Overexpression of acetyl CoA carboxylase β exacerbates podocyte injury in the kidney of streptozotocin-induced diabetic mice

Tanaka, Yuki; Kume, Shinji; Maeda, Shiro; Osawa, Norihisa; Takeda, Naoko; Chin‐Kanasaki, Masami; Isshiki, Keiji; Ugi, Satoshi; Oshima, Itsuki; Uzu, Takashi; Maegawa, Hiroshi; Araki, Shin‐ichi

doi:10.1016/j.bbrc.2017.11.145

Cited by 3 publications

(3 citation statements)

References 30 publications

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“…Reciprocally, the renoprotective effects observed in high-fat-fed Stk25 -/mice were accompanied by attenuated lipid deposition in the kidney. To date, the molecular mechanisms controlling renal lipid accumulation remain elusive; however, renal steatosis has been shown to develop when lipogenesis in the kidney is enhanced or fatty acid oxidation is compromised (22,(28)(29)(30)(31)(32). Notably, kidneys preferentially oxidize fatty acids as energy source and are not a major contributor to circulating glucose catabolism (22).…”

Section: Discussionmentioning

confidence: 99%

Depletion of protein kinase STK25 ameliorates renal lipotoxicity and protects against diabetic kidney disease

Cansby

Caputo²,

Gao³

et al. 2020

JCI Insight

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Diabetic kidney disease (DKD) is the most common cause of severe renal disease worldwide and the single strongest predictor of mortality in diabetes patients. Kidney steatosis has emerged as a critical trigger in the pathogenesis of DKD; however, the molecular mechanism of renal lipotoxicity remains largely unknown. Our recent studies in genetic mouse models, human cell lines, and well-characterized patient cohorts have identified serine/threonine protein kinase 25 (STK25) as a critical regulator of ectopic lipid storage in several metabolic organs prone to diabetic damage. Here, we demonstrate that overexpression of STK25 aggravates renal lipid accumulation and exacerbates structural and functional kidney injury in a mouse model of DKD. Reciprocally, inhibiting STK25 signaling in mice ameliorates diet-induced renal steatosis and alleviates the development of DKD-associated pathologies. Furthermore, we find that STK25 silencing in human kidney cells protects against lipid deposition, as well as oxidative and endoplasmic reticulum stress. Together, our results suggest that STK25 regulates a critical node governing susceptibility to renal lipotoxicity and that STK25 antagonism could mitigate DKD progression.

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Section: Discussionmentioning

confidence: 99%

Depletion of protein kinase STK25 ameliorates renal lipotoxicity and protects against diabetic kidney disease

Cansby

Caputo²,

Gao³

et al. 2020

JCI Insight

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“…In response to high glucose, AMPK reduced autophagy activity in podocyte, HK-2, and human glomerular endothelial cells (HGECs) with increased cytotoxicity and apoptosis [11, 20, 33]. However, administration of AICAR, an AMPK agonist, can reverse high glucose-induced podocyte injury [34], implying the therapeutical potential of activated autophagy in regard to DKD.…”

Section: Impaired Autophagy and Its Mechanisms In Dkdmentioning

confidence: 99%

Chinese Herbal Medicine in Ameliorating Diabetic Kidney Disease via Activating Autophagy

Wang

Zhao

Wang

et al. 2019

Journal of Diabetes Research

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Diabetic kidney disease (DKD), a leading cause of end-stage renal disease (ESRD), has become a serious public health problem worldwide and lacks effective therapies due to its complex pathogenesis. Recent studies suggested defective autophagy involved in the pathogenesis and progression of DKD. Chinese herbal medicine, as an emerging option for the treatment of DKD, could improve diabetic kidney injury by activating autophagy. In this review, we briefly summarize underlying mechanisms of autophagy dysregulation in DKD, including AMP-activated protein kinase (AMPK), the mechanistic target of rapamycin (mTOR), and the sirtuin (Sirt) pathways, and we particularly concentrate on the current status of Chinese herbal medicine treating DKD by regulating autophagy. The advances in our understanding regarding the treatment of DKD via regulating autophagy with Chinese herbal medicine will enhance the clinical application of Chinese medicine as well as discovery of novel therapeutic agents for diabetic patients.

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“…Hence, upregulation of renal DNL by hyperglycemia may be a distinct mechanism of diabetic kidney disease progression. However, the effect of lipogenesis in kidneys, especially in podocytes, is understudied [ 30 , 31 , 32 ], so further studies are required to demonstrate the importance of ACC-mediated lipogenesis in podocytes. In this study, our aims are (A) to show the causal effect of glycemic stress on the upregulation of DNL in podocytes and tubular epithelial cells, two principal cell types involved in metabolic response to a diabetic state; (B) to demonstrate the downregulation of DNL by ACC manipulation using various means including CRISPR/cas9 mediated Acaca and Acacb knocking down (KO), oligonucleotide mediated gene silencing, and ACC pharmacological inhibitor; and (C) to provide more insight on the effect of ACC blockade on markers of fibrosis ( Col1a1, Col3a1, Col6a1, Tgfb1 ), on the expression of other lipid regulatory genes ( Acly, Elovl6, Scd1, Pnpla3, Srebp1c, Gpat, Pltp, G6pd, and Dgat ), and on the upstream regulator of cell death and apoptosis ( Fas ).…”

Section: Introductionmentioning

confidence: 99%

Acetyl Co-A Carboxylase Inhibition Halts Hyperglycemia Induced Upregulation of De Novo Lipogenesis in Podocytes and Proximal Tubular Cells

et al. 2022

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The effect of glycemic stress on de novo lipogenesis (DNL) in podocytes and tubular epithelial cells is understudied. This study is aimed (A) to show the effect of glycemic stress on DNL, and (B) to assess the effect of acetyl-Co A (ACC) inhibition on halting upregulation of DNL, on the expression of other lipid regulatory genes in the DNL pathway, and on markers of fibrosis and apoptosis in podocytes and tubular epithelial cells. We used cultured mouse primary tubular epithelial cells, mouse proximal tubular (BUMPT) cells, and immortal mouse podocytes and measured their percentage of labeled 13C2-palmitate as a marker of DNL after incubation with 13C2 acetate in response to high glucose concentration (25 mM). We then tested the effect of ACC inhibition by complimentary strategies utilizing CRISPR/cas9 deletion or incubation with Acaca and Acacb GapmeRs or using a small molecule inhibitor on DNL under hyperglycemic concentration. Exposure to high glucose concentration (25 mM) compared to osmotic controlled low glucose concentration (5.5 mM) significantly increased labeled palmitate after 24 h up to 72 h in podocytes and primary tubular cells. Knocking out of the ACC coding Acaca and Acacb genes by CRISPR/cas9, downregulation of Acaca and Acacb by specific antisense LNA GapmeRs and inhibition of ACC by firsocostat similarly halted/mitigated upregulation of DNL and decreased markers of fibrosis and programmed cell death in podocytes and various tubular cells. ACC inhibition is a potential therapeutic target to mitigate or halt hyperglycemia-induced upregulation of DNL in podocytes and tubular cells.

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Overexpression of acetyl CoA carboxylase β exacerbates podocyte injury in the kidney of streptozotocin-induced diabetic mice

Cited by 3 publications

References 30 publications

Depletion of protein kinase STK25 ameliorates renal lipotoxicity and protects against diabetic kidney disease

Depletion of protein kinase STK25 ameliorates renal lipotoxicity and protects against diabetic kidney disease

Chinese Herbal Medicine in Ameliorating Diabetic Kidney Disease via Activating Autophagy

Acetyl Co-A Carboxylase Inhibition Halts Hyperglycemia Induced Upregulation of De Novo Lipogenesis in Podocytes and Proximal Tubular Cells

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