Testis-Specific Protein, Y-Encoded-Like 2 Activates JAK2/STAT3 Pathway in Hypothalamic Paraventricular Nucleus to Sustain Hypertension

Abstract

Abstract BACKGROUND In the hypothalamic paraventricular nucleus (PVN) of spontaneously hypertensive rats (SHRs), the expression of the testis-specific protein, Y-encoded-like 2 (TSPYL2) and the phosphorylation level of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) are higher comparing with the normotensive Wistar Kyoto rats (WKY). But how they are involved in hypertension remains unclear. TSPYL2 may interact with JAK2/STAT3 in PVN to sustain high blood pressure during hypertension. METHODS Knockdown of TSPYL2 via adeno-associated virus (AAV) carrying shRNA was conducted through bilateral microinjection into the PVN of SHR and WKY rats. JAK2/STAT3 inhibition was achieved by intraperitoneally or PVN injection of AG490 into the SHRs. Blood pressure (BP), plasma norepinephrine (NE), PVN inflammatory response, and PVN oxidative stress were measured. RESULTS TSPYL2 knock-down in the PVN of SHRs but not WKYs led to reduced BP and plasma NE, deactivation of JAK2/STAT3, decreased expression of pro-inflammatory cytokine IL-1β, and increased expression of anti-inflammatory cytokine IL-10 in the PVN. Meanwhile, AG490 administrated in both ways reduced the BP in the SHRs and deactivated JAK2/STAT3 but failed to change the expression of TSPYL2 in PVN. AG490 also downregulated expression of IL-1β and upregulated expression of IL-10. Both knockdown of TSPYL2 and inhibition of JAK2/STAT3 can reduce the oxidative stress in the PVN of SHRs. CONCLUSION JAK2/STAT3 is regulated by TSPYL2 in the PVN of SHRs, and PVN TSPYL2/JAK2/STAT3 is essential for maintaining high BP in hypertensive rats, making it a potential therapeutic target for hypertension.