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20-HETE and EETs in Diabetic Nephropathy: A Novel Mechanistic Pathway

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submitted on 2024-06-24, 06:33 and posted on 2024-06-24, 06:34 authored by Stephanie Eid, Rita Maalouf, Ayad A. Jaffa, Joseph Nassif, Ahmed Hamdy, Awad Rashid, Fuad N. Ziyadeh, Assaad A. Eid

Diabetic nephropathy (DN), a major complication of diabetes, is characterized by hypertrophy, extracellular matrix accumulation, fibrosis and proteinuria leading to loss of renal function. Hypertrophy is a major factor inducing proximal tubular epithelial cells injury. However, the mechanisms leading to tubular injury is not well defined. In our study, we show that exposure of rats proximal tubular epithelial cells to high glucose (HG) resulted in increased extracellular matrix accumulation and hypertrophy. HG treatment increased ROS production and was associated with alteration in CYPs 4A and 2C11 expression concomitant with alteration in 20-HETE and EETs formation. HG-induced tubular injury were blocked by HET0016, an inhibitor of CYPs 4A. In contrast, inhibition of EETs promoted the effects of HG on cultured proximal tubular cells. Our results also show that alteration in CYPs 4A and 2C expression and 20HETE and EETs formation regulates the activation of the mTOR/p70S6Kinase pathway, known to play a major role in the development of DN. In conclusion, we show that hyperglycemia in diabetes has a significant effect on the expression of Arachidonic Acid (AA)-metabolizing CYPs, manifested by increased AA metabolism, and might thus alter kidney function through alteration of type and amount of AA metabolites.

Other Information

Published in: PLoS ONE
License: http://creativecommons.org/licenses/by/4.0/
See article on publisher's website: https://dx.doi.org/10.1371/journal.pone.0070029

Funding

National Council for Scientific Research, Lebanese National Scientific Research Center (CNRS).

Qatar National Research Fund (NPRP 5 - 410 - 3 - 113), Mechanisms of epithelial cells injury in Diabetes.

History

Language

  • English

Publisher

Public Library of Science (PLoS)

Publication Year

  • 2013

License statement

This Item is licensed under the Creative Commons Attribution 4.0 International License.

Institution affiliated with

  • Hamad Medical Corporation
  • Hamad General Hospital - HMC