X-Linked Alport Dogs Demonstrate Mesangial Filopodial Invasion of the Capillary Tuft as an Early Event in Glomerular Damage

• Published in: PloS one Vol. 11; no. 12; p. e0168343
• Main Authors: Clark, Sabrina D, Nabity, Mary B, Cianciolo, Rachel E, Dufek, Brianna, Cosgrove, Dominic
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 13.12.2016; Public Library of Science (PLoS)
• Subjects: Albumins - chemistry; Alport syndrome; Analysis; Animals; Biology and Life Sciences; Biomechanics; Biopsy; Collagen; Collagen (type IV); Collagen Type IV - metabolism; Diagnosis; Disease Models, Animal; Disease Progression; Dogs; Electron microscopy; Euthanasia; Fibronectin; Fibrosis; Genes; Genomics; Glomerular Basement Membrane - pathology; Glomerular Mesangium - metabolism; Hereditary nephritis; Histopathology; Humans; Immunohistochemistry; Inflammation; Internal medicine; Kidney diseases; Kinases; Laminin; Laminin - genetics; Light microscopy; Localization; Male; Medicine and Health Sciences; Mice; Microscopy; Microscopy, Confocal; Microscopy, Electron; Microscopy, Fluorescence; Mutation; Nephritis, Hereditary - genetics; Nephritis, Hereditary - physiopathology; Nephrology; Pathogenesis; Pathological histology; Proteinuria; Proteinuria - metabolism; Pseudopodia - metabolism; Renal function; Research and Analysis Methods; Risk factors; Rodents; Signaling; Veterinary colleges; Veterinary medicine
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0168343

X-linked Alport syndrome (XLAS), caused by mutations in the type IV collagen COL4A5 gene, accounts for approximately 80% of human Alport syndrome. Dogs with XLAS have a similar clinical progression. Prior studies in autosomal recessive Alport mice demonstrated early mesangial cell invasion as the source of laminin 211 in the glomerular basement membrane (GBM), leading to proinflammatory signaling. The objective of this study was to verify this process in XLAS dogs. XLAS dogs and WT littermates were monitored with serial clinicopathologic data and kidney biopsies. Biopsies were obtained at set milestones defined by the onset of microalbuminuria (MA), overt proteinuria, onset of azotemia, moderate azotemia, and euthanasia. Kidney biopsies were analyzed by histopathology, immunohistochemistry, and electron microscopy. XLAS dogs showed progressive decrease in renal function and progressive increase in interstitial fibrosis and glomerulosclerosis (based on light microscopy and immunostaining for fibronectin). The only identifiable structural abnormality at the time of microalbuminuria was ultrastructural evidence of mild segmental GBM multilamination, which was more extensive when overt proteinuria developed. Co-localization studies showed that mesangial laminin 211 and integrin α8β1 accumulated in the GBM at the onset of overt proteinuria and coincided with ultrastructural evidence of mild cellular interpositioning, consistent with invasion of the capillary loops by mesangial cell processes. In a large animal model, the induction of mesangial filopodial invasion of the glomerular capillary loop leading to the irregular deposition of laminin 211 is an early initiating event in Alport glomerular pathology.