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Original Article

Pex11a Deficiency Is Associated With a Reduced Abundance of Functional Peroxisomes and Aggravated Renal Interstitial Lesions

Huachun Weng, Xu Ji, Kosuke Endo, Naoharu Iwai
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https://doi.org/10.1161/HYPERTENSIONAHA.114.04094
Hypertension. 2014;HYPERTENSIONAHA.114.04094
Originally published August 11, 2014
Huachun Weng
From the Department of Genomic Medicine, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
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Xu Ji
From the Department of Genomic Medicine, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
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Kosuke Endo
From the Department of Genomic Medicine, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
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Naoharu Iwai
From the Department of Genomic Medicine, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
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Abstract

Although proteinuria is known to be associated with the deterioration of chronic kidney disease, the molecular basis of this mechanism is not fully understood. We previously found that Pex11a deficiency was associated with a reduction of functional peroxisomes and impaired fatty acid metabolism in hepatocytes and resulted in steatosis. Proximal tubule cells are rich in peroxisomes. We assessed whether Pex11a deficiency might result in the derangement of peroxisome systems in proximal tubule cells and the aggravation of tubulointerstitial lesions in chronic kidney disease. Histological analyses showed that the number of functional peroxisomes in proximal tubule cells was reduced in Pex11a knockout (Pex11a−/−) mice. To clarify whether a decrease in the number of tubular peroxisomes might aggravate interstitial lesions, we assessed 2 models in which proximal tubule cells are overloaded with fatty acids (ie, deoxycorticosterone acetate and salt hypertension and the overload of fatty acid–bound albumin). Deoxycorticosterone acetate -salt–treated Pex11a−/− mice exhibited greater interstitial lesions than deoxycorticosterone acetate-salt–treated wild-type mice in terms of tubular lipid accumulation, blood pressure, urinary albumin, urinary N-acetyl-β-d-glucosaminidase, urinary 8-iso-prostane, and the histological evaluation of fibrosis and inflammation. An overload of fatty acid–bound albumin also resulted in more severe tubulointerstitial lesions in Pex11a−/− mice than in wild-type mice. Fenofibrate, a peroxisome proliferator-activated receptor-α agonist, restored the abundance of peroxisomes and reduced the tubulointerstitial lesions induced by deoxycorticosterone acetate-salt hypertension. In conclusion, our results indicate that proximal tubule peroxisomes play an important role in proteinuria-induced interstitial lesions. The activation of tubular peroxisomes might be an excellent therapeutic strategy against chronic kidney disease.

  • fatty acid–binding proteins
  • hypertension
  • peroxisomes
  • renal insufficiency, chronic
  • Received June 17, 2014.
  • Revision received June 28, 2014.
  • Accepted July 22, 2014.
  • © 2014 American Heart Association, Inc.
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    Pex11a Deficiency Is Associated With a Reduced Abundance of Functional Peroxisomes and Aggravated Renal Interstitial Lesions
    Huachun Weng, Xu Ji, Kosuke Endo and Naoharu Iwai
    Hypertension. 2014;HYPERTENSIONAHA.114.04094, originally published August 11, 2014
    https://doi.org/10.1161/HYPERTENSIONAHA.114.04094

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    Pex11a Deficiency Is Associated With a Reduced Abundance of Functional Peroxisomes and Aggravated Renal Interstitial Lesions
    Huachun Weng, Xu Ji, Kosuke Endo and Naoharu Iwai
    Hypertension. 2014;HYPERTENSIONAHA.114.04094, originally published August 11, 2014
    https://doi.org/10.1161/HYPERTENSIONAHA.114.04094
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