title: Activation of autophagy and nucleotide-binding domain leucine-rich repeat-containing-like receptor family, pyrin domain-containing 3 inflammasome during Leishmania infantum-associated glomerulonephritis.
abstract: Chronic kidney disease is a major contributor to human and companion animal morbidity and mortality. Renal complications are sequelae of canine and human visceral leishmaniasis (VL). Despite the high incidence of infection-mediated glomerulonephritis, little is known about pathogenesis of VL-associated renal disease. Leishmania infantum-infected dogs are a naturally occurring model of VL-associated glomerulonephritis. Membranoproliferative glomerulonephritis type I [24 of 25 (96%)], with interstitial lymphoplasmacytic nephritis [23 of 25 (92%)], and glomerular and interstitial fibrosis [12 of 25 (48%)] were predominant lesions. An ultrastructural evaluation of glomeruli from animals with VL identified mesangial cell proliferation and interposition. Immunohistochemistry demonstrated significant Leishmania antigen, IgG, and C3b deposition in VL dog glomeruli. Asymptomatic and symptomatic dogs had increased glomerular nucleotide-binding domain leucine-rich repeat-containing-like receptor family, pyrin domain containing 3 and autophagosome-associated microtubule-associated protein 1 light chain 3 associated with glomerular lesion severity. Transcriptional analyses from symptomatic dogs confirmed induction of autophagy and inflammasome genes within glomeruli and tubules. On the basis of temporal VL staging, glomerulonephritis was initiated by IgG and complement deposition. This deposition preceded presence of nucleotide-binding domain leucine-rich repeat-containing-like receptor family, pyrin domain containing 3-associated inflammasomes and increased light chain 3 puncta indicative of autophagosomes in glomeruli from dogs with clinical VL and renal failure. These findings indicate potential roles for inflammasome complexes in glomerular damage during VL and autophagy in ensuing cellular responses.
authors.affiliation: Department of Veterinary Pathology, College of Veterinary Medicine, Iowa State University, Ames, Iowa.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Esch
authors.affiliation: Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, Iowa.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Schaut
authors.affiliation: Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, Iowa.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Lamb
authors.affiliation: Inflammation Program, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa.
authors.forename: Gwendolyn
authors.initials: G
authors.lastname: Clay
authors.affiliation: Department of Biochemistry, Institute of Tropical Medicine, Federal University of Rio Grande do Norte, Natal, Brazil.
authors.forename: Ádila L
authors.initials: ÁL
authors.lastname: Morais Lima
authors.affiliation: Department of Biochemistry, Institute of Tropical Medicine, Federal University of Rio Grande do Norte, Natal, Brazil.
authors.forename: Paulo R P
authors.initials: PR
authors.lastname: do Nascimento
authors.affiliation: Department of Veterinary Pathology, College of Veterinary Medicine, Iowa State University, Ames, Iowa.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Whitley
authors.affiliation: Department of Biochemistry, Institute of Tropical Medicine, Federal University of Rio Grande do Norte, Natal, Brazil.
authors.forename: Selma M B
authors.initials: SM
authors.lastname: Jeronimo
authors.affiliation: Inflammation Program, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa.
authors.forename: Fayyaz S
authors.initials: FS
authors.lastname: Sutterwala
authors.affiliation: Department of Veterinary Pathology, College of Veterinary Medicine, Iowa State University, Ames, Iowa.
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Haynes
authors.affiliation: Department of Veterinary Pathology, College of Veterinary Medicine, Iowa State University, Ames, Iowa; Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, Iowa. Electronic address: christine-petersen@uiowa.edu.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Petersen
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D002352:Carrier Proteins / Q000378:metabolism*; D004285:Dogs; D005921:Glomerulonephritis / Q000378:metabolism / Q000469:parasitology / Q000662:veterinary*; D058847:Inflammasomes / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000378:metabolism / Q000469:parasitology / Q000473:pathology; D018314:Leishmania infantum; D007898:Leishmaniasis, Visceral / Q000150:complications / Q000378:metabolism / Q000662:veterinary*
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes