Mitochondria as therapeutic targets in acute kidney injury

Hall, Andrew M.; Schuh, Claus-Dieter

doi:10.1097/mnh.0000000000000228

Cited by 56 publications

(53 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been identified that normally elongated mitochondria in the proximal tubule rapidly fragment in response to cisplatin [29]. Drp1 is the master regulator of mitochondrial morphology [30].…”

Section: Discussionmentioning

confidence: 99%

Drp1-dependent mitophagy protects against cisplatin-induced apoptosis of renal tubular epithelial cells by improving mitochondrial function

et al. 2017

View full text Add to dashboard Cite

Cisplatin chemotherapy often causes acute kidney injury (AKI) in cancer patients. There is increasing evidence that mitochondrial dysfunction plays an important role in cisplatin-induced nephrotoxicity. Degradation of damaged mitochondria is carried out by mitophagy. Although mitophagy is considered of particular importance in protecting against AKI, little is known of the precise role of mitophagy and its molecular mechanisms during cisplatin-induced nephrotoxicity. Also, evidence that activation of mitophagy improved mitochondrial function is lacking. Furthermore, several evidences have shown that mitochondrial fission coordinates with mitophagy. The aim of this study was to investigate whether activation of mitophagy protects against mitochondrial dysfunction and renal proximal tubular cells injury during cisplatin treatment. The effect of mitochondrial fission on mitophagy was also investigated. In cultured human renal proximal tubular cells, we observed that 3-methyladenine, a pharmacological inhibitor of autophagy, blocked mitophagy and exacerbated cisplatin-induced mitochondrial dysfunction and cells injury. In contrast, autophagy activator rapamycin enhanced mitophagy and protected against the harmful effects of cisplatin on mitochondrial function and cells viability. Suppression of mitochondrial fission by knockdown of its main regulator dynamin-related protein-1 (Drp1) decreased cisplatin-induced mitophagy. Meanwhile, Drp1 suppression protected against cisplatin-induced cells injury by inhibiting mitochondrial dysfunction. Our results provide evidence that Drp1-depedent mitophagy has potential as renoprotective targets for the treatment of cisplatin-induced AKI.

show abstract

Section: Discussionmentioning

confidence: 99%

Drp1-dependent mitophagy protects against cisplatin-induced apoptosis of renal tubular epithelial cells by improving mitochondrial function

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Previous studies have suggested that MtD is mainly observed in acute kidney injury and CKD [28,29]. Our previous study demonstrated that NLRP3 deficiency may attenuate renal fibrosis by improving MtD in a mouse unilateral ureteral obstruction model for CKD [22].…”

Section: Discussionmentioning

confidence: 99%

1,25-Dihydroxyvitamin D3 Attenuates Angiotensin II-Induced Renal Injury by Inhibiting Mitochondrial Dysfunction and Autophagy

Shen

Ling

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: A recent study has shown that 1,25-dihydroxyvitamin D3 (1,25-D3), the active form of vitamin D, can ameliorate renal dysfunction. In this study, we aimed to determine the role of 1,25-D3 in angiotensin (Ang II)-induced renal injury and investigate the underlying mechanisms involved. Methods: C57BL/6J mice were treated with Ang II and/or 1,25-D3 (or saline as the control) for 2 weeks. Renal injury was evaluated using transmission electron microscopy and periodic acid-Schiff reagent and Masson’s trichrome staining. The pro-fibrotic and pro-inflammatory factors were assessed using real-time PCR. The renal apoptotic pathway was evaluated with TUNEL staining and western blot. Mitochondrial dysfunction (MtD) was determined using real-time PCR and electron microscopy. The activation of autophagy was detected using western blot. Results: In the Ang II-infused mice, expanded mesangial regions, tubulointerstitial fibrosis, and foot process fusion were observed; the levels of the pro-fibrotic and pro-inflammatory cytokines and MtD were also increased when compared with the control group. However, we found that administration of 1,25-D3 significantly improved renal function and MtD and reduced the pro-fibrotic and pro-inflammatory cytokine levels. Furthermore, 1,25-D3 significantly inhibited Ang II-induced autophagy dysfunction (determined by inhibition of Beclin-1 activation and reduction of the LC3-II/LC3-I ratio). Conclusion: Our findings suggest that 1,25-D3 may attenuate Ang II-induced renal injury by improving MtD and modulating autophagy. 1,25-D3 may be a new therapeutic for the treatment of CKD.

show abstract

“…Renal tubules are densely packed with mitochondria. Mitochondrial dysfunction is thought to be a key mechanism in the pathogenesis of AKI [10]. Under the physiological conditions, excessive inhibition the mitochondrial activity could be toxic to cells and organs.…”

Section: Discussionmentioning

confidence: 99%

“…The renal tubule is densely packed with mitochondria to generate sufficient ATP via oxidative phosphorylation (OXPHOS) to power the solute transport in the kidney [10]. Besides the energy production, mitochondria also play important roles in mediating the signaling transduction, cell proliferation, cell growth, and cell death [11,12].…”

Section: Introductionmentioning

confidence: 99%

Rotenone Protects Against Acetaminophen-Induced Kidney Injury by Attenuating Oxidative Stress and Inflammation

et al. 2018

Kidney Blood Press Res

View full text Add to dashboard Cite

Background/Aims: In clinic, excessive acetaminophen (APAP) can cause kidney damage with uncertain mechanisms. Recently, accumulating evidence demonstrated a pathogenic role of mitochondrial dysfunction in the kidney injury. Thus, in this study, rotenone, a mitochondrial complex I inhibitor, was applied to the mice with APAP-induced acute kidney injury to evaluate the effect of mitochondrial complex I inhibition on APAP nephrotoxicity. Methods: After 3 days of rotenone pretreatment, mice were administered with APAP (300mg/kg) by intraperitoneal injection for 24 h. Then the kidney injury, inflammation, and oxidative stress were evaluated. Results: APAP significantly enhanced the BUN, serum creatine, and cystatin C levels in line with a moderate alteration of renal morphology. Strikingly, rotenone treatment normalized BUN, serum creatinine, and cystatin C levels, as well as the kidney morphology. Meanwhile, APAP enhanced tubular injury markers of NGAL and KIM-1 by 347- and 5-fold at mRNA levels, respectively. By Western blotting, we confirmed a 15-fold increment of NGAL in APAP-exposed kidneys. Importantly, rotenone treatment largely normalized NGAL and KIM-1 levels and attenuated inflammatory response in APAP-treated mice. Similarly, rotenone treatment enhanced the expressions of SOD1-3 compared with APAP group in line with a significant suppression of kidney MDA content. Finally, we observed that inhibition of mitochondrial complex III failed to protect against APAP-induced nephrotoxicity. Conclusion: Mitochondrial complex I inhibitor rotenone protected kidneys against APAP-induced injury possibly via the inhibition of mitochondrial oxidative stress and inflammation.

show abstract

Mitochondria as therapeutic targets in acute kidney injury

Cited by 56 publications

References 53 publications

Drp1-dependent mitophagy protects against cisplatin-induced apoptosis of renal tubular epithelial cells by improving mitochondrial function

Drp1-dependent mitophagy protects against cisplatin-induced apoptosis of renal tubular epithelial cells by improving mitochondrial function

1,25-Dihydroxyvitamin D3 Attenuates Angiotensin II-Induced Renal Injury by Inhibiting Mitochondrial Dysfunction and Autophagy

Rotenone Protects Against Acetaminophen-Induced Kidney Injury by Attenuating Oxidative Stress and Inflammation

Contact Info

Product

Resources

About