Mast Cells and MCPT4 Chymase Promote Renal Impairment after Partial Ureteral Obstruction.

Maguelonne Pons,Lydia Celia Madjène,Gunnar Pejler,Liza Ali,Marianne Alison,Shamila Vibhushan,Julien Claver,Jessica Calvo,Alaa El Ghoneimi,Luca Danelli,Marie-Laurence Poli-Mérol,Magnus Åbrink,Michel Peuchmaur,Walid Beghdadi,Ulrich Blank

doi:10.3389/fimmu.2017.00450

Abstract

Obstructive nephropathy constitutes a major cause of pediatric renal progressive disease. The mechanisms leading to disease progression are still poorly understood. Kidney fibrotic lesions are reproduced using a model of partial unilateral ureteral obstruction (pUUO) in newborn mice. Based on data showing significant mast cell (MC) infiltration in patients, we investigated the role of MC and murine MCPT4, a MC-released chymase, in pUUO using MC- (Wsh/sh), MCPT4-deficient (Mcpt4−/−), and wild-type (WT) mice. Measurement of kidney length and volume by magnetic resonance imaging (MRI) as well as postmortem kidney weight revealed hypotrophy of operated right kidneys (RKs) and compensatory hypertrophy of left kidneys. Differences between kidneys were major for WT, minimal for Wsh/sh, and intermediate for Mcpt4−/− mice. Fibrosis development was focal and increased only in WT-obstructed kidneys. No differences were noticed for local inflammatory responses, but serum CCL2 was significantly higher in WT versus Mcpt4−/− and Wsh/sh mice. Alpha-smooth muscle actin (αSMA) expression, a marker of epithelial–mesenchymal transition (EMT), was high in WT, minimal for Wsh/sh, and intermediate for Mcpt4−/− RK. Supernatants of activated MC induced αSMA in co-culture experiments with proximal tubular epithelial cells. Our results support a role of MC in EMT and parenchyma lesions after pUUO involving, at least partly, MCPT4 chymase. They confirm the importance of morphologic impairment evaluation by MRI in pUUO.

Highlights

Obstructive uropathies represent a sizable proportion (~50%) of antenatal renal diseases with ureteropelvic junction (UPJ) obstruction being the first congenital etiology [1, 2]
Our data indicate that mast cell (MC) infiltrate the kidney in UPJ patients and that their presence is correlated with the degree of inflammation, but not with the degree of fibrosis
The current challenge in congenital hydronephrosis or UPJ pathology is the indication for surgery, which depends on the degree of damage and the evolution of disease

Summary

Introduction

Obstructive uropathies represent a sizable proportion (~50%) of antenatal renal diseases with ureteropelvic junction (UPJ) obstruction being the first congenital etiology [1, 2]. The pelvic dilatation may regress spontaneously with age but the others will require surgery. Indication for surgery largely depends on imaging criteria requiring a few months follow-up of patients. Renal function and kidney morphology data are evaluated by renal ultrasound, scintigraphy, and more. MCs in Renal Obstructive Pathology recently, uro-magnetic resonance imaging (MRI) [3, 4]. These examinations are non-invasive, but poorly predict the optimal timing for surgery and renal recovery after surgical repair. A better understanding of the pathophysiology combined with biochemical and imaging investigations is necessary to delineate new biomarkers, evaluate the impact of these lesions in the long term, and improve patient care

Methods

Results

Conclusion