title: Early development of podocyte injury independently of hyperglycemia and elevations in arterial pressure in nondiabetic obese Dahl SS leptin receptor mutant rats.
abstract: The current study examined the effect of obesity on the development of renal injury within the genetic background of the Dahl salt-sensitive rat with a dysfunctional leptin receptor derived from zinc-finger nucleases (SSLepRmutant strain). At 6 wk of age, body weight was 35% higher in the SSLepRmutant strain compared with SSWTrats and remained elevated throughout the entire study. The SSLepRmutant strain exhibited impaired glucose tolerance and increased plasma insulin levels at 6 wk of age, suggesting insulin resistance while SSWTrats did not. However, blood glucose levels were normal throughout the course of the study. Systolic arterial pressure (SAP) was similar between the two strains from 6 to 10 wk of age. However, by 18 wk of age, the development of hypertension was more severe in the SSLepRmutant strain compared with SSWTrats (201 ± 10 vs. 155 ± 3 mmHg, respectively). Interestingly, proteinuria was substantially higher at 6 wk of age in the SSLepRmutant strain vs. SSWTrats (241 ± 27 vs. 24 ± 2 mg/day, respectively) and remained elevated until the end of the study. The kidneys from the SSLepRmutant strain displayed significant glomerular injury, including podocyte foot process effacement and lipid droplets compared with SSWTrats as early as 6 wk of age. By 18 wk of age, plasma creatinine levels were twofold higher in the SSLepRmutant strain vs. SSWTrats, suggesting the presence of chronic kidney disease (CKD). Overall, these results indicate that the SSLepRmutant strain develops podocyte injury and proteinuria independently of hyperglycemia and elevated arterial pressure that later progresses to CKD.
authors.affiliation: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi; and.
authors.forename: Kasi C
authors.initials: KC
authors.lastname: McPherson
authors.affiliation: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi; and.
authors.forename: Lateia
authors.initials: L
authors.lastname: Taylor
authors.affiliation: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi; and.
authors.forename: Ashley C
authors.initials: AC
authors.lastname: Johnson
authors.affiliation: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi; and.
authors.forename: Sean P
authors.initials: SP
authors.lastname: Didion
authors.affiliation: Human Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Aron M
authors.initials: AM
authors.lastname: Geurts
authors.affiliation: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi; and.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Garrett
authors.affiliation: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi; and jmwilliams5@umc.edu.
authors.forename: Jan M
authors.initials: JM
authors.lastname: Williams
mesh_terms: D000818:Animals; D062186:Arterial Pressure / Q000502:physiology*; D001786:Blood Glucose / Q000378:metabolism; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008297:Male; D009765:Obesity / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D050199:Podocytes / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D020303:Rats, Inbred Dahl; D055647:Rats, Transgenic; D054411:Receptors, Leptin / Q000235:genetics* / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
chemical_list: D001786:Blood Glucose; D054411:Receptors, Leptin
keywords: CKD; Dahl S rats; leptin receptor; lipid droplets; obesity; podocyte injury