Myeloperoxidase deficiency ameliorates progression of chronic kidney disease in mice

TY - JOUR

T1 - Myeloperoxidase deficiency ameliorates progression of chronic kidney disease in mice

AU - Lehners, Alexander

AU - Lange, Sascha

AU - Niemann, Gianina

AU - Rosendahl, Alva

AU - Meyer-Schwesinger, Catherine

AU - Oh, Jun

AU - Stahl, Rolf

AU - Ehmke, Heimo

AU - Benndorf, Ralf

AU - Klinke, Anna

AU - Baldus, Stephan

AU - Wenzel, Ulrich Otto

N1 - Copyright © 2014 the American Physiological Society.

PY - 2014/8/15

Y1 - 2014/8/15

N2 - Myeloperoxidase (MPO) is an enzyme expressed in neutrophils and monocytes/macrophages. Beside its well-defined role in innate immune defence, it may also be responsible for tissue damage. To identify the role of MPO in the progression of chronic kidney disease (CKD), we investigated CKD in a model of renal ablation in MPO knockout and wild-type mice. CKD was induced by 5/6 nephrectomy. Mice were followed for 10 wk to evaluate the impact of MPO deficiency on renal morbidity. Renal ablation induced CKD in wild-type mice with increased plasma levels of MPO compared with controls. No difference was found between MPO-deficient and wild-type mice regarding albuminuria 1 wk after renal ablation, indicating similar acute responses to renal ablation. Over the next 10 wk, however, MPO-deficient mice developed significantly less albuminuria and glomerular injury than wild-type mice. This was accompanied by a significantly lower renal mRNA expression of the fibrosis marker genes plasminogen activator inhibitor-I, collagen type III, and collagen type IV as well as matrix metalloproteinase-2 and matrix metalloproteinase-9. MPO-deficient mice also developed less renal inflammation after renal ablation, as indicated by a lower infiltration of CD3-positive T cells and F4/80-positive monocytes/macrophages compared with wild-type mice. In vitro chemotaxis of monocyte/macrophages isolated from MPO-deficient mice was impaired compared with wild-type mice. No significant differences were observed for mortality and blood pressure after renal ablation. In conclusion, these results demonstrate that MPO deficiency ameliorates renal injury in the renal ablation model of CKD in mice.

AB - Myeloperoxidase (MPO) is an enzyme expressed in neutrophils and monocytes/macrophages. Beside its well-defined role in innate immune defence, it may also be responsible for tissue damage. To identify the role of MPO in the progression of chronic kidney disease (CKD), we investigated CKD in a model of renal ablation in MPO knockout and wild-type mice. CKD was induced by 5/6 nephrectomy. Mice were followed for 10 wk to evaluate the impact of MPO deficiency on renal morbidity. Renal ablation induced CKD in wild-type mice with increased plasma levels of MPO compared with controls. No difference was found between MPO-deficient and wild-type mice regarding albuminuria 1 wk after renal ablation, indicating similar acute responses to renal ablation. Over the next 10 wk, however, MPO-deficient mice developed significantly less albuminuria and glomerular injury than wild-type mice. This was accompanied by a significantly lower renal mRNA expression of the fibrosis marker genes plasminogen activator inhibitor-I, collagen type III, and collagen type IV as well as matrix metalloproteinase-2 and matrix metalloproteinase-9. MPO-deficient mice also developed less renal inflammation after renal ablation, as indicated by a lower infiltration of CD3-positive T cells and F4/80-positive monocytes/macrophages compared with wild-type mice. In vitro chemotaxis of monocyte/macrophages isolated from MPO-deficient mice was impaired compared with wild-type mice. No significant differences were observed for mortality and blood pressure after renal ablation. In conclusion, these results demonstrate that MPO deficiency ameliorates renal injury in the renal ablation model of CKD in mice.

KW - Animals

KW - Autophagy

KW - Chemotaxis, Leukocyte

KW - Male

KW - Metabolism, Inborn Errors

KW - Mice

KW - Mice, Knockout

KW - Nephrectomy

KW - Peroxidase

KW - Renal Insufficiency, Chronic

U2 - 10.1152/ajprenal.00262.2014

DO - 10.1152/ajprenal.00262.2014

M3 - SCORING: Journal article

C2 - 24990898

VL - 307

SP - F407-17

JO - AM J PHYSIOL-RENAL

JF - AM J PHYSIOL-RENAL

SN - 1931-857X

IS - 4

ER -