The struggle for energy in podocytes leads to nephrotic syndrome

Kou, Yan; Ito, Noriko; Nakajo, Aya; Kurayama, Ryota; Fukuhara, Daisuke; Nishibori, Yukino; Kudo, Akihiko; Akimoto, Yoshihiro; Takenaka, Hiroyuki

doi:10.4161/cc.19825

Cited by 18 publications

(9 citation statements)

References 95 publications

(110 reference statements)

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“…In proteinuric animal models, the application of the mTOR inhibitor EV was demonstrated to significantly reduce proteinuria [32]. To study the molecular effects of EV in podocyte injury in detail, we applied puromycin aminonucleoside (PAN) as a well-recognized in vitro model.…”

Section: Resultsmentioning

confidence: 99%

Protective Effects of the mTOR Inhibitor Everolimus on Cytoskeletal Injury in Human Podocytes Are Mediated by RhoA Signaling

Jeruschke

Büscher

et al. 2013

PLoS ONE

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Podocytes are highly differentiated kidney cells playing an important role in maintaining the glomerular filtration barrier. Particularly, the integrity of the actin cytoskeleton is crucial as cytoskeletal damage associated with foot process effacement and loss of slit diaphragms constitutes a major aspect of proteinuria Previously, the mammalian target of rapamycin (mTOR) was linked to actin regulation and aberrant activity of the kinase was associated with renal disease. In this study, actin-related effects of mTOR inhibition by the immunosuppressant everolimus (EV) were investigated in human podocytes using an in vitro model of puromycin aminonucleoside (PAN) induced proteinuria. EV substantially recovered aberrant podocyte behavior by re-establishing a stationary phenotype with decreased migration efficiency, enhanced cell adhesion and recovery of actin stress fibers. Biochemical studies revealed substantial increase in the activity of RhoA and the effector pathway Rho-associated protein kinase (ROCK) and myosin light chain (MLC) by EV, all known regulators of stress fiber generation. Taken together, we show for the first time cytoskeleton stabilizing effects of the mTOR inhibitor EV and establish RhoA signaling as a key mediator in this process.

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Section: Resultsmentioning

confidence: 99%

Protective Effects of the mTOR Inhibitor Everolimus on Cytoskeletal Injury in Human Podocytes Are Mediated by RhoA Signaling

Jeruschke

Büscher

et al. 2013

PLoS ONE

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“…In addition to the generation of ROS, a major function of mitochondria is ATP production (18). A large energy supply ensures protein stability and signal transduction in podocytes (51). PGC1-␣ is a transcriptional coactivator essential for mitochondrial gene transcription (52).…”

Section: Discussionmentioning

confidence: 99%

“…Glucose is the major energy substrate for most mammalian cells. However, other molecules, including amino acids, nucleosides, and fatty acids, are also metabolized to produce energy in the form of ATP (51). Therefore, the energy metabolism pathways affected by PKA signaling in podocyte protection need to be further investigated.…”

Section: Discussionmentioning

confidence: 99%

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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“…This is consistent with previous studies that have shown that mTOR is activated in podocytes in diabetic nephropathy (51, 52). Recently, mTOR inactivation (52, 53), restoration of the LKB1‐ AMPK activity (54), and PGC‐1α activation (55) were proposed as novel potential therapeutic options for diabetic nephropathy. Our findings further suggest that stimulation of MEF2C and MYF5 expression could permit the restoration of podocyte bioenergetics and mitochondrial biogenesis in these conditions.…”

Section: Discussionmentioning

confidence: 99%

High glucose repatterns human podocyte energy metabolism during differentiation and diabetic nephropathy

et al. 2016

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Podocytes play a key role in diabetic nephropathy pathogenesis, but alteration of their metabolism remains unknown in human kidney. By using a conditionally differentiating human podocyte cell line, we addressed the functional and molecular changes in podocyte energetics during in vitro development or under high glucose conditions. In 5 mM glucose medium, we observed a stepwise activation of oxidative metabolism during cell differentiation that was characterized by peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α)–dependent stimulation of mitochondrial biogenesis and function, with concomitant reduction of the glycolytic enzyme content. Conversely, when podocytes were cultured in high glucose (20 mM), stepwise oxidative phosphorylation biogenesis was aborted, and a glycolytic switch occurred, with consecutive lactic acidosis. Expression of the master regulators of oxidative metabolism transcription factor A mitochondrial, PGC-1α, AMPK, and serine–threonine liver kinase B1 was altered by high glucose, as well as their downstream signaling networks. Focused transcriptomics revealed that myocyte-specific enhancer factor 2C (MEF2C) and myogenic factor 5 (MYF5) expression was inhibited by high glucose levels, and endoribonuclease-prepared small interfering RNA–mediated combined inhibition of those transcription factors phenocopied the glycolytic shift that was observed in high glucose conditions. Accordingly, a reduced expression of MEF2C, MYF5, and PGC-1α was found in kidney tissue sections that were obtained from patients with diabetic nephropathy. These findings obtained in human samples demonstrate that MEF2C-MYF5–dependent bioenergetic dedifferentiation occurs in podocytes that are confronted with a high-glucose milieu.—Imasawa, T., Obre, E., Bellance, N., Lavie, J., Imasawa, T., Rigothier, C., Delmas, Y., Combe, C., Lacombe, D., Benard, G., Claverol, S., Bonneu, M., Rossignol, R. High glucose repatterns human podocyte energy metabolism during differentiation and diabetic nephropathy.

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The struggle for energy in podocytes leads to nephrotic syndrome

Cited by 18 publications

References 95 publications

Protective Effects of the mTOR Inhibitor Everolimus on Cytoskeletal Injury in Human Podocytes Are Mediated by RhoA Signaling

Protective Effects of the mTOR Inhibitor Everolimus on Cytoskeletal Injury in Human Podocytes Are Mediated by RhoA Signaling

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

High glucose repatterns human podocyte energy metabolism during differentiation and diabetic nephropathy

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