Renin activates PI3K-Akt-eNOS signalling through the angiotensin AT₁ and Mas receptors to modulate central blood pressure control in the nucleus tractus solitarii.
OBJECTIVE
The renin-angiotensin system (RAS) is critical for the control of blood pressure by the CNS. Recently, direct renin inhibitors were approved as antihypertensive agents. However, the signalling mechanism of renin, which regulates blood pressure in the nucleus tractus solitarii (NTS) remains unclear. Here we have investigated the signalling pathways involved in renin-mediated blood pressure regulation, at the NTS.


METHODS
Depressor responses to renin microinjected into the NTS of Wistar-Kyoto rats were elicited in the absence and presence of the endothelial nitric oxide synthase (eNOS)-specific inhibitor, N(5)-(-iminoethyl)-L-ornithine, Akt inhibitor IV and LY294002, a PI3K inhibitor and GP antagonist-2A [G(q) inhibitor]. Lisinopril (angiotensin converting enzyme inhibitor), losartan, valsartan (angiotensin AT(1) receptor antagonists), D-Ala7-Ang-(1-7) (angiotensin-(1-7) receptor antagonist) were used to study the involvement of RAS on renin-induced depressor effects.


RESULTS
Microinjection of renin into the NTS produced a prominent depressor effect and increased NO production. Pretreatment with G(q) -PI3K-Akt-eNOS pathway-specific inhibitors significantly attenuated the depressor response evoked by renin. Immunoblotting and immunohistochemical studies further showed that inhibition of PI3K significantly blocked renin-induced eNOS-Ser ¹¹⁷ and Akt-Ser⁴⁷³ phosphorylation in situ. In addition, pre-treatment of the NTS with RAS inhibitors attenuated the vasodepressor effects evoked by renin. Microinjection of renin also increased Ras activation in the NTS.


CONCLUSIONS
Taken together, these results suggest renin modulated blood pressure at the NTS by AT₁ and Mas receptor-mediated activation of G(q) and Ras to evoke PI3K-Akt-eNOS signalling.
Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
Wen-Han
WH
Cheng
Pei-Jung
PJ
Lu
Michael
M
Hsiao
Chun-Hui
CH
Hsiao
Wen-Yu
WY
Ho
Pei-Wen
PW
Cheng
Chia-Te
CT
Lin
Ling-Zong
LZ
Hong
Ching-Jiunn
CJ
Tseng
D000803:Angiotensin I / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D011921:Rats, Inbred WKY; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D012083:Renin / Q000494:pharmacology*; D015398:Signal Transduction; D017552:Solitary Nucleus / Q000187:drug effects* / Q000502:physiology; D018631:ras Proteins / Q000378:metabolism
D000803:Angiotensin I; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D043562:Receptors, G-Protein-Coupled; D012083:Renin; D018631:ras Proteins; C496316:Nos3 protein, rat