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Dis Model Mech. 2017 Jun 1;10(6):773-786. doi: 10.1242/dmm.029488. Epub 2017 Mar 21.

A mouse model for inherited renal fibrosis associated with endoplasmic reticulum stress.

Author information

1
Academic Endocrine Unit, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Headington, Oxford OX3 7LJ, UK.
2
Institute of Physiology, University of Zurich, Zurich CH-8057, Switzerland.
3
School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, UK.
4
MRC Mammalian Genetics Unit and Mary Lyon Centre, MRC Harwell Institute, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, UK.
5
Academic Endocrine Unit, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Headington, Oxford OX3 7LJ, UK rajesh.thakker@ndm.ox.ac.uk.

Abstract

Renal fibrosis is a common feature of renal failure resulting from multiple etiologies, including diabetic nephropathy, hypertension and inherited renal disorders. However, the mechanisms of renal fibrosis are incompletely understood and we therefore explored these by establishing a mouse model for a renal tubular disorder, referred to as autosomal dominant tubulointerstitial kidney disease (ADTKD) due to missense uromodulin (UMOD) mutations (ADTKD-UMOD). ADTKD-UMOD, which is associated with retention of mutant uromodulin in the endoplasmic reticulum (ER) of renal thick ascending limb cells, is characterized by hyperuricemia, interstitial fibrosis, inflammation and renal failure, and we used targeted homologous recombination to generate a knock-in mouse model with an ADTKD-causing missense cysteine to arginine uromodulin mutation (C125R). Heterozygous and homozygous mutant mice developed reduced uric acid excretion, renal fibrosis, immune cell infiltration and progressive renal failure, with decreased maturation and excretion of uromodulin, due to its retention in the ER. The ER stress marker 78 kDa glucose-regulated protein (GRP78) was elevated in cells expressing mutant uromodulin in heterozygous and homozygous mutant mice, and this was accompanied, both in vivo and ex vivo, by upregulation of two unfolded protein response pathways in primary thick ascending limb cells from homozygous mutant mice. However, this did not lead to an increase in apoptosis in vivo Thus, we have developed a novel mouse model for renal fibrosis, which will be a valuable resource to decipher the mechanisms linking uromodulin mutations with ER stress and renal fibrosis.

KEYWORDS:

ER stress; Endoplasmic reticulum; Fibrosis; Kidney; Mouse model

PMID:
28325753
PMCID:
PMC5483009
DOI:
10.1242/dmm.029488
[Indexed for MEDLINE]
Free PMC Article

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