Matrix metalloproteinase-12 deficiency attenuates experimental crescentic anti-glomerular basement membrane glomerulonephritis

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6 Citations (Scopus)

Abstract

Aim: Matrix metalloproteinase-12 (MMP-12; macrophage elastase) is an enzyme that can cleave various extracellular matrix proteins and is required for macrophage infiltration and pulmonary fibrosis in experimental emphysema. We have shown previously that MMP-12 is highly up-regulated in experimental anti-glomerular basement membrane (GBM) disease. The aim of this study was to determine whether MMP-12 is required for glomerular macrophage infiltration and crescent formation in anti-GBM glomerulonephritis. Methods: Accelerated anti-GBM disease was induced in groups of MMP-12 gene deficient mice (MMP-12−/−) and wild-type C57BL/6J controls, which were killed 12 days after injection of anti-GBM serum. Results: Wild-type and MMP-12−/− mice developed glomerular damage and glomerular tuft adhesions to Bowman's capsule. Both groups developed severe proteinuria. Wild-type mice also developed significant loss of renal function and crescents in 22% of glomeruli, which were associated with macrophage infiltration and Bowman's capsule rupture. In contrast, MMP-12−/− mice were partially protected from renal function decline, crescent formation and Bowman's capsule rupture. This was associated with reduced macrophage infiltration in both glomeruli and the interstitium, and with reduced expression of CCL2, TNF-α and iNOS mRNA in MMP-12−/− kidneys. In addition, KIM-1 mRNA levels were reduced in MMP-12−/− mice indicating less tubular damage. Conclusion: These data demonstrate that endogenous MMP-12 facilitates macrophage accumulation and activation in anti-GBM glomerulonephritis which is required for glomerular crescent formation, Bowman's capsule rupture, tubular damage and renal function decline.

Original languageEnglish
Pages (from-to)183-189
Number of pages7
JournalNephrology
Volume23
Issue number2
DOIs
Publication statusPublished - 1 Feb 2018

Keywords

  • glomerular crescent
  • glomerulonephritis
  • kidney disease
  • macrophage
  • matrix metalloproteinase-12

Cite this

@article{7f8ee21c5175432ba0b1a9a7d4c9e43e,
title = "Matrix metalloproteinase-12 deficiency attenuates experimental crescentic anti-glomerular basement membrane glomerulonephritis",
abstract = "Aim: Matrix metalloproteinase-12 (MMP-12; macrophage elastase) is an enzyme that can cleave various extracellular matrix proteins and is required for macrophage infiltration and pulmonary fibrosis in experimental emphysema. We have shown previously that MMP-12 is highly up-regulated in experimental anti-glomerular basement membrane (GBM) disease. The aim of this study was to determine whether MMP-12 is required for glomerular macrophage infiltration and crescent formation in anti-GBM glomerulonephritis. Methods: Accelerated anti-GBM disease was induced in groups of MMP-12 gene deficient mice (MMP-12−/−) and wild-type C57BL/6J controls, which were killed 12 days after injection of anti-GBM serum. Results: Wild-type and MMP-12−/− mice developed glomerular damage and glomerular tuft adhesions to Bowman's capsule. Both groups developed severe proteinuria. Wild-type mice also developed significant loss of renal function and crescents in 22{\%} of glomeruli, which were associated with macrophage infiltration and Bowman's capsule rupture. In contrast, MMP-12−/− mice were partially protected from renal function decline, crescent formation and Bowman's capsule rupture. This was associated with reduced macrophage infiltration in both glomeruli and the interstitium, and with reduced expression of CCL2, TNF-α and iNOS mRNA in MMP-12−/− kidneys. In addition, KIM-1 mRNA levels were reduced in MMP-12−/− mice indicating less tubular damage. Conclusion: These data demonstrate that endogenous MMP-12 facilitates macrophage accumulation and activation in anti-GBM glomerulonephritis which is required for glomerular crescent formation, Bowman's capsule rupture, tubular damage and renal function decline.",
keywords = "glomerular crescent, glomerulonephritis, kidney disease, macrophage, matrix metalloproteinase-12",
author = "Abraham, {Abu P.} and Ma, {Frank Y.} and Mulley, {William R.} and Nikolic-Paterson, {David J.} and Tesch, {Greg H.}",
year = "2018",
month = "2",
day = "1",
doi = "10.1111/nep.12964",
language = "English",
volume = "23",
pages = "183--189",
journal = "Nephrology",
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Matrix metalloproteinase-12 deficiency attenuates experimental crescentic anti-glomerular basement membrane glomerulonephritis. / Abraham, Abu P.; Ma, Frank Y.; Mulley, William R.; Nikolic-Paterson, David J.; Tesch, Greg H.

In: Nephrology, Vol. 23, No. 2, 01.02.2018, p. 183-189.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Matrix metalloproteinase-12 deficiency attenuates experimental crescentic anti-glomerular basement membrane glomerulonephritis

AU - Abraham, Abu P.

AU - Ma, Frank Y.

AU - Mulley, William R.

AU - Nikolic-Paterson, David J.

AU - Tesch, Greg H.

PY - 2018/2/1

Y1 - 2018/2/1

N2 - Aim: Matrix metalloproteinase-12 (MMP-12; macrophage elastase) is an enzyme that can cleave various extracellular matrix proteins and is required for macrophage infiltration and pulmonary fibrosis in experimental emphysema. We have shown previously that MMP-12 is highly up-regulated in experimental anti-glomerular basement membrane (GBM) disease. The aim of this study was to determine whether MMP-12 is required for glomerular macrophage infiltration and crescent formation in anti-GBM glomerulonephritis. Methods: Accelerated anti-GBM disease was induced in groups of MMP-12 gene deficient mice (MMP-12−/−) and wild-type C57BL/6J controls, which were killed 12 days after injection of anti-GBM serum. Results: Wild-type and MMP-12−/− mice developed glomerular damage and glomerular tuft adhesions to Bowman's capsule. Both groups developed severe proteinuria. Wild-type mice also developed significant loss of renal function and crescents in 22% of glomeruli, which were associated with macrophage infiltration and Bowman's capsule rupture. In contrast, MMP-12−/− mice were partially protected from renal function decline, crescent formation and Bowman's capsule rupture. This was associated with reduced macrophage infiltration in both glomeruli and the interstitium, and with reduced expression of CCL2, TNF-α and iNOS mRNA in MMP-12−/− kidneys. In addition, KIM-1 mRNA levels were reduced in MMP-12−/− mice indicating less tubular damage. Conclusion: These data demonstrate that endogenous MMP-12 facilitates macrophage accumulation and activation in anti-GBM glomerulonephritis which is required for glomerular crescent formation, Bowman's capsule rupture, tubular damage and renal function decline.

AB - Aim: Matrix metalloproteinase-12 (MMP-12; macrophage elastase) is an enzyme that can cleave various extracellular matrix proteins and is required for macrophage infiltration and pulmonary fibrosis in experimental emphysema. We have shown previously that MMP-12 is highly up-regulated in experimental anti-glomerular basement membrane (GBM) disease. The aim of this study was to determine whether MMP-12 is required for glomerular macrophage infiltration and crescent formation in anti-GBM glomerulonephritis. Methods: Accelerated anti-GBM disease was induced in groups of MMP-12 gene deficient mice (MMP-12−/−) and wild-type C57BL/6J controls, which were killed 12 days after injection of anti-GBM serum. Results: Wild-type and MMP-12−/− mice developed glomerular damage and glomerular tuft adhesions to Bowman's capsule. Both groups developed severe proteinuria. Wild-type mice also developed significant loss of renal function and crescents in 22% of glomeruli, which were associated with macrophage infiltration and Bowman's capsule rupture. In contrast, MMP-12−/− mice were partially protected from renal function decline, crescent formation and Bowman's capsule rupture. This was associated with reduced macrophage infiltration in both glomeruli and the interstitium, and with reduced expression of CCL2, TNF-α and iNOS mRNA in MMP-12−/− kidneys. In addition, KIM-1 mRNA levels were reduced in MMP-12−/− mice indicating less tubular damage. Conclusion: These data demonstrate that endogenous MMP-12 facilitates macrophage accumulation and activation in anti-GBM glomerulonephritis which is required for glomerular crescent formation, Bowman's capsule rupture, tubular damage and renal function decline.

KW - glomerular crescent

KW - glomerulonephritis

KW - kidney disease

KW - macrophage

KW - matrix metalloproteinase-12

UR - http://www.scopus.com/inward/record.url?scp=85040777016&partnerID=8YFLogxK

U2 - 10.1111/nep.12964

DO - 10.1111/nep.12964

M3 - Article

VL - 23

SP - 183

EP - 189

JO - Nephrology

JF - Nephrology

SN - 1320-5358

IS - 2

ER -