A mouse model for inherited renal fibrosis associated with endoplasmic reticulum stress.
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, bothin vivoandex 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 apoptosisin vivoThus, 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.
Academic Endocrine Unit, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Headington, Oxford OX3 7LJ, UK.
Sian E
SE
Piret
Institute of Physiology, University of Zurich, Zurich CH-8057, Switzerland.
Eric
E
Olinger
Academic Endocrine Unit, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Headington, Oxford OX3 7LJ, UK.
Anita A C
AAC
Reed
Academic Endocrine Unit, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Headington, Oxford OX3 7LJ, UK.|School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, UK.
M Andrew
MA
Nesbit
MRC Mammalian Genetics Unit and Mary Lyon Centre, MRC Harwell Institute, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, UK.
Tertius A
TA
Hough
MRC Mammalian Genetics Unit and Mary Lyon Centre, MRC Harwell Institute, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, UK.
Liz
L
Bentley
Institute of Physiology, University of Zurich, Zurich CH-8057, Switzerland.
Olivier
O
Devuyst
MRC Mammalian Genetics Unit and Mary Lyon Centre, MRC Harwell Institute, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, UK.
Roger D
RD
Cox
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.
Rajesh V
0000-0002-1438-3220
RV
Thakker
D000818:Animals; D004195:Disease Models, Animal; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D005355:Fibrosis; D005854:Germ Cells / Q000378:metabolism; D007249:Inflammation / Q000473:pathology; D040582:Inheritance Patterns / Q000235:genetics*; D007668:Kidney / Q000473:pathology*; D007674:Kidney Diseases / Q000097:blood / Q000473:pathology* / Q000652:urine; D051379:Mice; D009154:Mutation / Q000235:genetics; D051742:Transcription Factor CHOP / Q000378:metabolism; D056811:Unfolded Protein Response; D015854:Up-Regulation; D058949:Uromodulin / Q000378:metabolism
D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse; D058949:Uromodulin; D051742:Transcription Factor CHOP
ER stress; Endoplasmic reticulum; Fibrosis; Kidney; Mouse model