Abstract
ABSTRACTCollagen 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.
Highlights
Collagen IV is a major component of the basement membrane (BM), a specialised extracellular matrix structure that provides structural support and influences cell behaviour and signalling
Col4a1 renal disease includes renal and tubular disease that develops with age We assessed in vivo renal function in 3- to 4-month-old Col4a1+/Raw (Fig. 1; Table 1) and Col4a1+/Svc (Table 1; Fig. S1) mice, which revealed a reduction in blood pressure of ∼20 mmHg (Fig. 1A; Fig. S1A)
We used diuretic profiling to determine the in vivo activity of the major aldosteronesensitive sodium transport proteins in Col4a1+/Raw mice (Fig. 1D), whereby responses to furosemide, thiazide and amiloride were measured to assess in vivo activity of the Na+-K+-2Cl− cotransporter (NKCC2), the Na+-Cl− cotransporter (NCC) and the epithelial sodium channel (ENaC), respectively (Bailey et al, 2009; Hunter et al, 2014, 2015)
Summary
Collagen IV is a major component of the basement membrane (BM), a specialised extracellular matrix structure that provides structural support and influences cell behaviour and signalling. All BMs contain α1α1α2(IV), whereas in adult kidney it is mainly expressed in vascular, Bowman’s capsule, mesangial and tubular BMs (Hudson et al, 2003). The adult glomerular BM (GBM) predominantly contains α3α4α5 (IV), and mutations affecting this network cause Alport syndrome (Hudson et al, 2003). We have previously identified mouse models with Col4a1 mutations: Col4a1+/Raw and Col4a1+/Svc, containing a lysine (K950E) and a glycine substitution (G1064D), respectively (Van Agtmael et al, 2005). HANAC syndrome has been proposed as a clinical sub-entity within COL4A1/COL4A2 disease (Alamowitch et al, 2009), resulting from mutations located in or close to the integrin-binding CB3 region of the collagen protomer predicted to affect integrin signalling (Plaisier et al, 2010). COL4A1/COL4A2 variants have been implicated in sporadic cases of cerebral vascular disease in the general population (Rannikmae et al, 2015; Weng et al, 2012)
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