CCL20 blockade increases the severity of nephrotoxic folic acid-induced acute kidney injury

J Pathol. 2018 Oct;246(2):191-204. doi: 10.1002/path.5132. Epub 2018 Aug 27.

Abstract

The chemokine CCL20 activates the CCR6 receptor and has been implicated in the pathogenesis of glomerular injury. However, it is unknown whether it contributes to acute kidney injury (AKI). We identified CCL20 as upregulated in a systems biology strategy combining transcriptomics of kidney tissue from experimental toxic folic acid-induced AKI and from stressed cultured tubular cells and have explored the expression and function of CCL20 in experimental and clinical AKI. CCL20 upregulation was confirmed in three models of kidney injury induced by a folic acid overdose, cisplatin or unilateral ureteral obstruction. In injured kidneys, CCL20 was expressed by tubular, endothelial, and interstitial cells, and was also upregulated in human kidneys with AKI. Urinary CCL20 was increased in human AKI and was associated with severity. The function of CCL20 in nephrotoxic folic acid-induced AKI was assessed by using neutralising anti-CCL20 antibodies or CCR6-deficient mice. CCL20/CCR6 targeting increased the severity of kidney failure and mortality. This was associated with more severe histological injury, nephrocalcinosis, capillary rarefaction, and fibrosis, as well as higher expression of tubular injury-associated genes. Surprisingly, mice with CCL20 blockade had a lower tubular proliferative response and a higher number of cells in the G2/M phase, suggesting impaired repair mechanisms. This may be related to a lower influx of Tregs, despite a milder inflammatory response in terms of chemokine expression and infiltration by IL-17+ cells and neutrophils. In conclusion, CCL20 has a nephroprotective role during AKI, both by decreasing tissue injury and by facilitating repair. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Keywords: CCL20; CCR6; Treg; acute kidney injury; calcification; chemokine; inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / chemically induced
  • Acute Kidney Injury / metabolism*
  • Acute Kidney Injury / pathology
  • Acute Kidney Injury / prevention & control
  • Adult
  • Aged
  • Animals
  • Antibodies, Neutralizing / toxicity*
  • Case-Control Studies
  • Cell Line
  • Chemokine CCL20 / antagonists & inhibitors
  • Chemokine CCL20 / genetics
  • Chemokine CCL20 / immunology
  • Chemokine CCL20 / metabolism*
  • Chemotaxis, Leukocyte / drug effects
  • Disease Models, Animal
  • Female
  • Fibrosis
  • Folic Acid*
  • Gene Expression Profiling / methods
  • Humans
  • Immunity, Innate / drug effects
  • Kidney Tubules / drug effects*
  • Kidney Tubules / metabolism
  • Kidney Tubules / pathology
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Receptors, CCR6 / genetics
  • Receptors, CCR6 / metabolism
  • Severity of Illness Index
  • Signal Transduction / drug effects
  • Systems Biology / methods
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / metabolism
  • Th17 Cells / drug effects
  • Th17 Cells / metabolism
  • Young Adult

Substances

  • Antibodies, Neutralizing
  • CCL20 protein, human
  • CCL20 protein, mouse
  • CCR6 protein, human
  • CCR6 protein, mouse
  • Chemokine CCL20
  • Receptors, CCR6
  • Folic Acid