Megalin is downregulated via LPS-TNF-α-ERK1/2 signaling pathway in proximal tubule cells

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Myeloid Innate Signaling Pathway Regulation by MALT1 Paracaspase Activity

Published on: January 7, 2019

Aya Takeyama1, Hiroyoshi Sato, Taeko Soma-Nagae

  • 1Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata 951-8510, Japan.

Biochemical and Biophysical Research Communications
|March 5, 2011
PubMed

Insights

Low-level lipopolysaccharide (LPS) signaling reduces megalin expression in kidney cells via TNF-α and ERK1/2 pathways. This finding is crucial for understanding diabetic nephropathy and proteinuria development.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Endocrinology

Background:

  • Diabetic nephropathy is characterized by reduced megalin expression and function in proximal tubule cells (PTCs), contributing to proteinuria.
  • Metabolic endotoxemia, indicated by elevated serum lipopolysaccharide (LPS), is a common feature in diabetes.

Purpose of the Study:

  • To investigate the mechanisms by which low-level LPS signaling regulates megalin expression in immortalized rat PTCs (IRPTCs).
  • To elucidate the role of tumor necrosis factor-alpha (TNF-α) and the ERK1/2 pathway in LPS-induced changes in megalin.

Main Methods:

  • IRPTCs were treated with LPS (10 ng/ml) for 48 hours to assess megalin expression and function.
  • Tumor necrosis factor-alpha (TNF-α) mRNA was targeted using siRNA, and cells were treated with exogenous TNF-α.
  • The MEK1 inhibitor PD98059 was used to assess the involvement of the ERK1/2 pathway.

Main Results:

  • LPS treatment significantly suppressed megalin protein expression and endocytic function in IRPTCs.
  • LPS increased TNF-α mRNA expression, and its knockdown partially reversed the downregulation of megalin mRNA.
  • Exogenous TNF-α mimicked LPS effects, suppressing megalin mRNA and protein, an effect partially inhibited by PD98059.

Conclusions:

  • Low-level LPS-mediated signaling, involving TNF-α and the ERK1/2 pathway, downregulates megalin expression in proximal tubule cells.
  • These findings offer insights into the molecular mechanisms linking metabolic endotoxemia to kidney dysfunction in diabetic nephropathy.

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