Abstract
Alport syndrome is a genetic disease of collagen IV (α3, 4, 5) resulting in renal failure. This study was designed to investigate sex-phenotype correlations and evaluate the contribution of macrophage infiltration to disease progression using Col4a3 knock out (Col4a3KO) mice, an established genetic model of autosomal recessive Alport syndrome. No sex differences in the evolution of body mass loss, renal pathology, biomarkers of tubular damage KIM-1 and NGAL, or deterioration of kidney function were observed during the life span of Col4a3KO mice. These findings confirm that, similar to human autosomal recessive Alport syndrome, female and male Col4a3KO mice develop renal failure at the same age and with similar severity. The specific contribution of macrophage infiltration to Alport disease, one of the prominent features of the disease in human and Col4a3KO mice, remains unknown. This study shows that depletion of kidney macrophages in Col4a3KO male mice by administration of clodronate liposomes, prior to clinical onset of disease and throughout the study period, does not protect the mice from renal failure and interstitial fibrosis, nor delay disease progression. These results suggest that therapy targeting macrophage recruitment to kidney is unlikely to be effective as treatment of Alport syndrome.
Highlights
Alport syndrome is an inherited genetic disease which affects approximately 1 in 5000 people and is caused by mutations in the type IV collagen genes [1]
Uremic cachexia is prevalent in chronic kidney disease including Alport syndrome and is associated with mortality [23,24]
Both female and male Col4a3KO mice are predictive of Alport syndrome and can be used to study pathogenic mechanisms and to evaluate experimental therapies
Summary
Alport syndrome is an inherited genetic disease which affects approximately 1 in 5000 people and is caused by mutations in the type IV collagen genes [1]. Mutations in the type IV collagen α5 chain gene (COL4A5) are responsible for the X-linked form of the disease, which accounts for ~85% of the patients and mutations in the type IV collagen α3 or α4 chain gene (COL4A3 or COL4A4) lead to the autosomal form of the Alport syndrome [2]. Type IV collagen assembles primarily as α3α4α5 heterotrimers in the adult glomerular basement. Macrophage Contribution to Progression of Kidney Alport Disease
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