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...
| Main Authors: | , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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Company of Biologists
2017
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| _version_ | 1797082518708551680 |
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| author | Piret, S Olinger, E Reed, A Nesbit, M Hough, T Bentley, L Devuyst, O Cox, R Thakker, R |
| author_facet | Piret, S Olinger, E Reed, A Nesbit, M Hough, T Bentley, L Devuyst, O Cox, R Thakker, R |
| author_sort | Piret, S |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T01:29:03Z |
| format | Journal article |
| id | oxford-uuid:92fa566e-8644-4630-9596-b8c1c15a6110 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T01:29:03Z |
| publishDate | 2017 |
| publisher | Company of Biologists |
| record_format | dspace |
| spelling | oxford-uuid:92fa566e-8644-4630-9596-b8c1c15a61102022-03-26T23:29:12ZA mouse model for inherited renal fibrosis associated with endoplasmic reticulum stress.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:92fa566e-8644-4630-9596-b8c1c15a6110EnglishSymplectic Elements at OxfordCompany of Biologists2017Piret, SOlinger, EReed, ANesbit, MHough, TBentley, LDevuyst, OCox, RThakker, RRenal 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. |
| spellingShingle | Piret, S Olinger, E Reed, A Nesbit, M Hough, T Bentley, L Devuyst, O Cox, R Thakker, R A mouse model for inherited renal fibrosis associated with endoplasmic reticulum stress. |
| title | A mouse model for inherited renal fibrosis associated with endoplasmic reticulum stress. |
| title_full | A mouse model for inherited renal fibrosis associated with endoplasmic reticulum stress. |
| title_fullStr | A mouse model for inherited renal fibrosis associated with endoplasmic reticulum stress. |
| title_full_unstemmed | A mouse model for inherited renal fibrosis associated with endoplasmic reticulum stress. |
| title_short | A mouse model for inherited renal fibrosis associated with endoplasmic reticulum stress. |
| title_sort | mouse model for inherited renal fibrosis associated with endoplasmic reticulum stress |
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