title: Feline chronic kidney disease is associated with upregulation of transglutaminase 2: a collagen cross-linking enzyme.
abstract: Chronic kidney disease is a major cause of morbidity and mortality in cats. Transglutaminase 2 (TG2) is a calcium-dependent enzyme proposed to mediate tubulointerstitial fibrosis in the kidney by cross-linking collagen fibrils. Postmortem kidney tissue was obtained from primary renal azotemic (n = 10) and nonazotemic (n = 5) cats (14 domestic short hair, 1 Burmese; aged 9-23.7 years). Extracellular matrix protein deposition was determined by Masson's trichrome staining and collagen immunofluorescence. Total kidney transglutaminase (TG) enzyme activity and TG2 protein were measured in tissue homogenates by putrescine incorporation and Western blotting. Extracellular TG enzyme activity and TG2 protein were determined in situ by immunofluorescence, quantified by multiphase image analysis. Results were compared using the unpaired Student's t-test with Welch's correction. Elevated plasma creatinine, urea, and phosphate concentrations were associated with tubulointerstitial fibrosis but not glomerular fibrosis. Kidney homogenates from azotemic cats showed a 3-fold higher total TG enzyme activity and TG2 protein compared with kidneys from nonazotemic cats. Immunofluorescent studies performed in situ confirmed a 3-fold higher extracellular TG enzyme activity and TG2 protein in cats with azotemia. Tubulointerstitial TG2 showed a positive linear correlation with both renal function and tubulointerstitial fibrosis. In conclusion, for cats with azotemia, both filtration failure and tubulointerstitial fibrosis were associated with the upregulation of TG2, a collagen cross-linking enzyme and the major isoform of transglutaminase in the kidney. TG2 may provide a new therapeutic target for drugs designed to slow the progression of feline chronic kidney disease.
authors.affiliation: Academic Nephrology Unit, Department of Infection and Immunity, University of Sheffield, Sheffield, UK.
authors.forename: A C
authors.initials: AC
authors.lastname: Sánchez-Lara
authors.affiliation: Department of Comparative Biomedical Sciences, Royal Veterinary College, Royal College Street, London, UK.
authors.forename: J
authors.initials: J
authors.lastname: Elliott
authors.affiliation: Department of Clinical Science and Services, Royal Veterinary College, North Mimms, Hertfordshire, UK.
authors.forename: H M
authors.initials: HM
authors.lastname: Syme
authors.affiliation: Athens Veterinary Diagnostic Laboratory, College of Veterinary Medicine, University of Georgia, Athens, Georgia, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Brown
authors.affiliation: Academic Nephrology Unit, Department of Infection and Immunity, University of Sheffield, Sheffield, UK j.l.haylor@sheffield.ac.uk.
authors.forename: J L
authors.initials: JL
authors.lastname: Haylor
mesh_terms: D000818:Animals; D053099:Azotemia / Q000201:enzymology / Q000662:veterinary; D001806:Blood Urea Nitrogen; D015153:Blotting, Western / Q000662:veterinary; D002371:Cat Diseases / Q000201:enzymology*; D002415:Cats; D003404:Creatinine / Q000097:blood; D016326:Extracellular Matrix Proteins / Q000032:analysis; D005260:Female; D005355:Fibrosis; D019204:GTP-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D005919:Glomerular Filtration Rate; D007668:Kidney / Q000737:chemistry / Q000201:enzymology / Q000473:pathology; D008297:Male; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D051436:Renal Insufficiency, Chronic / Q000201:enzymology / Q000662:veterinary*; D011503:Transglutaminases / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D016326:Extracellular Matrix Proteins; D003404:Creatinine; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins
keywords: cat; chronic kidney disease; interstitial fibrosis; transglutaminase 2