title: Structural equation modeling identifies markers of damage and function in the aging male Fischer 344 rat.
abstract: The male Fischer 344 rat is an established model to study progressive renal dysfunction that is similar, but not identical, to chronic kidney disease (CKD) in humans. These studies were designed to assess age-dependent alterations in renal structure and function at late-life timepoints, 16-24 months. Elevations in BUN and plasma creatinine were not significant until 24 months, however, elevations in the more sensitive markers of function, plasma cystatin C and proteinuria, were detectable at 16 and 18 months, respectively. Interestingly, cystatin C levels were not corrected by caloric restriction. Urinary Kim-1, a marker of CKD, was elevated as early as 16 months. Klotho gene expression was significantly decreased at 24 months, but not at earlier timepoints. Alterations in renal structure, glomerulosclerosis and tubulointerstitial fibrosis, were noted at 16 months, with little change from 18 to 24 months. Tubulointerstitial inflammation was increased at 16 months, and remained similar from 18 to 24 months. A SEM (structural equation modeling) model of age-related renal dysfunction suggests that proteinuria is a marker of renal damage, while urinary Kim-1 is a marker of both damage and function. Taken together, these results demonstrate that age-dependent nephropathy begins as early as 16 months and progresses rapidly over the next 8 months.
authors.affiliation: Medical Pharmacology and Physiology, School of Medicine, University of Missouri, United States.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Grunz-Borgmann
authors.affiliation: Medical Pharmacology and Physiology, School of Medicine, University of Missouri, United States.
authors.forename: LaNita A
authors.initials: LA
authors.lastname: Nichols
authors.affiliation: Veterinary Medical Diagnostic Laboratory, University of Missouri, United States.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Wiedmeyer
authors.affiliation: Comparative Health Sciences, Oregon State University, United States.
authors.forename: Sean
authors.initials: S
authors.lastname: Spagnoli
authors.affiliation: Department of Medical Physiology, College of Medicine, Texas A&M Health Science Center, United States.
authors.forename: Jerome P
authors.initials: JP
authors.lastname: Trzeciakowski
authors.affiliation: Medical Pharmacology and Physiology, School of Medicine, University of Missouri, United States. Electronic address: parrishar@health.missouri.edu.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Parrish
mesh_terms: D000375:Aging / Q000097:blood / Q000652:urine; D000818:Animals; D015815:Cell Adhesion Molecules / Q000652:urine*; D055316:Cystatin C / Q000097:blood*; D005966:Glucuronidase / Q000378:metabolism; D006801:Humans; D000090265:Klotho Proteins; D008297:Male; D008954:Models, Biological; D011507:Proteinuria / Q000097:blood / Q000652:urine; D051381:Rats; D011916:Rats, Inbred F344; D051436:Renal Insufficiency, Chronic / Q000097:blood / Q000652:urine
chemical_list: D015815:Cell Adhesion Molecules; D055316:Cystatin C; D005966:Glucuronidase; D000090265:Klotho Proteins; C110936:Havcr1 protein, rat
keywords: Aging; Kim-1; Proteinuria; Structural equation modeling