyte loss, albuminuria, and glomerulosclerosis. In human DKD, increased urine 8-oxo-deoxyguanosine was associated with rapid DKD progression, and biopsies from patients with DKD showed increased mitochondrial DNA damage associated with glomerular endothelial EDNRA expression. Our studies show that DKD susceptibility was linked to mitochondrial dysfunction, mediated largely by Edn1–Ednra in glomerular endothelial cells representing an early event in DKD progression, and suggest that cross talk between glomerular endothelial injury and podocytes leads to defects and depletion, albuminuria, and glomerulosclerosis.

Combined use of electron microscopy and intravital imaging captures morphological and functional features of podocyte detachment

“…The interdependence of podocyte-endothelium dysfunction and injury that involves microthrombus formation has been visualized with MPM in an earlier report [27]. Also, recent works reported the importance of glomerular endothelial mitochondrial dysfunction and disruption of the endothelial glycocalyx in endothelial and podocyte crosstalk, albuminuria, and glomerulosclerosis development [4, 28]. Based on the data shown in Fig.…”

NR4A1 Promotes Diabetic Nephropathy by Activating Mff-Mediated Mitochondrial Fission and Suppressing Parkin-Mediated Mitophagy

“…Furthermore, the mitochondrial outer-membrane permeabilization induced by excessive ROS production promotes proapoptotic factor leakage and initiates caspase-9-related mitochondrial apoptosis [61,62]. The hyperglycemiamediated glomerular death via mitochondrial apoptosis gradually leads to a reduction in functional cells in the kidneys, which unfortunately is repaired via collagen accumulation, progressively contributing to renal dysfunction [63,64]. These data show the functional importance of mitochondrial damage in regulating the progression of diabetic nephropathy.…”

The Warburg Effect in Diabetic Kidney Disease

“…Therefore, in diabetic patients, activation of aerobic glycolysis might help metabolize glucose rapidly from systemic circulation. In addition, with the evidence of mitochondrial dysfunction including low peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) levels, abnormalities in electron transport chain complex assembly/activity, alterations in pyruvate dehydrogenase complex (PDH) phosphorylation, and altered TCA cycle intermediates in DKD, 20,25 it is not surprising that the glucose oxidation through glycolysis is a more favorable process toward ATP synthesis.…”