Loss of Krüppel-like factor 6 cripples podocyte mitochondrial function

Kopp, Jeffrey B.

doi:10.1172/jci80280

Cited by 8 publications

(7 citation statements)

References 33 publications

(27 reference statements)

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“…As a prototypical pro‐oxidant, ADR is known to cause podocyte loss by inducing oxidative stress and podocyte mitochondrial dysfunction, ensued by podocyte loss and podocytopenia . In concordance with this, fluorescence immunohistochemistry (Figure A) and immunoblot analysis of isolated glomeruli for WT1 (Figure B) indicated that ADR injury resulted in striking podocytopenia in Ctrl mice on day 6, associated with evident mitochondria damage in podocytes, characterized by a decreased number of mitochondria, mitochondrial swelling and fragmentation, destruction of the inner mitochondrial membrane, and disruption of mitochondrial cristae on electron microscopy (Figure C).…”

Section: Resultssupporting

confidence: 59%

“…As a prototypical pro-oxidant, ADR is known to cause podocyte loss by inducing oxidative stress and podocyte mitochondrial dysfunction, ensued by podocyte loss and podocytopenia [50]. In concordance with this, fluorescence immunohistochemistry ( Figure 6A) and immunoblot analysis of isolated glomeruli for WT1 ( Figure 6B) indicated that ADR injury resulted in Figure 5.…”

Section: Gsk3β Knockout Mitigates the Adr-elicited Mitochondria Dysfusupporting

confidence: 53%

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The β isoform of GSK3 mediates podocyte autonomous injury in proteinuric glomerulopathy

Dworkin

et al. 2016

J. Pathol.

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Converging evidence points to glycogen synthase kinase (GSK) 3 as a key player in the pathogenesis of podocytopathy and proteinuria. However, it remains unclear if GSK3 is involved in podocyte autonomous injury in glomerular disease. In normal kidneys, the β isoform of GSK3 was found to be the major GSK3 expressed in glomeruli and intensely stained in podocytes. GSK3β expression in podocytes was markedly elevated in experimental or human proteinuric glomerulopathy. Podocyte specific somatic ablation of GSK3β in adult mice attenuated proteinuria and ameliorated podocyte injury and glomerular damage in experimental adriamycin (ADR) nephropathy. Mechanistically, actin cytoskeleton integrity in podocytes was largely preserved in GSK3β knockout mice following ADR insult, concomitant with a correction of podocyte hypermotility and lessened phosphorylation and activation of paxillin, a focal adhesion associated adaptor protein. In addition, GSK3β knockout diminished ADR induced NFκB RelA/p65 phosphorylation selectively at serine 467, suppressed de novo expression by podocytes of NFκB dependent podocytopathic mediators, including B7-1, cathepsin L and MCP-1, but barely affected the induction of NFκB target prosurvival factors, such as Bcl-xL. Moreover, the ADR-elicited podocytopenia and podocyte death was significantly attenuated in GSK3β knockout mice, associated with a protection against podocyte mitochondrial damage and reduced phosphorylation and activation of cyclophilin F, a structural component of mitochondria permeability transition pores. Overall, our findings suggest that the β isoform of GSK3 mediates autonomous podocyte injury in glomerulopathy by integrating multiple podocytopathic signalling pathways.

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Section: Resultssupporting

confidence: 59%

Section: Gsk3β Knockout Mitigates the Adr-elicited Mitochondria Dysfusupporting

confidence: 53%

The β isoform of GSK3 mediates podocyte autonomous injury in proteinuric glomerulopathy

Dworkin

et al. 2016

J. Pathol.

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“…Along with others, we have reported an essential role of Krüppel-like factors (KLFs) in glomerular biology (16–18). KLFs are a subtype of zinc-finger transcriptional factors that are involved in several fundamental cellular processes (18,19).…”

Section: Introductionmentioning

confidence: 59%

Podocyte-Specific Loss of Krüppel-Like Factor 6 Increases Mitochondrial Injury in Diabetic Kidney Disease

et al. 2018

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Mitochondrial injury is uniformly observed in several murine models as well as in individuals with diabetic kidney disease (DKD). Although emerging evidence has highlighted the role of key transcriptional regulators in mitochondrial biogenesis, little is known about the regulation of mitochondrial cytochrome c oxidase assembly in the podocyte under diabetic conditions. We recently reported a critical role of the zinc finger Krüppel-like factor 6 (KLF6) in maintaining mitochondrial function and preventing apoptosis in a proteinuric murine model. In this study, we report that podocyte-specific knockdown of increased the susceptibility to streptozotocin-induced DKD in the resistant C57BL/6 mouse strain. We observed that the loss of in podocytes reduced the expression of with resultant increased mitochondrial injury, leading to activation of the intrinsic apoptotic pathway under diabetic conditions. Conversely, mitochondrial injury and apoptosis were significantly attenuated with overexpression of in cultured human podocytes under hyperglycemic conditions. Finally, we observed a significant reduction in glomerular and podocyte-specific expression of KLF6 in human kidney biopsies with progression of DKD. Collectively, these data suggest that podocyte-specific KLF6 is critical to preventing mitochondrial injury and apoptosis under diabetic conditions.

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“…Some studies reported that mitochondrial dysfunction is involved in podocyte injury (16,17). The results of our previous study revealed that PKA signaling prevented PAN-induced mitochondrial fission and apoptosis in podocytes, suggesting that mitochondrial function may be important in this process (12).…”

mentioning

confidence: 87%

Protein Kinase A/CREB Signaling Prevents Adriamycin-Induced Podocyte Apoptosis via Upregulation of Mitochondrial Respiratory Chain Complexes

Xie

Zhu

Xiang

et al. 2018

Molecular and Cellular Biology

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Previous work showed that the activation of protein kinase A (PKA) signaling promoted mitochondrial fusion and prevented podocyte apoptosis. The cAMP response element binding protein (CREB) is the main downstream transcription factor of PKA signaling. Here we show that the PKA agonist 8-(4-chlorophenylthio)adenosine 3',5'-cyclic monophosphate-cyclic AMP (pCPT-cAMP) prevented the production of adriamycin (ADR)-induced reactive oxygen species and apoptosis in podocytes, which were inhibited by CREB RNA interference (RNAi). The activation of PKA enhanced mitochondrial function and prevented the ADR-induced decrease of mitochondrial respiratory chain complex I subunits, NADH-ubiquinone oxidoreductase complex (ND) 1/3/4 genes, and protein expression. Inhibition of CREB expression alleviated pCPT-cAMP-induced ND3, but not the recovery of ND1/4 protein, in ADR-treated podocytes. In addition, CREB RNAi blocked the pCPT-cAMP-induced increase in ATP and the expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1-α). The chromatin immunoprecipitation assay showed enrichment of CREB on PGC1-α and ND3 promoters, suggesting that these promoters are CREB targets. , both an endogenous cAMP activator (isoproterenol) and pCPT-cAMP decreased the albumin/creatinine ratio in mice with ADR nephropathy, reduced glomerular oxidative stress, and retained Wilm's tumor suppressor gene 1 (WT-1)-positive cells in glomeruli. We conclude that the upregulation of mitochondrial respiratory chain proteins played a partial role in the protection of PKA/CREB signaling.

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Loss of Krüppel-like factor 6 cripples podocyte mitochondrial function

Abstract: C o m m e n t a r y 9 6 8

Cited by 8 publications

References 33 publications

The β isoform of GSK3 mediates podocyte autonomous injury in proteinuric glomerulopathy

The β isoform of GSK3 mediates podocyte autonomous injury in proteinuric glomerulopathy

Podocyte-Specific Loss of Krüppel-Like Factor 6 Increases Mitochondrial Injury in Diabetic Kidney Disease

Protein Kinase A/CREB Signaling Prevents Adriamycin-Induced Podocyte Apoptosis via Upregulation of Mitochondrial Respiratory Chain Complexes

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