Abstract P250: Targeting The Thrombospondin-CD47 Axis Attenuates Blood Pressure And Renal Injury In Female Hypertensive (mRen2)27 Rats

Alterations in the extracellular matrix (ECM) can influence vascular stiffness and compromise organ function contributing to hypertension. A key component of the ECM is the type I integral membrane receptor CD47 that regulates the ECM by binding to the matricellular protein thrombospondin-1(TSP1). Increased circulating levels of TSP1 and CD47 activation are associated with cardiac and renal pathologies. Thus, the objective of the current study determined the efficacy of targeting CD47 with an anti-sense morpholinos to reduce blood pressure and renal injury in 20-week old hypertensive (mRen2)27 female rats. The CD47 morpholino (Morph) or the missense probe (Control) were dissolved in sterile PBS and administered by tail vein injection twice weekly for 6 weeks. Systolic blood pressures (SBPs) were monitored in conscious rats by a tail cuff auscultation and expression of RAS components assessed by RT-qPCR; all data are means ± SEM with n=8-10 per group. Prior to treatment, the baseline SBPs did not differ between the Control and Morph groups [196 ± 5 vs.197 ± 4 mmHg; p=0.87]. However, as early as one week of treatment, the CD47 Morph group exhibited a significant reduction in SBPs compared to the Control transgenics [185 ± 5 vs. 204 ± 3 mmHg; p<0.01]. At the end of the 6 week treatment period, SBPs remained significantly lower in the CD47 Morph group compared to the Controls [185 ± 4 vs.199 ± 3 mmHg; p<0.02]. In addition, CD47 blockade was associated with reduced proteinuria in the CD47 Morph compared to Controls [7 ± 1 vs. 26 ± 7 mg protein/24 hr excretion; p<0.05]. Regarding the mechanism of CD47 blockade to reduce blood pressure and proteinuria, mRNA analysis revealed lower renal renin mRNA levels in the CD47 Morph versus the Control group [0.54 ± 0.11 vs.1.04 ± 0.11; p<0.01]. Moreover, CD47 Morph treatment significantly reduced the mRNA levels of renal ACE [0.78 ± 0.13 vs.1.05 ± 0.14; p<0.05] and the renal AT1A receptor [0.74 ± 0.07 vs.1.05 ± 0.12; p<0.05], however, renal angiotensinogen mRNA levels were not different among the CD47 Morph and Controls [1.04.± 0.10 vs. 1.16 ± 0.20, p=0.83]. We conclude that silencing CD47 attenuates hypertension and renal injury in the female (mRen2)27 potentially by reducing expression of the renin-ACE-AT1 receptor axis within the kidney.