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Hyperinnervation and Immune-endocrine Interactions in Renal Arteriolar Hypertrophy during Inhibition of The Renin-Angiotensin System

Abstract Body: Background: Chronic stimulation of renin cells by long-term use of renin-angiotensin system (RAS) inhibitors or renin deletion leads to concentric renal arteriolar hypertrophy frequently surrounded by immune-inflammatory cells. The disease is caused by the renin cells which increase in number and adopt an embryonic-secretory phenotype and induce the accumulation of smooth muscle cells that obstruct the vessels leading to ischemia. Normally, renin cells are innervated but it is unclear whether innervation of the renal arterial tree is affected under RAS inhibition.
Hypothesis: Long-term RAS inhibition increases renal arteriolar innervation.
Methods: We used two models of RAS inhibition: 1) Ren1c-/-; Ren1c-Cre; R26RmTmG mice studied at 3 months of age; 2) SMMHCCreERT2; R26RtdTomato; Ren1cYFP mice were treated with captopril for 6 months. We performed tissue clearing and 3D staining with an anti-tubulin β3 antibody. The expression of neurogenesis-related genes in renin lineage cells was examined using our previous single-cell RNA sequencing (scRNA-seq) data from mouse kidneys. We compared RNA expression of nerve growth factor (NGF) between Ren1c−/− mice and control mice by qPCR and in situ hybridization (ISH). T cell infiltration was observed by immunostaining with anti-CD3 antibody.
Results: 3-D imaging revealed that in both RAS inhibition models there was marked hyperinnervation. Renin cells expanded along and around the renal arterioles, and covered the glomeruli. Axons grew in numerous branches surrounding thickened afferent arterioles, bound tightly to renin cells and encasing the glomeruli. Our scRNA-seq data showed that Ngf, a gene important for neurogenesis and produced by immune cells, was highly expressed in renin cells. In Ren1c−/− mice, expression of Ngf was significantly increased compared to controls (p=0.0054). ISH revealed that Ngf was highly expressed in Ren1c−/− mice in the juxtaglomerular area and in the renal cortical stroma. Infiltration of T cells around affected arterioles was prominent in both models of RAS inhibition.
Conclusion: Long-term inhibition of RAS leads to renal hyperinnervation, infiltration of immune cells and arteriolar hypertrophy. The identification of this neuro-immune-endocrine arterioles may help understand and treat vascular disease and hypertension.
  • Yamaguchi, Manako  ( University of Virginia , Charlottesville , Virginia , United States )
  • Almeida, Lucas  ( University of Virginia , Charlottesville , Virginia , United States )
  • Yamaguchi, Hiroki  ( University of Virginia , Charlottesville , Virginia , United States )
  • Smith, Jason  ( University of Virginia , Charlottesville , Virginia , United States )
  • Medrano, Silvia  ( University of Virginia , Charlottesville , Virginia , United States )
  • Sequeira, Maria Luisa  ( University of Virginia , Charlottesville , Virginia , United States )
  • Gomez, Ariel  ( University of Virginia , Charlottesville , Virginia , United States )
  • Author Disclosures:
    Manako Yamaguchi: DO NOT have relevant financial relationships | Lucas Almeida: DO NOT have relevant financial relationships | Hiroki Yamaguchi: DO NOT have relevant financial relationships | Jason Smith: DO NOT have relevant financial relationships | Silvia Medrano: DO NOT have relevant financial relationships | Maria Luisa Sequeira: DO NOT have relevant financial relationships | Ariel Gomez: No Answer
Meeting Info:
Session Info:

12. Annual Hypertension Awards Session

Friday, 09/06/2024 , 03:30PM - 05:00PM

Award Lecture

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