Dissertation Defense: Amrita Pai
Candidate Name: Amrita Pai
Major: Cell Biology
Advisor: Kathryn Sandberg, Ph.D.
Title: The Role of T Cells in the Hypertension of the Female Dahl Salt-Sensitive Rat
Hypertension (HT) is a major risk factor for cardiovascular diseases (CVD) and affects 1 billion men and women globally. The underlying cause of HT in women is far less studied than in men. Hence it is critically important to investigate the mechanisms of HT that underlie CVD in women. Recently the immune system has been shown to play a major role in HT; numerous studies in male animals suggest that T cells contribute to the pathogenesis of HT in part through renal injury as a result of T cell infiltration. Less is known regarding the role of T cells in animal models of HT in females. In this study, we found that female Rapp (Jr) salt-sensitive (SS) rats recently purchased from Envigo (ENV), formerly Harlan (Hsd) and maintained on a low sodium diet rapidly developed HT within 12 weeks (wks) of age. Radio telemetry confirmed that 1 month old (mo) SS/JrHsd rats obtained from ENV (referred to as SS) had normal mean arterial pressure (MAP) [(mmHg): 100 ± 1; n=13]. Blood pressure rapidly increased with age and was significantly higher in 4 mo SS rats compared to age matched normotensive salt-resistant rats SR/JrHsd (referred to as SR) [MAP (mmHg): SR, 103 ± 2 vs. SS, 160 ± 11; p<0.007; n=3/group. To further investigate the role of T cells in the spontaneous HT we compared the T cell profile in 1 and 4 mo SS with that of SR. The frequencies of CD4+ (1.3 fold; p<0.0001), CD4+ CD25+ (1.5 fold; p=0.002) T cells and the CD4+/CD8+ ratio (2 fold; p<0.0001; n=8/group) were significantly higher in SS compared to SR rats. These strain differences were magnified by age as frequencies of CD4+ (1.4 fold; p<0.0001), CD4+ CD25+ (2.1 fold; p<0.0001) T cells and the CD4+/CD8+ ratio (3.5 fold; p<0.0001; n=8/group) were even higher in 4 mo SS compared to SR rats. Eleven wks of hydralazine (HDZ) treatment impeded the development of HT in SS rats compared to vehicle (VEH) controls [MAP (mmHg): SS-VEH, 157 ± 4 vs. SS-HDZ, 133±3; p<0.001; n=6-7/group] without having any effect on frequencies of CD4+, CD8+, CD4+ RORγt+ and CD4+ FoxP3+ T cells in the SS kidney, circulation and lymphoid tissues. Frequency of CD4+ CD25+ T cells in the HDZ treatment animals were 12% lower (p=0.0180) compared to VEH controls but only in the kidney. These findings suggest that spontaneously hypertensive SS rats have compensatory increase in renal CD4+ CD25+ T cells as compared to normotensive SR rats and further studies with this cell lineage can illuminate the mechanisms involved in female spontaneous HT. The overall impact of this research lies in the possibility that discovering immune regulatory phenotypes associated with resistance and susceptibility to HT, which could lead to improved therapeutic strategies for treating the major risk factor for death in women and men.
Thursday, June 14 at 2:00pm to 4:00pm
New Research Building, Auditorium
3800 Reservoir Road, N.W., Washington