Predisposition to cortical neurodegenerative changes in brains of hypertension prone rats

J Transl Med. 2023 Jan 27;21(1):51. doi: 10.1186/s12967-023-03916-y.

Abstract

Background: Substantial evidence suggests that hypertension is a significant risk factor for cognitive decline. However, it is unclear whether the genetic predisposition to hypertension is also associated with cellular dysfunction that promotes neurodegeneration.

Methods: Changes in blood pressure were evaluated following dietary salt-loading or administration of a regular diet in Sabra Normotensive (SBN/y) and Sabra Hypertension-prone rats (SBH/y). We performed quantitative RT-PCR and immunofluorescence staining in brain cortical tissues before salt loading and 6 and 9 months after salt loading. To examine the expression of brain cortical proteins involved in the gene regulation (Histone Deacetylase-HDAC2; Histone Acetyltransferase 1-HAT1), stress response (Activating Transcription Factor 4-ATF4; Eukaryotic Initiation Factor 2- eIF2α), autophagy (Autophagy related 4A cysteine peptidase- Atg4a; light-chain 3-LC3A/B; mammalian target of rapamycin complex 1- mTORC1) and apoptosis (caspase-3).

Results: Prior to salt loading, SBH/y compared to SBN/y expressed a significantly higher level of cortical HAT1 (protein), Caspase-3 (mRNA/protein), LC3A, and ATF4 (mRNA), lower levels of ATG4A (mRNA/protein), LC3A/B, HDAC2 (protein), as well as a lower density of cortical neurons. Following dietary salt loading, SBH/y but not SBN/y developed high blood pressure. In hypertensive SBH/y, there was significant upregulation of cortical HAT1 (protein), Caspase-3 (protein), and eIF2α ~ P (protein) and downregulation of HDAC2 (protein) and mTORC1 (mRNA), and cortical neuronal loss.

Conclusions: The present findings suggest that genetic predisposition to hypertension is associated in the brain cortex with disruption in autophagy, gene regulation, an abnormal response to cellular stress, and a high level of cortical apoptosis, and could therefore exacerbate cellular dysfunction and thereby promote neurodegeneration.

Keywords: Dietary Salt Loading; Genetic predisposition; Hypertension; Neurodegeneration; SBH/y; SBN/y.

MeSH terms

  • Animals
  • Brain / metabolism
  • Caspase 3 / metabolism
  • Genetic Predisposition to Disease
  • Hypertension* / genetics
  • Mammals / metabolism
  • RNA, Messenger
  • Rats
  • Sodium Chloride
  • Sodium Chloride, Dietary*

Substances

  • Sodium Chloride, Dietary
  • Caspase 3
  • Sodium Chloride
  • RNA, Messenger