Angiotensin II promotes inflammation and DA sympathoexcitation in the Hypothalamic Paraventricular Nuclei through IGF‐1R upregulation
Authors: Ogundele Olalekan Micheal , Lee Charles C. , Francis Joseph 
Published: November 2023

Background

Angiotensin II (Ang II)‐induced hypertension is accompanied by an increase in inflammatory proteins coupled with the depletion of neurotrophic factors in the paraventricular nucleus (PVN) of the hypothalamus. Similarly, changes in the expression pattern of receptors associated with the inflammatory molecules have been described extensively. However, the effect of Ang II on neurotropin receptor (insulin‐like growth factor 1 receptor; IGF‐1R) expression pattern and how it mediates neural and inflammatory changes in the PVN during hypertension remains underexplored. This study examines the hypothesis that changes to PVN IGF‐1R expression is a possible mechanism through which Ang II promotes inflammation and PVN dopaminergic synaptic activity in the progression of hypertension.

Method

Retrograde tracer (Rhodamine B+ Amine, 10,000MW) was injected into the rostral ventrolateral medulla (RVLM) of C57BL/6 mice to identify the sympathoexcitatory PVN projection neurons. After a survival period of 7 days, in vitro coronal PVN slices were prepared in oxygenated artificial cerebrospinal fluid (ACSF) and the retrogradely labelled neurons were identified via fluorescence microscopy. Using patch‐clamping electrophysiology, whole cell parameters were recorded in the labelled PVN neurons following which 200μM Ang II was administered through the ACSF bath. Subsequent changes in neuronal activity were then measured in voltage and current clamp modes. In a separate set of experiments, cortical slices were incubated acutely in either ACSF or ACSF containing 200μM Ang II for 120 minutes. Coronal sections were processed for immunofluorescence to demonstrate the distribution of post‐synaptic protein (PSD‐95), DA activity (Tyrosine hydroxylase; THx), IGF‐1 Receptor and inflammatory markers; high‐mobility group box protein 1 (HMGB‐1) and nuclear factor Kappa Beta (NF‐κβ).

Results and Discussion

Ang II induced depolarization of the membrane potential (−35 to −40mV), resulting in spontaneous bursting potentials in PVN neurons when compared with untreated PVN neurons (−59.5 to −62mV). The observed increase in neuronal activity was also associated with a change in post‐synaptic morphology which was characterized by an increase in PSD‐95 expression in the PVN. Subsequent analysis of DA neuronal marker suggests an increase DA neurotransmission associated with the up‐regulation of PVN tyrosine hydroxylase. Furthermore, Ang II treatment caused an increase in the expression of HMGB‐1 and NF‐κβ, proteins linked with the danger associated molecular patterns (DAMP), in PVN neurons. Interestingly, the described increase in tyrosine hydroxylase/PSD‐95 and HMGB‐1/NF‐κβ in the PVN was also characterized by a corresponding up‐regulation of PVN IGF‐1R expression. This represents a physiological response to IGF‐1 depletion, known to promote inflammation and DA synaptic dysfunction in the brain. Ultimately, these outcomes suggest that Ang II mediated PVN‐driven systemic cardiovascular dysfunction involves the simultaneous progression of inflammation and DA sympathoexcitation which are intrinsically linked to IGF‐1R expression pattern of PVN neurons.

Conclusion

Taken together, our results show that Ang II‐mediated hypertension is a result of both PVN inflammation and dopaminergic sympathoexcitation associated with changes in the expression of neurotropin receptor IGF‐1R.

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