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Abstract: PO2132

Male Sex Hormones Drive an Increase in Renal Necrosis in Spontaneously Hypertensive Rats (SHR)

Session Information

Category: Hypertension and CVD

  • 1403 Hypertension and CVD: Mechanisms

Authors

  • Abdelbary, Mahmoud, Augusta University Medical Center, Augusta, Georgia, United States
  • Gillis, Ellen Elizabeth, Augusta University Medical Center, Augusta, Georgia, United States
  • Brands, Michael W., Augusta University Medical Center, Augusta, Georgia, United States
  • Sullivan, Jennifer C., Augusta University Medical Center, Augusta, Georgia, United States
Background

We recently published that maturation in male SHR increases necrosis which contributes to the development of hypertension. Maturation in male SHR is associated with both increases in sex hormones and blood pressure (BP). Testosterone has been shown to induce renal tubular cell necrosis in vitro. This study tested the hypothesis that male sex hormones drive maturation-induced increases in renal necrosis in male SHR.

Methods

At 4 wks of age, male SHR were randomly assigned to one of three groups: sham, gonadectomy (ORX), or treatment with the BP lowering drugs hydrochlorothiazide (HCTZ; 55mg/kg/day) and reserpine (Res; 4.5 mg/kg/day) in drinking water to prevent age-related increases in BP (n=6-8). At 8 wks of age, telemeters were implanted in a subset of rats (n=3-4/group). Rats were allowed 1 wk of recovery, then BP was continuously recorded. All rats were euthanized at 13 wks of age. Renal necrosis was quantified using FACS analysis of 7AAD+ cells. Data are expressed as mean ± standard error. Kidneys were isolated from additional untreated 5 and 15 wk old male SHR (pre- and post-maturation) and processed for Western blot analysis of key proteins mediating necrosis, receptor-interacting protein kinase 3 (RIP-3) and high mobility group box 1 (HMGB-1).

Results

BP was significantly lower in ORX and HCTZ/Res-treated SHR compared to sham (mean arterial BP (mmHg): Sham = 139±2; HCTZ/Res = 117±3; ORX = 126±2; p=0.002). As expected, renal necrosis was greatest in sham control (renal necrosis expressed as % total gated kidney cells: Sham = 6±0.3%). ORX significantly decreased renal necrosis vs. sham, while necrosis in HCTZ/Res treated rats was not significantly altered vs. sham despite having the lowest BP (ORX = 4±0.4%; HCTZ/Res = 5.3±0.3%; p=0.003). To begin to gain insight into the mechanisms mediating maturation-induced increases in necrosis, RIP3 and HMGB1 protein expression were measured in 5 and 15 wk old SHR. Expression of RIP-3 (1±0.1 vs. 0.7±0.1; P=0.008; n=5-6) and HMGB-1 (1±0.06 vs. 0.7±0.1; P=0.005; n=5-6) were greater in 15 wk old SHR.

Conclusion

In conclusion, these data suggest that male sex hormones contribute to maturation induced increase in renal necrosis in male SHR to a greater extent than maturation-induced increases in BP. Future studies will determine the relative contributions of RIP3 and HMGB1 to renal necrosis in adult male SHR.

Funding

  • Other NIH Support