Mitochondrial Fission Triggered by Hyperglycemia Is Mediated by ROCK1 Activation in Podocytes and Endothelial Cells

Wang, Wenjian; Wang, Yin; Jiang, Long; Wang, Jinrong; Haudek, Sandra B.; Overbeek, Paul A.; Chang, Benny Hung-Junn; Schumacker, Paul T.; Danesh, Farhad R.

doi:10.1016/j.cmet.2012.01.009

Cited by 417 publications

(446 citation statements)

References 38 publications

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“…A few reports have indicated a pivotal role of mitochondrial dynamics in the homeostasis of different kidney cells during DKD and AKI. 8,28 However, autophagy is believed to exert a cytoprotective effect during kidney injury, such as in AKI, DKD, and obesity, where the basal rate of autophagy may increase initially but because of its relative decrease, subsequently, the podocytes and tubular cells get readily damaged. [33][34][35][36] In addition, elimination of damaged mitochondria by mitophagy was reported to be relatively deficient or decreased in the cardiac musculature of patients with diabetes.…”

Section: Discussionmentioning

confidence: 99%

“…5,6 Although the pathogenesis of DKD still remains unclear, recent studies in animals and humans have led to an emerging concept that mitochondrial dysfunctions, which are pivotal events, lead to activation of various cellular processes and aberrant signaling in different cell types of the kidney. [7][8][9] Mitochondria are dynamic organelles that constantly undergo fusion and fission cycles to maintain a balance of cellular reticular network and mitochondrial turnover. 10 Their dynamics are regulated by profission proteins (Drp1 and Fis1) and profusion mediators (Mfn1/2 and OPA1).…”

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confidence: 99%

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Disruption of Renal Tubular Mitochondrial Quality Control by Myo-Inositol Oxygenase in Diabetic Kidney Disease

Zhan

Usman

Sun

et al. 2015

Journal of the American Society of Nephrology

245

251

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Diabetic kidney disease (DKD) is associated with oxidative stress and mitochondrial injury. Myo-inositol oxygenase (MIOX), a tubular-specific enzyme, modulates redox imbalance and apoptosis in tubular cells in diabetes, but these mechanisms remain unclear. We investigated the role of MIOX in perturbation of mitochondrial quality control, including mitochondrial dynamics and autophagy/mitophagy, under highglucose (HG) ambience or a diabetic state. HK-2 or LLC-PK1 cells subjected to HG exhibited an upregulation of MIOX accompanied by mitochondrial fragmentation and depolarization, inhibition of autophagy/ mitophagy, and altered expression of mitochondrial dynamic and mitophagic proteins. Furthermore, dysfunctional mitochondria accumulated in the cytoplasm, which coincided with increased reactive oxygen species generation, Bax activation, cytochrome C release, and apoptosis. Overexpression of MIOX in LLC-PK1 cells enhanced the effects of HG, whereas MIOX siRNA or D-glucarate, an inhibitor of MIOX, partially reversed these perturbations. Moreover, decreasing the expression of MIOX under HG ambience increased PTEN-induced putative kinase 1 expression and the dependent mitofusin-2-Parkin interaction. In tubules of diabetic mice, increased MIOX expression and mitochondrial fragmentation and defective autophagy were observed. Dietary supplementation of D-glucarate in diabetic mice decreased MIOX expression, attenuated tubular damage, and improved renal functions. Notably, D-glucarate administration also partially attenuated mitochondrial fragmentation, oxidative stress, and apoptosis and restored autophagy/mitophagy in the tubular cells of these mice. These results suggest a novel mechanism linking MIOX to impaired mitochondrial quality control during tubular injury in the pathogenesis of DKD and suggest D-glucarate as a potential therapeutic agent for the amelioration of DKD.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Disruption of Renal Tubular Mitochondrial Quality Control by Myo-Inositol Oxygenase in Diabetic Kidney Disease

Zhan

Usman

Sun

et al. 2015

Journal of the American Society of Nephrology

245

251

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“…DN is a leading cause of end-stage renal disease, and alterations in mitochondrial bioenergetics and dynamics in the kidney in experimental diabetes have been documented (4,37,38). Hence, we superimposed diabetes onto AIF knockdown in mice to determine whether the renal phenotype could be worsened.…”

Section: Superimposition Of Diabetes On Aifm1 Knockdown Worsens Kidnementioning

confidence: 99%

Deficiency in Apoptosis-Inducing Factor Recapitulates Chronic Kidney Disease via Aberrant Mitochondrial Homeostasis

et al. 2016

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Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein with dual roles in redox signaling and programmed cell death. Deficiency in AIF is known to result in defective oxidative phosphorylation (OXPHOS), via loss of complex I activity and assembly in other tissues. Because the kidney relies on OXPHOS for metabolic homeostasis, we hypothesized that a decrease in AIF would result in chronic kidney disease (CKD). Here, we report that partial knockdown of Aif in mice recapitulates many features of CKD, in association with a compensatory increase in the mitochondrial ATP pool via a shift toward mitochondrial fusion, excess mitochondrial reactive oxygen species production, and Nox4 upregulation. However, despite a 50% lower AIF protein content in the kidney cortex, there was no loss of complex I activity or assembly. When diabetes was superimposed onto Aif knockdown, there were extensive changes in mitochondrial function and networking, which augmented the renal lesion. Studies in patients with diabetic nephropathy showed a decrease in AIF within the renal tubular compartment and lower AIFM1 renal cortical gene expression, which correlated with declining glomerular filtration rate. Lentiviral overexpression of Aif1m rescued glucose-induced disruption of mitochondrial respiration in human primary proximal tubule cells. These studies demonstrate that AIF deficiency is a risk factor for the development of diabetic kidney disease.

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“…29 In addition, diabetic mouse models and in vitro studies have demonstrated that hyperglycemia induced mitochondrial fragmentation in podocytes, endothelial cells, and renal tubular cells. 7,30 Finally, WBCs are involved in the kidney's response to injury as evidenced by leukocyte infiltration in kidney tissues of patients with CKD and in experimental models. [31][32][33] Lower mtDNA copy number might alter the role of WBCs and platelets in injury response.…”

Section: Main Findingsmentioning

confidence: 99%

Association between Mitochondrial DNA Copy Number in Peripheral Blood and Incident CKD in the Atherosclerosis Risk in Communities Study

Tin

Grams²,

Ashar

et al. 2016

JASN

120

115

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Mitochondrial dysfunction in kidney cells has been implicated in the pathogenesis of CKD. Mitochondrial DNA (mtDNA) copy number is a surrogate measure of mitochondrial function, and higher mtDNA copy number in peripheral blood has been associated with lower risk of two important risk factors for CKD progression, diabetes and microalbuminuria. We evaluated whether mtDNA copy number in peripheral blood associates with incident CKD in a population-based cohort of middle-aged adults. We estimated mtDNA copy number using 25 high-quality mitochondrial single nucleotide polymorphisms from the Affymetrix 6.0 array. Among 9058 participants, those with higher mtDNA copy number had a lower rate of prevalent diabetes and lower C-reactive protein levels and white blood cell counts. Baseline eGFR did not differ significantly by mtDNA copy number. Over a median follow-up of 19.6 years, 1490 participants developed CKD. Higher mtDNA copy number associated with lower risk of incident CKD (highest versus lowest quartile: hazard ratio 0.65; 95% confidence interval, 0.56 to 0.75; P,0.001) after adjusting for age, sex, and race. After adjusting for additional risk factors of CKD, including prevalent diabetes, hypertension, C-reactive protein level, and white blood cell count, this association remained significant (highest versus lowest quartile: hazard ratio 0.75; 95% confidence interval, 0.64 to 0.87; P,0.001). In conclusion, higher mtDNA copy number associated with lower incidence of CKD independent of traditional risk factors and inflammation biomarker levels in this cohort. Further research on modifiable factors influencing mtDNA copy number may lead to improvement in the prevention and treatment of CKD.

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Mitochondrial Fission Triggered by Hyperglycemia Is Mediated by ROCK1 Activation in Podocytes and Endothelial Cells

Cited by 417 publications

References 38 publications

Disruption of Renal Tubular Mitochondrial Quality Control by Myo-Inositol Oxygenase in Diabetic Kidney Disease

Disruption of Renal Tubular Mitochondrial Quality Control by Myo-Inositol Oxygenase in Diabetic Kidney Disease

Deficiency in Apoptosis-Inducing Factor Recapitulates Chronic Kidney Disease via Aberrant Mitochondrial Homeostasis

Association between Mitochondrial DNA Copy Number in Peripheral Blood and Incident CKD in the Atherosclerosis Risk in Communities Study

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