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Gonadal steroid regulation of renal injury in renal wrap hypertension

¹Center for the Study of Sex Differences and Departments of ⁴Medicine and ²Physiology and Biophysics, Georgetown University, Washington, District of Columbia; and ³Departments of Science and Technology, Biophysics, and Medicine and Odontostomatology, University of Genoa, Genoa, Italy

Submitted 2 February 2004 ; accepted in final form 12 November 2004

Renal injury is greater in male compared with female rats after renal wrap (RW) hypertension. We investigated the role of gonadal steroids in the sex differences in RW disease severity in male (M) and female (F), castrated (Cast), and ovariectomized (OVX) rats and after dihydrotestosterone (DHT) and 17-estradiol (E₂) treatment. Male castration attenuated the severity of RW-induced glomerulosclerosis (GS) [GS index (GSI): RW-M, 2.1 ± 0.2; RW-Cast, 1.3 ± 0.2; RW-Cast+DHT, 2.4 ± 0.4], mean glomerular volume (MGV; µm³ x 10⁶: RW-M, 1.9 ± 0.1; RW-Cast, 1.45 ± 0.15; RW-Cast+DHT, 1.91 ± 0.15), tubular damage, and proteinuria (mg/day: RW-M, 130 ± 8; RW-Cast, 105 ± 5; RW-Cast+DHT, 142 ± 9), whereas DHT treatment abrogated these effects. Ovariectomy increased the GSI (RW-F, 0.69 ± 0.05; RW-OVX, 1.2 ± 0.1; RW-OVX+E₂, 0.65 ± 0.05), tubular damage, and MGV (µm³ x 10⁶: RW-F, 1.0 ± 0.06; RW-OVX, 1.5 ± 0.05; RW-OVX+E₂, 0.96 ± 0.06), whereas E₂ treatment prevented these effects. Furthermore, DHT treatment of RW-OVX animals exacerbated the GSI (1.9 ± 0.19), MGV (1.7 ± 0.2 x 10⁶ µm³), and proteinuria (171 ± 21 mg/day) even further. Our data show that the lack of E₂ and presence of androgens contribute to progressive renal disease induced by RW hypertension, suggesting that gonadal steroid status is an independent factor in the greater susceptibility men exhibit toward hypertension-associated renal disease compared with women.

testosterone; 5-dihydrotestosterone; 17-estradiol; sexual dimorphism

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