The Not So ‘Mighty Chondrion’: Emergence of Renal Diseases due to Mitochondrial Dysfunction

Hall, Andrew M.; Unwin, Robert J.

doi:10.1159/000096860

Cited by 104 publications

(85 citation statements)

References 125 publications

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“…There is increasing evidence to indicate that the disruption of mitochondrial bioenergetics, which leads to altered capacity for ATP production, may contribute to the development and progression of chronic kidney disease (CKD) (2,3). This includes in the setting of diabetic nephropathy (DN) (4)(5)(6)(7)(8)(9)(10), but the specific molecular mechanisms linking mitochondrial dysfunction to CKD remain to be elucidated.…”

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

et al. 2016

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“…Mitochondrial damage is a major contributor to the lethal and sublethal tubular cell injury observed in the disease progression of AKI (10,13,15,16,23,37). Increased production of reactive oxygen species and nitric oxide, formed prominently within the mitochondria, as well as compromised antioxidant mechanisms following ischemic periods make the mitochondria particularly susceptible (24,25,28,43).…”

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Persistent disruption of mitochondrial homeostasis after acute kidney injury

Funk

Schnellmann

2012

American Journal of Physiology-Renal Physiology

212

192

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Funk JA, Schnellmann RG. Persistent disruption of mitochondrial homeostasis after acute kidney injury. Am J Physiol Renal Physiol 302: F853-F864, 2012. First published December 7, 2011 doi:10.1152/ajprenal.00035.2011.-While mitochondrial dysfunction is a pathological process that occurs after acute kidney injury (AKI), the state of mitochondrial homeostasis during the injury and recovery phases of AKI remains unclear. We examined markers of mitochondrial homeostasis in two nonlethal rodent AKI models. Myoglobinuric AKI was induced by glycerol injection into rats, and mice were subjected to ischemic AKI. Animals in both models had elevated serum creatinine, indicative of renal dysfunction, 24 h after injury which partially recovered over 144 h postinjury. Markers of proximal tubule function/injury, including neutrophil gelatinase-associated lipocalin and urine glucose, did not recover during this same period. The persistent pathological state was confirmed by sustained caspase 3 cleavage and evidence of tubule dilation and brush-border damage. Respiratory proteins NDUFB8, ATP synthase ␤, cytochrome c oxidase subunit I (COX I), and COX IV were decreased in both injury models and did not recover by 144 h. Immunohistochemical analysis confirmed that COX IV protein was progressively lost in proximal tubules of the kidney cortex after ischemia-reperfusion (I/R). Expression of mitochondrial fission protein Drp1 was elevated after injury in both models, whereas the fusion protein Mfn2 was elevated after glycerol injury but decreased after I/R AKI. LC3-I/II expression revealed that autophagy increased in both injury models at the later time points. Markers of mitochondrial biogenesis, such as PGC-1␣ and PRC, were elevated in both models. These findings reveal that there is persistent disruption of mitochondrial homeostasis and sustained tubular damage after AKI, even in the presence of mitochondrial recovery signals and improved glomerular filtration.

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“…TGFb can also induce generation of reactive oxygen species (ROS) in vitro, [9][10][11][12] and mitochondrial dysfunction and ROS generation are important in tubular injury and apoptosis in acute and chronic kidney injury. [13][14][15] Initial reports suggested a role for TGFb predominantly in activation of interstitial (myo)fibroblasts manifesting with progressive fibrogenesis and extracellular matrix accumulation. 16 However, it remains unclear whether interstitial cell activation and fibrogenesis are direct targets or secondary phenomena dependent on primary epithelial damage induced by TGFb.…”

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confidence: 99%

Epithelial Cell TGFβ Signaling Induces Acute Tubular Injury and Interstitial Inflammation

Gentle

Shi

Daehn

et al. 2013

Journal of the American Society of Nephrology

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TGFb signaling plays a central role in the development of acute and chronic kidney diseases. Previous in vivo studies involved systemic alteration of TGFb signaling, however, limiting conclusions about the direct role of TGFb in tubular cell injury. Here, we generated a double transgenic mouse that inducibly expresses a ligand-independent constitutively active TGFb receptor type 1 (TbR1) kinase specifically in tubular epithelial cells, with expression restricted by the Pax8 promoter. In this model, activation of TGFb signaling in the tubular epithelium alone was sufficient to cause AKI characterized by marked tubular cell apoptosis and necrosis, oxidative stress, dedifferentiation and regenerative cell proliferation, reduced renal function, and interstitial accumulation of inflammatory cells. This tubular injury was associated with mitochondrial-derived generation of reactive oxygen species (ROS), but cell damage and apoptosis were partially independent of mitochondrial-derived ROS.

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The Not So ‘Mighty Chondrion’: Emergence of Renal Diseases due to Mitochondrial Dysfunction

Cited by 104 publications

References 125 publications

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

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

Persistent disruption of mitochondrial homeostasis after acute kidney injury

Epithelial Cell TGFβ Signaling Induces Acute Tubular Injury and Interstitial Inflammation

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