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MD2 blockade prevents oxLDL-induced renal epithelial cell injury and protects against high-fat-diet-induced kidney

Sujing Xu1, Wu Luo1, Xiaohong Xu1

  • 1Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.

The Journal of Nutritional Biochemistry
|June 1, 2019
PubMed

Insights

Obesity-related kidney disease involves the immune system. Myeloid differentiation factor 2 (MD2) and Toll-like receptor 4 (TLR4) mediate kidney injury from oxidized LDL and high-fat diets, suggesting MD2-TLR4 as a therapeutic target.

Area of Science:

  • Immunology
  • Nephrology
  • Metabolic Syndrome

Background:

  • Obesity is a global health issue strongly linked to kidney disease.
  • The innate immune system, specifically Toll-like receptor 4 (TLR4), is implicated in obesity-related kidney disease pathogenesis.
  • Oxidized low-density lipoprotein (oxLDL) is a potential mediator of kidney injury in metabolic conditions.

Purpose of the Study:

  • To investigate the role of myeloid differentiation factor 2 (MD2), a TLR4 co-receptor, in renal epithelial cell injury induced by oxLDL.
  • To determine if renal dysfunction in a high-fat diet (HFD) mouse model is dependent on MD2.
  • To explore the MD2-TLR4 immune signaling complex as a pathogenic factor in obesity-associated kidney disease.

Main Methods:

  • Utilized a selective MD2 inhibitor (L6H21) and siRNA to block MD2 and TLR4 in NRK-52E renal proximal tubular epithelial cells.
  • Assessed oxLDL-induced cell injury by measuring profibrotic molecules, autophagy, and apoptosis.
  • Employed a high-fat diet (HFD) mouse model with MD2 knockout to evaluate in vivo renal dysfunction and tissue injury.

Main Results:

  • MD2 selective inhibitor (L6H21) and siRNA targeting MD2 or TLR4 abrogated oxLDL-induced MD2-TLR4 dimerization and subsequent cell injury in NRK-52E cells.
  • MD2 blockade prevented oxLDL-induced profibrotic responses, autophagy, and apoptosis.
  • MD2 knockout in HFD mice significantly protected against kidney dysfunction and renal tissue damage.

Conclusions:

  • MD2 is essential for oxLDL-induced renal tubular epithelial cell injury, including profibrotic responses, autophagy, and apoptosis.
  • MD2-dependent pathways mediate renal dysfunction and tissue impairment in a HFD-induced obesity mouse model.
  • The MD2-TLR4 immune signaling complex represents a critical pathogenic factor in obesity- and metabolic syndrome-related kidney disease, offering a potential therapeutic target.
Keywords:
Kidney injuryMD2ObesityTLR4oxLDL

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