title: Glomerulosclerosis in the diet-induced obesity model correlates with sensitivity to nitric oxide inhibition but not glomerular hyperfiltration or hypertrophy.
abstract: The diet-induced obesity (DIO) model is frequently used to examine the pathogenesis of obesity-related pathologies; however, only minimal glomerulosclerosis (GS) has been reported after 3 mo. We investigated if GS develops over longer periods of DIO and examined the potential role of hemodynamic mechanisms in its pathogenesis. Eight-week-old male obesity-prone (OP) and obesity-resistant (OR) rats (Charles River) were administered a moderately high-fat diet for 5 mo. Radiotelemetrically measured blood pressure, proteinuria, and GS were assessed. OP (n=10) rats developed modest hypertension (142±3 vs. 128±2 mmHg, P<0.05) and substantial levels of proteinuria (63±12 vs. 12±1 mg/day, P<0.05) and GS (7.7±1.4% vs. 0.4±0.2%) compared with OR rats (n=8). Potential hemodynamic mechanisms of renal injury were assessed in additional groups of OP and OR rats fed a moderately high-fat diet for 3 mo. Kidney weight (4.3±0.2 vs. 4.3±0.1 g), glomerular filtration rate (3.3±0.3 vs. 3.1±0.1 ml/min), and glomerular volume (1.9±0.1 vs. 2.0±0.1 μm3×10(-6)) were similar between OP (n=6) and OR (n=9) rats. Renal blood flow autoregulation was preserved in both OP (n=7) and OR (n=7) rats. In contrast, Nω-nitro-L-arginine methyl ester (L-NAME) administration in conscious, chronically instrumented OP (n=11) rats resulted in 15% and 39% increases in blood pressure and renal vascular resistance, respectively, and a 16% decrease in renal blood flow. Minimal effects of L-NAME were seen in OR (n=9) rats. In summary, DIO-associated GS is preceded by an increased hemodynamic sensitivity to L-NAME but not renal hypertrophy or hyperfiltration.
authors.affiliation: Department of Medicine, Loyola University, and Hines Veterans Affairs Hospital, Maywood, Illinois;
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Polichnowski
authors.affiliation: Department of Medicine, Loyola University, and Hines Veterans Affairs Hospital, Maywood, Illinois;
authors.forename: Hector
authors.initials: H
authors.lastname: Licea-Vargas
authors.affiliation: Department of Pathology, Loyola University, Maywood, Illinois.
authors.forename: Maria
authors.initials: M
authors.lastname: Picken
authors.affiliation: Department of Electrical and Computer Engineering, Illinois Institute of Technology, Chicago, Illinois; and.
authors.forename: Jianrui
authors.initials: J
authors.lastname: Long
authors.affiliation: Department of Medicine, Loyola University, and Hines Veterans Affairs Hospital, Maywood, Illinois;
authors.forename: Rashmi
authors.initials: R
authors.lastname: Bisla
authors.affiliation: Department of Electrical and Computer Engineering, Illinois Institute of Technology, Chicago, Illinois; and.
authors.forename: Geoffrey A
authors.initials: GA
authors.lastname: Williamson
authors.affiliation: Department of Medicine, Loyola University, and Hines Veterans Affairs Hospital, Maywood, Illinois;
authors.forename: Anil K
authors.identifier: http://orcid.org/0000-0001-7160-6411
authors.initials: AK
authors.lastname: Bidani
authors.affiliation: Department of Medicine, Loyola University, and Hines Veterans Affairs Hospital, Maywood, Illinois; kgriffi@lumc.edu.
authors.forename: Karen A
authors.initials: KA
authors.lastname: Griffin
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D005921:Glomerulonephritis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects*; D006973:Hypertension / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D006984:Hypertrophy; D007678:Kidney Glomerulus / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009765:Obesity / Q000209:etiology* / Q000378:metabolism; D011507:Proteinuria / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects; D013997:Time Factors; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester
keywords: Nω-nitro-l-arginine methyl ester; glomerular filtration rate; radiotelemetry; rat; renal hemodynamics