MicroRNA-709 Mediates Acute Tubular Injury through Effects on Mitochondrial Function

Abstract

Mitochondrial dysfunction has important roles in the pathogenesis of AKI, yet therapeutic approaches to improve mitochondrial function remain limited. In this study, we investigated the pathogenic role of microRNA-709 (miR-709) in mediating mitochondrial impairment and tubular cell death in AKI. In a cisplatin-induced AKI mouse model and in biopsy samples of human AKI kidney tissue, miR-709 was significantly upregulated in the proximal tubular cells (PTCs). The expression of miR-709 in the renal PTCs of patients with AKI correlated with the severity of kidney injury. In cultured mouse PTCs, overexpression of miR-709 markedly induced mitochondrial dysfunction and cell apoptosis, and inhibition of miR-709 ameliorated cisplatin-induced mitochondrial dysfunction and cell injury. Further analyses showed that mitochondrial transcriptional factor A (TFAM) is a target gene of miR-709, and genetic restoration of TFAM attenuated mitochondrial dysfunction and cell injury induced by cisplatin or miR-709 overexpression Moreover, antagonizing miR-709 with an miR-709 antagomir dramatically attenuated cisplatin-induced kidney injury and mitochondrial dysfunction in mice. Collectively, our results suggest that miR-709 has an important role in mediating cisplatin-induced AKI negative regulation of TFAM and subsequent mitochondrial dysfunction. These findings reveal a pathogenic role of miR-709 in acute tubular injury and suggest a novel target for the treatment of AKI.

Celastrol ameliorates cisplatin nephrotoxicity by inhibiting NF-κB and improving mitochondrial function

“…The pathogenesis of AKI involves complex pathway crosstalk associated with oxidative stress, inflammation, and apoptosis. Moreover, AKI is also an important pathogenic factor in the development and progression of chronic kidney disease [ 11 , 35 ]. Nephrotoxicity is a major side effect in cisplatin chemotherapy that limits the use of cisplatin in cancer patients.…”

“…Negative controls were performed using murine IgG instead of primary antibodies. An average score of the immunofluorescence was calculated as described previously [ 35 ].…”

Myo-inositol oxygenase expression profile modulates pathogenic ferroptosis in the renal proximal tubule

“…After a brief wash with deionized-distilled water, the sections were dehydrated with ethanol, treated with xylene, coverslip-mounted, and evaluated. The sections with H&E staining were used to assess tubular damage scoring, as previously reported (47,48). For each mouse, 100 tubules from 10 different views were evaluated by 2 investigators.…”

Circular RNA YAP1 acts as the sponge of microRNA‐21‐5p to secure HK‐2 cells from ischaemia/reperfusion‐induced injury

“…For instance, miR‐192 expression in blood plasma was perhaps useful to diagnose patients with AKI and recovery procedure of renal damage . In the context of clinical and experiment data, miR‐709 has been associated with regulatory mechanism by which mitochondrial dysfunction and proximal tubular cell apoptosis were ameliorated . In contrast, another AKI‐related miRNA (miR‐688) acted protective role in AKI by inhibiting mitochondrial fragmentation .…”