Estrogen worsens incipient hypertriglyceridemic glomerular injury in the obese Zucker rat.
BACKGROUND
The obese Zucker rat (OZR) is a model of glomerulosclerosis and renal failure in the setting of hyperlipidemia, hyperinsulinemia, and obesity. Our prior work in OZRs has shown that ovariectomy attenuates glomerulosclerosis, while added estrogen worsens it. To investigate the mechanism of estrogen's effects on glomerular disease in this model, we evaluated the effects of ovariectomy and estrogen supplementation on seven-week peripubertal OZRs. At this time point, rats exhibit no overt histologic glomerular disease, but are just beginning to show elevated urinary albumin excretion.


METHODS
Female OZRs fed ad libitum were ovariectomized at four weeks, with or without estrogen supplementation to raise estrogen levels to just below those of preoestral adults (mean 16.5 pg/mL). Sham-operated controls were included.


RESULTS
Ovariectomy normalized albuminuria, lowered total and very low-density lipoprotein triglycerides, and reduced glomerular fibronectin expression. Estrogen supplementation worsened albuminuria and raised total/very low-density lipoprotein triglycerides and total cholesterol. Estrogen-supplemented rats exhibited enhanced glomerular deposition of apo A-IV and apo B, increased glomerular expression of desmin and type IV collagen, and increased interstitial macrophage deposition.


CONCLUSIONS
Estrogen may be permissive for the early development of renal disease in OZRs and may act by increasing triglyceride-rich lipoproteins, which then bind to glomerular cells and initiate or accelerate glomerulosclerosis.
Stevenson
F T
FT
Divisions of Nephrology and Endocrinology, Department of Internal Medicine, School of Medicine, University of California, Davis 95616, USA. ftsteveson@ucdavis.edu
Wheeldon
C M
CM
Gades
M D
MD
Kaysen
G A
GA
Stern
J S
JS
van Goor
H
H
D000419:Albuminuria / Q000209:etiology; D000818:Animals; D003094:Collagen / Q000235:genetics; D004967:Estrogens / Q000633:toxicity*; D005260:Female; D005786:Gene Expression Regulation; D005923:Glomerulosclerosis, Focal Segmental / Q000209:etiology*; D015228:Hypertriglyceridemia / Q000150:complications*; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008079:Lipoproteins, VLDL / Q000097:blood; D009765:Obesity / Q000150:complications*; D051381:Rats; D011924:Rats, Zucker; D014280:Triglycerides / Q000097:blood
D004967:Estrogens; D008079:Lipoproteins, VLDL; D014280:Triglycerides; C030106:very low density lipoprotein triglyceride; D003094:Collagen