title: ER stress and basement membrane defects combine to cause glomerular and tubular renal disease resulting from Col4a1 mutations in mice.
abstract: Collagen IV is a major component of basement membranes, and mutations in COL4A1, which encodes collagen IV alpha chain 1, cause a multisystemic disease encompassing cerebrovascular, eye and kidney defects. However, COL4A1 renal disease remains poorly characterized and its pathomolecular mechanisms are unknown. We show that Col4a1 mutations in mice cause hypotension and renal disease, including proteinuria and defects in Bowman's capsule and the glomerular basement membrane, indicating a role for Col4a1 in glomerular filtration. Impaired sodium reabsorption in the loop of Henle and distal nephron despite elevated aldosterone levels indicates that tubular defects contribute to the hypotension, highlighting a novel role for the basement membrane in vascular homeostasis by modulation of the tubular response to aldosterone. Col4a1 mutations also cause diabetes insipidus, whereby the tubular defects lead to polyuria associated with medullary atrophy and a subsequent reduction in the ability to upregulate aquaporin 2 and concentrate urine. Moreover, haematuria, haemorrhage and vascular basement membrane defects confirm an important vascular component. Interestingly, although structural and compositional basement membrane defects occurred in the glomerulus and Bowman's capsule, no tubular basement membrane defects were detected. By contrast, medullary atrophy was associated with chronic ER stress, providing evidence for cell-type-dependent molecular mechanisms of Col4a1 mutations. These data show that both basement membrane defects and ER stress contribute to Col4a1 renal disease, which has important implications for the development of treatment strategies for collagenopathies.
authors.affiliation: Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK.
authors.forename: Frances E
authors.initials: FE
authors.lastname: Jones
authors.affiliation: British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, EH16 4TJ, UK.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Bailey
authors.affiliation: Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK.
authors.forename: Lydia S
authors.initials: LS
authors.lastname: Murray
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Yinhui
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: McNeilly
authors.affiliation: Department of Ophthalmology, University of Erlangen-Nürnberg, D-91054 Erlangen, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Schlötzer-Schrehardt
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Lennon
authors.affiliation: Division of Immunology, Shigei Medical Research Institute, Okayama 701-02, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Sado
authors.affiliation: Division of Pathology, School of Molecular and Clinical Medicine, University of Edinburgh, Edinburgh, EH16 4TJ, UK.
authors.forename: David G
authors.initials: DG
authors.lastname: Brownstein
authors.affiliation: British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, EH16 4TJ, UK.
authors.forename: John J
authors.initials: JJ
authors.lastname: Mullins
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Karl E
authors.initials: KE
authors.lastname: Kadler
authors.affiliation: Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK tom.vanagtmael@glasgow.ac.uk.
authors.forename: Tom
authors.initials: T
authors.lastname: Van Agtmael
mesh_terms: D000818:Animals; D001485:Basement Membrane / Q000378:metabolism*; D024141:Collagen Type IV / Q000235:genetics*; D059865:Endoplasmic Reticulum Stress; D006801:Humans; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology*; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009154:Mutation
chemical_list: C547475:COL4A1 protein, human; D024141:Collagen Type IV
keywords: Basement membrane; Collagen IV; Endoplasmic reticulum stress; Extracellular matrix; Kidney disease
references.citation: Kidney Int. 2010 Feb;77(3):201-10
references.pmid: 19924099
references.citation: Neurology. 2015 Mar 3;84(9):918-26
references.pmid: 25653287
references.citation: Hypertension. 2009 Oct;54(4):890-6
references.pmid: 19635986
references.citation: Cell Tissue Res. 2010 Jan;339(1):167-88
references.pmid: 19756754
references.citation: Science. 2005 May 20;308(5725):1167-71
references.pmid: 15905400
references.citation: Ann Neurol. 2012 Apr;71(4):470-7
references.pmid: 22522439
references.citation: J Clin Invest. 1997 May 15;99(10):2470-8
references.pmid: 9153291
references.citation: N Engl J Med. 2007 Dec 27;357(26):2687-95
references.pmid: 18160688
references.citation: Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):3030-4
references.pmid: 22323586
references.citation: J Am Soc Nephrol. 2015 Jul;26(7):1537-48
references.pmid: 25349206
references.citation: Diabetes Obes Metab. 2010 Oct;12 Suppl 2:108-15
references.pmid: 21029307
references.citation: Genetics. 2007 Feb;175(2):725-36
references.pmid: 17179069
references.citation: Am J Physiol Renal Physiol. 2014 Feb 15;306(4):F457-67
references.pmid: 24402096
references.citation: Curr Opin Neurol. 2011 Feb;24(1):63-8
references.pmid: 21157337
references.citation: Hum Mol Genet. 2007 Apr 1;16(7):798-807
references.pmid: 17317786
references.citation: PLoS One. 2011;6(1):e16337
references.pmid: 21298098
references.citation: Am J Med Genet A. 2010 Oct;152A(10):2550-5
references.pmid: 20818663
references.citation: Ann Neurol. 2007 Aug;62(2):177-84
references.pmid: 17696175
references.citation: N Engl J Med. 2003 Jun 19;348(25):2543-56
references.pmid: 12815141
references.citation: Kidney Int. 2013 Jun;83(6):1118-29
references.pmid: 23447063
references.citation: Neurology. 2009 Dec 1;73(22):1873-82
references.pmid: 19949034
references.citation: Hum Mol Genet. 2012 Oct 15;21(R1):R97-110
references.pmid: 22914737
references.citation: Hum Mol Genet. 2009 Aug 15;18(16):2963-74
references.pmid: 19465746
references.citation: PLoS Biol. 2007 Mar;5(3):e44
references.pmid: 17298185
references.citation: Nat Rev Mol Cell Biol. 2007 Jul;8(7):519-29
references.pmid: 17565364
references.citation: Nat Rev Endocrinol. 2011 Dec;7(12):701-14
references.pmid: 21727914
references.citation: Pediatr Neonatol. 2016 Dec;57(6):522-525
references.pmid: 24861536
references.citation: Hum Mol Genet. 2014 Apr 1;23(7):1709-22
references.pmid: 24203695
references.citation: Hum Mol Genet. 2010 Mar 15;19(6):1119-28
references.pmid: 20056676
references.citation: N Engl J Med. 2006 Apr 6;354(14):1489-96
references.pmid: 16598045
references.citation: Microsc Res Tech. 2008 May;71(5):357-70
references.pmid: 18219669
references.citation: J Am Soc Nephrol. 2013 Jul;24(8):1223-33
references.pmid: 23723427
references.citation: Hum Mol Genet. 2005 Nov 1;14(21):3161-8
references.pmid: 16159887
references.citation: Ann Neurol. 2013 Jan;73(1):48-57
references.pmid: 23225343
references.citation: J Am Soc Nephrol. 2009 Oct;20(10):2181-9
references.pmid: 19713307
references.citation: Nat Rev Genet. 2009 Mar;10(3):173-83
references.pmid: 19204719
references.citation: Am J Hum Genet. 2012 Jan 13;90(1):91-101
references.pmid: 22209247
references.citation: Am J Hum Genet. 2012 Jan 13;90(1):86-90
references.pmid: 22209246
references.citation: Am J Physiol Cell Physiol. 2013 Feb 15;304(4):C342-53
references.pmid: 23242184
references.citation: Hypertension. 2012 Sep;60(3):684-90
references.pmid: 22777941
references.citation: Dev Cell. 2011 Aug 16;21(2):245-56
references.pmid: 21839919
references.citation: Pediatr Nephrol. 2010 May;25(5):813-22
references.pmid: 20049615
references.citation: Nephron Exp Nephrol. 2009;112(1):e1-9
references.pmid: 19342868
references.citation: J Am Soc Nephrol. 2009 Jul;20(7):1471-9
references.pmid: 19423686
references.citation: J Am Soc Nephrol. 2016 Apr;27(4):1042-54
references.pmid: 26260163
references.citation: Hum Mol Genet. 2014 Jan 15;23(2):283-92
references.pmid: 24001601
references.citation: Am J Physiol Renal Physiol. 2009 Dec;297(6):F1566-74
references.pmid: 19794110