Intravital imaging reveals glomerular capillary distension and endothelial and immune cell activation early in Alport syndrome

Gyarmati G, Shroff UN, Izuhara A, Hou X, Da Sacco S, Sedrakyan S, Lemley KV, Amann KU, Perin L, Peti-Peterdi J (2022)

Publication Type: Journal article

Publication year: 2022

Journal

JCI Insight American Society for Clinical Investigation

Book Volume: 7

Article Number: e152676

Journal Issue: 1

DOI: 10.1172/jci.insight.152676

Abstract

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.

Authors with CRIS profile

Kerstin Ute Amann Professur für Nephropathologie

Involved external institutions

University of Southern California (USC) US United States (USA) (US) Children's Hospital Los Angeles US United States (USA) (US)

How to cite

APA:

Gyarmati, G., Shroff, U.N., Izuhara, A., Hou, X., Da Sacco, S., Sedrakyan, S.,... Peti-Peterdi, J. (2022). Intravital imaging reveals glomerular capillary distension and endothelial and immune cell activation early in Alport syndrome. JCI Insight, 7(1). https://doi.org/10.1172/jci.insight.152676

MLA:

Gyarmati, Georgina, et al. "Intravital imaging reveals glomerular capillary distension and endothelial and immune cell activation early in Alport syndrome." JCI Insight 7.1 (2022).

BibTeX: Download