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Comparative Study
.2009 Apr;296(4):F771-9.
doi: 10.1152/ajprenal.90389.2008. Epub 2009 Feb 11.

Testosterone-dependent hypertension and upregulation of intrarenal angiotensinogen in Dahl salt-sensitive rats

Affiliations
Comparative Study

Testosterone-dependent hypertension and upregulation of intrarenal angiotensinogen in Dahl salt-sensitive rats

Licy L Yanes et al. Am J Physiol Renal Physiol.2009 Apr.

Abstract

Blood pressure (BP) is more salt sensitive in men than in premenopausal women. In Dahl salt-sensitive rats (DS), high-salt (HS) diet increases BP more in males than females. In contrast to the systemic renin-angiotensin system, which is suppressed in response to HS in male DS, intrarenal angiotensinogen expression is increased, and intrarenal levels of ANG II are not suppressed. In this study, the hypothesis was tested that there is a sexual dimorphism in HS-induced upregulation of intrarenal angiotensinogen mediated by testosterone that also causes increases in BP and renal injury. On a low-salt (LS) diet, male DS had higher levels of intrarenal angiotensinogen mRNA than females. HS diet for 4 wk increased renal cortical angiotensinogen mRNA and protein only in male DS, which was prevented by castration. Ovariectomy of female DS had no effect on intrarenal angiotensinogen expression on either diet. Radiotelemetric BP was similar between males and castrated rats on LS diet. HS diet for 4 wk caused a progressive increase in BP, protein and albumin excretion, and glomerular sclerosis in male DS rats, which were attenuated by castration. Testosterone replacement in castrated DS rats increased BP, renal injury, and upregulation of renal angiotensinogen associated with HS diet. Testosterone contributes to the development of hypertension and renal injury in male DS rats on HS diet possibly through upregulation of the intrarenal renin-angiotensin system.

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Figures

Fig. 1.
Fig. 1.
Renal angiotensinogen mRNA expression in male, female, castrated (CAS), and ovariectomized (OVX) Dahl salt-sensitive (DS) rats on low (LS)- and high (HS)-salt diet. Animals were maintained in LS diet and at 17 wk of age were randomly assigned to receive LS or HS diet for a 4-wk period. At the end of the experimental protocol, kidneys were removed and separated into cortex (A) and medulla (B), and angiotensinogen (ATNG) mRNA levels were quantified by real-time RT-PCR. *P < 0.05.
Fig. 2.
Fig. 2.
Renal angiotensinogen protein expression in male, female, and CAS DS rats on LS and HS diet. Male and female (A) or male and CAS (B) DS rats were maintained on a LS diet and at 17 wk of age were randomly assigned to receive LS or HS diet for a 4-wk period. At the end of the experimental protocol, kidneys were removed and angiotensinogen protein levels were quantified by Western blot.P < 0.05 vs. intact male LS diet (*) and vs. male HS diet (#).
Fig. 3.
Fig. 3.
Renal renin mRNA expression in male, female, CAS, and OVX DS rats on LS and HS diet. Animals were maintained on LS diet and at 17 wk of age were randomly assigned to receive LS or HS diet for a 4-wk period. At the end of the experimental protocol, kidneys were removed and separated into cortex (A) and medulla (B), and renin mRNA levels were quantified by real-time RT-PCR. *P < 0.05.
Fig. 4.
Fig. 4.
Renal angiotensin-converting enzyme (ACE) mRNA expression in male, female, CAS, and OVX DS rats on LS and HS diet. Animals were maintained in LS diet and at 17 wk of age were randomly assigned to receive LS or HS diet for a 4-wk period. At the end of the experimental protocol, kidneys were removed and separated into cortex (A) and medulla (B), and ACE mRNA levels were quantified by real-time RT-PCR. *P < 0.05.
Fig. 5.
Fig. 5.
Renal ANG II type 1 receptor (AT1aR) mRNA expression in male, female, CAS, and OVX DS rats on LS and HS diet. Animals were maintained in LS diet and at 17 wk of age were randomly assigned to receive LS or HS diet for a 4-wk period. At the end of the experimental protocol, kidneys were removed and separated into cortex (A) and medulla (B), and AT1aR mRNA levels were quantified by real-time RT-PCR. *P < 0.05.
Fig. 6.
Fig. 6.
Effect of castration and HS diet on blood pressure. Intact and CAS males were maintained in LS diet and at 17 wk of age were challenged with HS diet for 4 wk. Mean arterial pressure (MAP) was measured by radiotelemetry during night time (A), day time (B), or averaged for 24 h (C). *P < 0.05 vs. intact males,n = 11/ group.
Fig. 7.
Fig. 7.
Effect of gonadectomy on urinary protein and albumin excretion in intact and CAS male DS rats. Intact and CAS males were maintained on LS diet and at 17 wk of age were challenged with HS diet for 4 wk. Rats were placed in metabolic cages, and urine was collected to measure total protein (A) or albumin (B) on LS diet and after 4 wk of HS diet. Data are expressed as mg protein or albumin excreted/24 h. *P < 0.05 vs. intact male,n = 11/group.
Fig. 8.
Fig. 8.
Effect of castration on glomerular sclerosis in intact and CAS male DS rats. Intact and CAS males were maintained on LS diet and at 17 wk of age were challenged with HS diet for 4 wk. At the end of the experimental protocol, kidneys were removed for histological analysis of glomerular injury. *P < 0.05 vs. intact male,n = 5/group.
Fig. 9.
Fig. 9.
Effect of testosterone replacement on blood pressure and renal injury in male and CAS rats on HS diet (data fromprotocol C). Testosterone pellets were implanted in CAS DS rats at 8 wk of age. At 15 wk of age, blood pressure was measured in intact, CAS, and CAS + testosterone replacement (CAS + Testo) (n = 4/group) rats during LS diet and after 4 wk of HS diet.A: MAP average of the last 5 days of LS or HS diet.B: urinary protein excretion.C: glomerular sclerosis.P < 0.05 vs. intact male (*) and vs. CAS (#).
Fig. 10.
Fig. 10.
Effect of testosterone replacement on kidney angiotensinogen expression (data fromprotocol C). Testosterone pellets were implanted in CAS DS rats at 8 wk of age, and, at 17 wk of age, intact males, CAS, and CAS + Testo (n = 4/group) rats were challenged with HS diet for 4 wk. At the end of the experimental protocol, mRNA (A) and protein (B) angiotensinogen levels were quantified in total kidney by real-time RT-PCR or Western blot, respectively.P < 0.05 vs. intact male (*) and vs. CAS (#).
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References

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