Knocking-down testis-specific protein Y-encoded-like 2 alleviates hypertension through down-regulating the transcription of GluN2A/B in hypothalamic paraventricular nucleus

Increased expression of both the nucleosome assembly protein (NAP) superfamily member testis-specific protein Y-encoded-like 2 (TSPYL2) and N-methyl-D-aspartate receptor (NMDAR) in the hypothalamic paraventricular nucleus (PVN) is crucial for the pathogenesis of hypertension, yet how they interact during hypertension is not fully understood. It is highly possible that NMDAR can be regulated by TSPYL2 in the PVN during hypertension. To examine the hypothesis, TSPYL2 is knocked-down or overexpressed in the PVN of spontaneously hypertensive rats (SHRs) and the normotensive control Wistar-Kyoto rats (WKYs), as well as the cultured primary PVN cells of SHRs. The transcription of NMDAR subunits, together with the blood pressure, plasma norepinephrine (NE) and the inflammatory responses and oxidative stress in the PVN were examined. Results suggested that TSPYL2 knockdown reduced blood pressure, downregulated the transcription of GluN2A/B and reduced inflammatory responses and oxidative stress in the PVN; while in the PVN of WKYs, it did not cause such significant changes. In vitro examination further revealed reduced basal cellular Ca²⁺ concentration after TSPYL2 knockdown, indicating tampered NMDAR function. These results suggest that TSPYL2 is critical for maintaining hypertension via transcriptional regulation of GluN2A/B. Interfering with TSPYL2 can block GluN2A/B expression and suppress the function of NMDARs in the PVN, which reduces the high blood pressure of hypertensive animals.