Deciphering Mechanosensitive Transcriptional Components Within the Renin Cell Baroreceptor

Background: Renin regulates blood pressure and fluid-electrolyte homeostasis. Renin cells possess a baroreceptor that senses perfusion pressure to control renin expression. However, the transcriptional mechanisms behind the renin cell baroreceptor remain unclear. Methods: We used an aortic coarctation (AoCo) model to impose low perfusion pressure on the left kidney (LK) and high pressure on the right kidney (RK). To identify transcription factors involved in pressure sensing, we performed single-nucleus multiome sequencing to simultaneously profile gene expression and chromatin accessibility from the same cells in the kidney cortices. Candidate transcription factors upregulated in the LK were further evaluated through mechanical stimulation of cultured renin cells. The most promising transcription factor was conditionally deleted in the renin lineage cells of mice. Mice were then tested under hypotensive stress induced by captopril and a low-sodium diet, as well as AoCo-induced pressure changes. Results: In the LKs, renin-related genes (Ren1, Akr1b7) and transcription factors, such as Fos, Jun, Egr1, and Krüppel-like factor 2 (Klf2), were upregulated. Motif enrichment analysis revealed strong enrichment of Klf and Sp family binding motifs in LKs. Mechanical stimulation on the renin cell culture suppressed Ren1, Klf2, and the closely related Klf family genes, suggesting pressure sensitivity. Deletion of Klf2 in the renin lineage cells of mice (Klf2cKO) resulted in reduced Ren1 mRNA expression in kidney cortices (p<0.0001) and plasma renin levels (p<0.0001). Klf2cKO mice exhibited increased susceptibility to hypotensive conditions and displayed impaired renin responses to changes in perfusion pressure. Conclusion: Klf2 is a pressure-sensitive transcription factor for renin expression and plays a key role in the control of the renin cell baroreceptor.