Journal
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
Volume 318, Issue 4, Pages F911-F921Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajprenal.00438.2019
Keywords
glomerular filtration rate; lipid accumulation; obesity; renal hyperfiltration; SS(LepR)mutant strain; salt-sensitive rats
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Funding
- National Institute of Diabetes and Digestive and Kidney Diseases [1-F31-DK-109571, DK-109133]
- National Heart, Lung, and Blood Institute [HL-130456, HL-137673]
- National Institute of General Medical Sciences Obesity, Cardiorenal, and Metabolic Diseases (COBRE) [P20-GM-104357]
- National Institute of General Medical Sciences [P20-GM-104357]
- COBRE Grant [P20-GM-104357]
- Mississippi Center of Excellence in Perinatal Research (MS-CEPR) COBRE Grant [P20-GM-121334]
- Mississippi IDeA Networks for Biomedical Research Excellence [P20-GM-103476]
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The present study examined whether development of renal injury in the nondiabetic obese Dahl salt-sensitive leptin receptor mutant (SS(LepR)mutant) strain is associated with elevations in glomerular filtration rate and renal lipid accumulation. Baseline mean arterial pressure at 6 wk of age was similar between Dahl salt-sensitive wild-type (SSWT) and SS(LepR)mutant rats. However, by 18 wk of age, the SS(LepR)mutant strain developed hypertension, while the elevation in mean arterial pressure was not as severe in SSWT rats (192 +/- 4 and 149 +/- 6 mmHg, respectively). At baseline, proteinuria was fourfold higher in SS(LepR)mutant than SSWT rats and remained elevated throughout the study. The early development of progressive proteinuria was associated with renal hyperfiltration followed by a decline in renal function over the course of study in the SS(LepR)mutant compared with SSWT rats. Kidneys from the SS(LepR)mutant strain displayed more glomerulosclerosis and glomerular lipid accumulation than SSWT rats. Glomeruli were isolated from the renal cortex of both strains at 6 and 18 wk of age, and RNA sequencing was performed to identify genes and pathways driving glomerular injury. We observed significant increases in expression of the influx lipid transporters, chemokine (C-X-C motif) ligand 16 (Cxcl16) and scavenger receptor and fatty acid translocase (Cd36), respectively, and a significant decrease in expression of the efflux lipid transporter, ATP-binding cassette subfamily A member 2 (Abca2; cholesterol efflux regulatory protein 2), in SS(LepR)mutant compared with SSWT rats at 6 and 18 wk of age, which were validated by RT-PCR analysis. These data suggest an association between glomerular hyperfiltration and glomerular lipid accumulation during the early development of proteinuria associated with obesity.
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