title: Progression of Alport Kidney Disease in Col4a3 Knock Out Mice Is Independent of Sex or Macrophage Depletion by Clodronate Treatment.
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.
authors.affiliation: Developmental and Molecular Pathways, Novartis Institute for Biomedical Research, Basel, Switzerland.
authors.forename: Munkyung
authors.initials: M
authors.lastname: Kim
authors.affiliation: Preclinical Safety, Novartis Institute for Biomedical Research, Basel, Switzerland.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Piaia
authors.affiliation: Preclinical Safety, Novartis Institute for Biomedical Research, Cambridge, Massachusetts, Unites States of America.
authors.forename: Neeta
authors.initials: N
authors.lastname: Shenoy
authors.affiliation: Preclinical Safety, Novartis Institute for Biomedical Research, Cambridge, Massachusetts, Unites States of America.
authors.forename: David
authors.initials: D
authors.lastname: Kagan
authors.affiliation: Developmental and Molecular Pathways, Novartis Institute for Biomedical Research, Basel, Switzerland.
authors.forename: Berangere
authors.initials: B
authors.lastname: Gapp
authors.affiliation: Developmental and Molecular Pathways, Novartis Institute for Biomedical Research, Basel, Switzerland.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Kueng
authors.affiliation: Developmental and Molecular Pathways, Novartis Institute for Biomedical Research, Basel, Switzerland.
authors.forename: Delphine
authors.initials: D
authors.lastname: Weber
authors.affiliation: Developmental and Molecular Pathways, Novartis Institute for Biomedical Research, Cambridge, Massachusetts, Unites States of America.
authors.forename: William
authors.initials: W
authors.lastname: Dietrich
authors.affiliation: Developmental and Molecular Pathways, Novartis Institute for Biomedical Research, Basel, Switzerland.
authors.forename: Iwona
authors.initials: I
authors.lastname: Ksiazek
mesh_terms: D000818:Animals; D017209:Apoptosis; D001324:Autoantigens / Q000235:genetics; D004002:Clodronic Acid / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D024141:Collagen Type IV / Q000172:deficiency* / Q000235:genetics; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical; D005260:Female; D007668:Kidney / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000209:etiology; D008081:Liposomes; D008264:Macrophages / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D023421:Models, Animal; D009394:Nephritis, Hereditary / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000503:physiopathology*; D012727:Sex Characteristics
chemical_list: D001324:Autoantigens; D024141:Collagen Type IV; D008081:Liposomes; C057112:type IV collagen alpha3 chain; D004002:Clodronic Acid