Krüppel-like factor 2 regulates renin expression in mature juxtaglomerular cells

Renin regulates blood pressure and fluid-electrolyte homeostasis via the renin-angiotensin-aldosterone system (RAAS), and renin cells function as renal baroreceptors that couple perfusion pressure to renin output. Krüppel-like factor 2 (Klf2), a canonical flow-responsive transcription factor, repeatedly emerged from our multiomics profiling linked to renin cell identity, but its role in renin cells remained unknown. We generated mice with renin-lineage-specific Klf2 deletion (Klf2cKO: Ren1^dCre/+;Klf2^fl/fl) and assessed renin expression and kidney morphology. Klf2cKO mice showed reduced plasma renin at 2 mo that persisted at older ages, decreased Ren1 mRNA, a lower juxtaglomerular renin area index by immunohistochemistry, and reduced carotid blood pressure, whereas the renal architecture and overall vasculature structure were largely conserved. Analysis of single-cell RNA-seq spanning Foxd1⁺ progenitors to mature renin-lineage cells revealed low Klf2 during embryogenesis and the neonatal period but enrichment in the mature postnatal juxtaglomerular cluster, consistent with a role in maintenance rather than early lineage specification. To test renin hypotensive stress and altered perfusion pressure, we challenged Klf2cKO mice with low-salt plus captopril and with surgical aortic coarctation (AoCo; right kidney high pressure, left kidney low pressure). In both models, plasma renin and cortical Ren1 mRNA remained lower than in controls, and AoCo yielded a significantly blunted left-to-right Ren1 ratio, indicating impaired pressure-responsive renin transcription. Together, the findings identify Klf2 as a transcriptional effector linking hemodynamic signals to renin transcription in mature juxtaglomerular cells. Identifying key transcriptional pathways in renin cells could reveal novel targets for modulating the RAAS and blood pressure.NEW & NOTEWORTHY Using renin lineage cell-specific Klf2 knockout mice, we identify Klf2 as a transcriptional effector linking hemodynamic pressure sensing to renin transcription in mature juxtaglomerular cells. Loss of Klf2 blunted the upregulation of renin in response to low-salt/captopril and the pressure-responsiveness to low and high perfusion.