Numb Depletion Promotes Drp1-Mediated Mitochondrial Fission and Exacerbates Mitochondrial Fragmentation and Dysfunction in Acute Kidney Injury

Liu, Ze; Li, Hao; Su, Jincang; Xu, Siqi; Zhu, Feiqi; Ai, Jun; Hu, Zheng; Zhou, Miaomiao; Tian, Jianwei; Su, Zhiyuan; Yang, Peiliang; Nie, Jing

doi:10.1089/ars.2017.7432

Cited by 64 publications

(57 citation statements)

References 70 publications

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“…Mitochondrial dysfunction and impaired energetics characterize the diabetic heart ultrastructural damage [2,4,28,34]. Previous studies have proved that RhoA/Rho kinase pathway is involved in the regulation of the mitochondrial dynamics in some cases [35][36][37][38]. In our study, ROCK inhibition improved the disturbed mitochondrial ssion/fusion in diabetic rats and facilitated mitochondrial fusion and uncoupling to restore the cardiac ultrastructural abnormalities.…”

Section: Discussionsupporting

confidence: 60%

Speckle-Tracking Echocardiography is Preferable Measurement for Detecting the Early and Subtle Alterations of Cardiac Dysfunction in Diabetic Rats

Chen

Wang

et al. 2021

Preprint

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BackgroundMyocardial damage caused by diabetic cardiomyopathy results in cardiac structural and functional abnormalities. Our previous studies have demonstrated that inhibiting RhoA/ROCK signaling pathway improved the structural abnormalities. The early detection of cardiac functional alterations accompanied by structural changes during therapy may facilitate better understanding on the pathophysiologic progress and guiding diabetic cardiomyopathy treatment. This study aimed to identify the optimal diagnostic measures for the early and subtle alterations of cardiac dysfunction in Type 2 diabetes mellitus rats.MethodsTwenty-four male Wistar rats were randomly divided into four groups and treated for 4 weeks: CON (control rats), DM (diabetic rats), DMF (DM + fasudil 10mg/kg/d) and CONF (CON + fasudil 10mg/kg/d). Left ventricular (LV) structure was quantified by histological staining and transmission electron microscopy. LV function and myocardial deformation were performed by high-frequency echocardiography.ResultsMyocardial hypertrophy and fibrosis were increased in diabetic rats and were remarkably alleviated in the DMF group. The diabetic rats had impaired LV performance evidenced by significant reduction of EF, FS and MV E/A, 26%, 34% and 20% respectively, while ROCK inhibition failed to improve the conventional ultrasonic parameters. However, the cardiac time intervals (CTI) parameters and speckle-tracking echocardiography (STE) parameters were significantly improved in the DMF group compared with the DM group (isovolumic contraction time, IVCT: P = 0.029; myocardial performance index, MPI: P = 0.037; fractional area change, FAC: P < 0.001; global circumferential strain, GCS: P = 0.003; global circumferential strain rate, GCSR: P = 0.021). Combining ROC curves with linear regression analysis, STE parameters were characterized by both the optimal predictions for cardiac damage [AUC (95% CI): FAC, 0.927 (0.744 to 0.993); GCS, 0.819 (0.610 to 0.945); GCSR, 0.899 (0.707 to 0.984)] and the strong correlations with cardiac fibrosis (FAC, r = -0.825; GCS, r = 0.772; GCSR, r = 0.829).ConclusionThe results suggest that STE strain and strain rate are preferable indicators of the early detection of subtle alterations in cardiac dysfunction and the quantitation of therapeutic efficacy in diabetic cardiomyopathy.

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Section: Discussionsupporting

confidence: 60%

Speckle-Tracking Echocardiography is Preferable Measurement for Detecting the Early and Subtle Alterations of Cardiac Dysfunction in Diabetic Rats

Chen

Wang

et al. 2021

Preprint

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“…Drug-induced injury in the tubular epithelial cell model and ischemia-reperfusion injury model assays showed a sharp increase in DRP1 expression. At the same time, DRP1 inhibitor administration improves the mitochondrial function and reduces apoptosis [27]. Recent studies have shown that mitochondrial damage, including mitochondrial volume release, is related to several cell events, including autophagy, pyroptosis, or other programmed cell death mechanisms [28,29], not limited to apoptosis.…”

Section: Discussionmentioning

confidence: 99%

An Inhibitor of DRP1 (Mdivi-1) Alleviates LPS-Induced Septic AKI by Inhibiting NLRP3 Inflammasome Activation

Liu

Wang

et al. 2020

BioMed Research International

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Mitochondria play an essential role in energy metabolism. Oxygen deprivation can poison cells and generate a chain reaction due to the free radical release. In patients with sepsis, the kidneys tend to be the organ primarily affected and the proximal renal tubules are highly susceptible to energy metabolism imbalances. Dynamin-related protein 1 (DRP1) is an essential regulator of mitochondrial fission. Few studies have confirmed the role and mechanism of DRP1 in acute kidney injury (AKI) caused by sepsis. We established animal and cell sepsis-induced AKI (S-AKI) models to keep DRP1 expression high. We found that Mdivi-1, a DRP1 inhibitor, can reduce the activation of the NOD-like receptor pyrin domain-3 (NLRP3) inflammasome-mediated pyroptosis pathway and improve mitochondrial function. Both S-AKI models showed that Mdivi-1 was able to prevent the mitochondrial content release and decrease the expression of NLRP3 inflammasome-related proteins. In addition, silencing NLRP3 gene expression further emphasized the pyroptosis importance in S-AKI occurrence. Our results indicate that the possible mechanism of action of Mdivi-1 is to inhibit mitochondrial fission and protect mitochondrial function, thereby reducing pyroptosis. These data can provide a potential theoretical basis for Mdivi-1 potential use in the S-AKI prevention.

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“…Mouse primary proximal tubular epithelial cells (PTCs) were separated with percoll buffer as described previously [21]. PTCs and NRK-49F cells were cultured in DMEM or DMEM/F12 medium supplemented with 10% fetal bovine serum (Gibco/Life Technologies, New York, USA).…”

Section: Methodsmentioning

confidence: 99%

Nicotinamide Supplementation Attenuates Renal Interstitial Fibrosis via Boosting the Activity of Sirtuins

Zhen¹,

Zhang²,

Xie³

et al. 2021

Kidney Dis

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Background: Progressive tubulointerstitial fibrosis (TIF) is the final common pathway leading to ESRD. There is an urgent need to develop effective approaches slowing the progression of TIF. Previous studies showed that systemic supplementation of nicotinamide (NAM) increases renal NAD+ and reverses ischemic-reperfusion induced acute renal injury. However, the role and mechanism of NAM in TIF has been unclear. Methods: In vivo, we injected NAM (0.25 mg/g) 3 days before unilateral ureter obstruction (UUO) till day 7 post-operation. In vitro, mouse primary proximal tubular epithelial cells (PTCs), rat renal NRK-49F cells, and human renal proximal tubular epithelial cell (HK-2) were pretreated with the indicated concentration of NAM 1 h before incubation with transform growth factor-β1 (TGF-β1) or aristolochic acid (AA) for 24 or 48 h. To evaluate the role of sirtuins (SIRTs), PTCs were pretreated with EX527 or resveratrol 30 min before incubation with NAM and TGF-β1. Results: In the present study, we demonstrated that NAM supplementation prevented UUO-induced TIF, and AA-induced renal injury. NAM also decreased the expression of pro-fibrotic proteins and pro-inflammatory cytokines (IL-6 and TNF-α) and attenuated interstitial inflammation. In vitro experiment showed that, NAM inhibited AA-induced G2/M arrest of HK-2 cells by downregulating the expression of cyclin G1, a target gene of p53. In addition, NAM inhibited TGF-β1-induced fibroblast proliferation and activation shown as downregulated expression of collagen I, fibronectin, PCNA, cyclin D1, IL-6, and TNF-α. NAM decreased the acetylation of Smad3 and p53. EX527, an inhibitor of SIRT1, reversed the effect of NAM on TGF-β1-induced matrix protein production. However, resveratrol, a SIRT1 activator, did not further boost the protective effect of NAM on reducing matrix protein production. Conclusions: Taken together, these data indicate that NAM supplementation could inhibit TIF at least partially by boosting the activity of sirtuins.

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Numb Depletion Promotes Drp1-Mediated Mitochondrial Fission and Exacerbates Mitochondrial Fragmentation and Dysfunction in Acute Kidney Injury

Cited by 64 publications

References 70 publications

Speckle-Tracking Echocardiography is Preferable Measurement for Detecting the Early and Subtle Alterations of Cardiac Dysfunction in Diabetic Rats

Speckle-Tracking Echocardiography is Preferable Measurement for Detecting the Early and Subtle Alterations of Cardiac Dysfunction in Diabetic Rats

An Inhibitor of DRP1 (Mdivi-1) Alleviates LPS-Induced Septic AKI by Inhibiting NLRP3 Inflammasome Activation

Nicotinamide Supplementation Attenuates Renal Interstitial Fibrosis via Boosting the Activity of Sirtuins

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