Angiotensin II acts in the hypothalamic paraventricular nucleus to differentially regulate blood pressure and sympathetic nerve activity in a rodent model of polycystic kidney disease

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Abstract

Angiotensin (Ang) II is implicated in the development of hypertension in polycystic kidney disease; whether this involves the central action of Ang II is unclear. The hypothalamic paraventricular nucleus (PVN) is a critical regulator of blood pressure and sympathetic nerve activity (SNA) and has been implicated in the development of sympathetic overactivity and therefore hypertension. Within the PVN, Ang II, via activation of the type 1 receptor (AT1R), has a pressor and sympathoexcitatory action. We tested the hypothesis, therefore, that enhanced AT1R signalling in the PVN produces hypertension and sympathetic overactivity in a rodent model of polycystic kidney disease, the Lewis polycystic kidney (LPK) rat. Urethane‐anaesthetised adult LPK (n=27 total) and control Lewis (n=12 total) rats were instrumented to record blood pressure and renal and splanchnic SNA and perform microinjections into the PVN. Unilateral microinjection of Ang II (10 mM, 50 nl) produced a greater pressor response in the LPK (33±5 vs.14±3 mmHg; LPK vs. Lewis, P<0.001). In the Lewis this was accompanied by an increase in splanchnic (10±3%) and renal (12±5%) SNA (both P<0.05 vs. baseline). In the LPK, however, a reduction in both splanchnic (−9±4%) and renal (−30±7%) SNA was observed (P<0.05 vs. baseline). Bilateral microinjection of the AT1R antagonist losartan (500 mM, 100 nl) did not affect blood pressure or SNA in either strain (P>0.05 vs. vehicle). To determine if the responses to Ang II were mediated by the AT1R, the effect of losartan microinjection on the responses to Ang II was determined. Losartan attenuated both the pressor (P=0.07) and increase in renal (P<0.05) and splanchnic (P=0.06) SNA observed in the Lewis. In the LPK, however, while losartan attenuated the pressor response and reduction in renal SNA (both P<0.05), the splanchnic sympathoinhibitory response was unaffected (P=0.84). Next, we determined what cell type and signalling pathways mediated the pressor and sympathoinhibitory response to Ang II in the LPK. Inhibition of astrocyte glutamate transporters prevented the pressor (P<0.001) but not sympathoinhibitory response to Ang II (renal P=0.24; splanchnic P=0.37). Conversely, p38 MAPK antagonism enhanced the pressor (P<0.05) and splanchnic sympathoinhibitory (P=0.06) response to PVN Ang II in LPK, without affecting the renal SNA response (P=0.63). The responses to Ang II in the LPK were unaffected by inhibition of the calcineurin/NFAT pathway or IP3‐dependent intracellular calcium‐release (P>0.05). Collectively, these data indicate that activation of AT1R within the PVN produces a heightened blood pressure response in the LPK model of polycystic kidney disease that is dependent on astrocytic regulation of synaptic glutamate levels and inhibition of the p38 MAPK pathway. Ang II differentially modulates target‐specific sympathetic outflow from the PVN in the LPK, which is likely mediated by the recruitment of AT1R‐dependent (renal) and AT1R‐independent (splanchnic) populations of neurons. Future work will be required to determine the role of PVN AT1R in the development of hypertension in this disease model.
Original languageEnglish
Pages (from-to)736.1
Number of pages1
JournalFASEB Journal
Volume32
Issue numberS1
Publication statusPublished - 2018
EventExperimental Biology 2018 Meeting - San Diego, United States
Duration: 21 Apr 201825 Apr 2018

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