Toll-like Receptor 4 Deficiency Reduces Oxidative Stress and Macrophage Mediated Inflammation in Hypertensive Kidney

Sci Rep. 2017 Jul 25;7(1):6349. doi: 10.1038/s41598-017-06484-6.


Oxidative stress and inflammation are integral to hypertension-induced renal injury. A unifying feature for the two components is Toll-like receptors (TLR), which are key regulators of the innate immune system. Recent studies implicate TLR4 activation and oxidative stress in cardiovascular diseases and also as a link between inflammation and hypertension. However, its role in hypertension induced renal injury remains unexplored. In the present study, we investigated whether TLR-4 deficiency reduces Ang-II-induced renal injury and fibrosis by attenuating reactive oxygen species (ROS) production and inflammation. C3H/HeOuJ mice with normal TLR-4 and C3H/HeJ Lps-d with dysfunctional TLR4 (TLR4 deficiency) were treated without or with Ang-II. In response to Ang-II, TLR4 deficient mice had reduced renal resistive index and increased renal cortical blood flow compared to mice with normal TLR4. Further, TLR4 deficiency reduced oxidative stress and increased antioxidant capacity (MnSOD, CuSOD and Catalase activity). TLR4 deficiency was also associated with reduced inflammation (MCP-1, MIP-2, TNF-α, IL-6 and CD68), decreased accumulation of bone marrow-derived fibroblasts and TGF-β expression. Our data suggests that in C3H/HeJ Lps-d mice, deficiency of functional TLR4 reduces oxidative stress and macrophage activation to decrease TGF-β-induced extracellular matrix protein deposition in the kidney in Ang-II induced hypertension.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / administration & dosage*
  • Angiotensin II / pharmacology
  • Animals
  • Cytokines / metabolism
  • Disease Models, Animal
  • Hypertension / chemically induced
  • Hypertension / complications*
  • Hypertension / genetics
  • Macrophages / immunology*
  • Mice
  • Mice, Inbred C3H
  • Oxidative Stress
  • Renal Insufficiency, Chronic / etiology
  • Renal Insufficiency, Chronic / immunology
  • Renal Insufficiency, Chronic / prevention & control*
  • Signal Transduction
  • Toll-Like Receptor 4 / deficiency
  • Toll-Like Receptor 4 / genetics*
  • Transforming Growth Factor beta / metabolism
  • Vascular Resistance / drug effects


  • Cytokines
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Transforming Growth Factor beta
  • Angiotensin II