Gender hormones and the progression of experimental polycystic kidney disease

Kenneth D. Stringer, Radko Komers, Shukri A. Osman, Terry T. Oyama, Jessie N. Lendsley, Sharon Anderson

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Background. Male gender is a risk factor for progression of autosomal-dominant polycystic kidney disease (ADPKD), clinically and in the Han:SPRD rat model. Orchiectomy limits progression, but mechanisms of the detrimental effect of androgen, and/or beneficial effects of estrogen, are not known. This protocol tested the hypothesis that male gender (intact androgen status) promotes progression, while female gender (intact estrogen status) is protective; and that these disease-modifying effects are due to changes in expression of known fibrotic mediators. Methods. Studies were performed in male and female noncystic control (+/+) and cystic (+/-) rats subjected to orchiectomy, ovariectomy, or sham operation. At 12 weeks of age, renal function was measured. Blood and kidneys were taken for measurement of plasma and renal renin, endothelin (ET-1), endothelial nitric oxide synthase (eNOS), and vascular endothelial growth factor (VEGF), using biochemical, protein expression, and immunohistochemical methods. Results. Cystic male rats exhibited significantly reduced glomerular filtration (GFR) and effective renal plasma flow (ERPF) rates, with suppression of plasma and renal renin, up-regulation of renal ET-1 and eNOS, and down-regulation of renal VEGF expression. Orchiectomy attenuated the fall in GFR and ERPF, while numerically limiting changes in eNOS and VEGF. Female rats exhibited less cystic growth, with normal renin status, lesser elevation of renal ET-1, and proportionately lesser changes in VEGF and eNOS. Ovariectomy led to higher blood pressure and reduced GFR and ERPF, with a trend toward upregulation of ET-1, and significant down-regulation of VEGF and eNOS. Conclusion. Female gender is protective, but ovariectomy attenuates the protective effect of female gender, in association with changes in renal expression of ET-1, VEGF, and eNOS. The accelerated disease in male rats can be attenuated by orchiectomy and consequent changes in expression of disease mediators.

Original languageEnglish (US)
Pages (from-to)1729-1739
Number of pages11
JournalKidney International
Volume68
Issue number4
DOIs
StatePublished - Oct 2005

Fingerprint

Polycystic Kidney Diseases
Nitric Oxide Synthase Type III
Hormones
Vascular Endothelial Growth Factor A
Kidney
Orchiectomy
Effective Renal Plasma Flow
Ovariectomy
Renin
Androgens
Estrogens
Up-Regulation
Down-Regulation
Autosomal Dominant Polycystic Kidney
Endothelin-1
Hypertension
Growth

Keywords

  • Endothelin
  • Estrogen
  • Gender
  • Nitric oxide
  • Polycystic kidney disease
  • VEGF

ASJC Scopus subject areas

  • Nephrology

Cite this

Gender hormones and the progression of experimental polycystic kidney disease. / Stringer, Kenneth D.; Komers, Radko; Osman, Shukri A.; Oyama, Terry T.; Lendsley, Jessie N.; Anderson, Sharon.

In: Kidney International, Vol. 68, No. 4, 10.2005, p. 1729-1739.

Research output: Contribution to journalArticle

Stringer, Kenneth D. ; Komers, Radko ; Osman, Shukri A. ; Oyama, Terry T. ; Lendsley, Jessie N. ; Anderson, Sharon. / Gender hormones and the progression of experimental polycystic kidney disease. In: Kidney International. 2005 ; Vol. 68, No. 4. pp. 1729-1739.
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AB - Background. Male gender is a risk factor for progression of autosomal-dominant polycystic kidney disease (ADPKD), clinically and in the Han:SPRD rat model. Orchiectomy limits progression, but mechanisms of the detrimental effect of androgen, and/or beneficial effects of estrogen, are not known. This protocol tested the hypothesis that male gender (intact androgen status) promotes progression, while female gender (intact estrogen status) is protective; and that these disease-modifying effects are due to changes in expression of known fibrotic mediators. Methods. Studies were performed in male and female noncystic control (+/+) and cystic (+/-) rats subjected to orchiectomy, ovariectomy, or sham operation. At 12 weeks of age, renal function was measured. Blood and kidneys were taken for measurement of plasma and renal renin, endothelin (ET-1), endothelial nitric oxide synthase (eNOS), and vascular endothelial growth factor (VEGF), using biochemical, protein expression, and immunohistochemical methods. Results. Cystic male rats exhibited significantly reduced glomerular filtration (GFR) and effective renal plasma flow (ERPF) rates, with suppression of plasma and renal renin, up-regulation of renal ET-1 and eNOS, and down-regulation of renal VEGF expression. Orchiectomy attenuated the fall in GFR and ERPF, while numerically limiting changes in eNOS and VEGF. Female rats exhibited less cystic growth, with normal renin status, lesser elevation of renal ET-1, and proportionately lesser changes in VEGF and eNOS. Ovariectomy led to higher blood pressure and reduced GFR and ERPF, with a trend toward upregulation of ET-1, and significant down-regulation of VEGF and eNOS. Conclusion. Female gender is protective, but ovariectomy attenuates the protective effect of female gender, in association with changes in renal expression of ET-1, VEGF, and eNOS. The accelerated disease in male rats can be attenuated by orchiectomy and consequent changes in expression of disease mediators.

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