Intravital imaging reveals glomerular capillary distension and endothelial and immune cell activation early in Alport syndrome
| Autor: | Audrey K. Izuhara, Kerstin Amann, Kevin V. Lemley, Janos Peti-Peterdi, Urvi Nikhil Shroff, Georgina Gyarmati, Laura Perin, Stefano Da Sacco, Sargis Sedrakyan, Xiaogang Hou |
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| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Male
Pathology medicine.medical_specialty Intravital Microscopy Endothelial cells Kidney Glomerulus Nephritis Hereditary Mouse models Glycocalyx Type IV collagen Mice medicine Animals Humans Alport syndrome Kidney business.industry Glomerular basement membrane Glomerulosclerosis General Medicine medicine.disease Capillaries Disease Models Animal medicine.anatomical_structure Cellular Microenvironment Nephrology Glomerular Filtration Barrier business Collagens Kidney disease Research Article |
| Zdroj: | JCI Insight |
| ISSN: | 2379-3708 |
| Popis: | Alport syndrome (AS) is a genetic disorder caused by mutations in type IV collagen that lead to defective glomerular basement membrane, glomerular filtration barrier (GFB) damage, and progressive chronic kidney disease. While the genetic basis of AS is well known, the molecular and cellular mechanistic details of disease pathogenesis have been elusive, hindering the development of mechanism-based therapies. Here, we performed intravital multiphoton imaging of the local kidney tissue microenvironment in a X-linked AS mouse model to directly visualize the major drivers of AS pathology. Severely distended glomerular capillaries and aneurysms were found accompanied by numerous microthrombi, increased glomerular endothelial surface layer (glycocalyx) and immune cell homing, GFB albumin leakage, glomerulosclerosis, and interstitial fibrosis by 5 months of age, with an intermediate phenotype at 2 months. Renal histology in mouse or patient tissues largely failed to detect capillary aberrations. Treatment of AS mice with hyaluronidase or the ACE inhibitor enalapril reduced the excess glomerular endothelial glycocalyx and blocked immune cell homing and GFB albumin leakage. This study identified central roles of glomerular mechanical forces and endothelial and immune cell activation early in AS, which could be therapeutically targeted to reduce mechanical strain and local tissue inflammation and improve kidney function. |
| Databáze: | OpenAIRE |
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