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 <i>Klf2</i> deletion (<i>Klf2</i>cKO: <i>Ren1^dCre/+;Klf2^fl/fl</i>) and assessed renin expression and kidney morphology. <i>Klf2</i>cKO mice showed reduced plasma renin at 2 mo that persisted at older ages, decreased <i>Ren1</i> 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 <i>Foxd1⁺</i> progenitors to mature renin-lineage cells revealed low <i>Klf2</i> 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 <i>Klf2</i>cKO 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 <i>Ren1</i> mRNA remained lower than in controls, and AoCo yielded a significantly blunted left-to-right <i>Ren1</i> 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.<b>NEW & NOTEWORTHY</b> Using renin lineage cell-specific <i>Klf2</i> knockout mice, we identify Klf2 as a transcriptional effector linking hemodynamic pressure sensing to renin transcription in mature juxtaglomerular cells. Loss of <i>Klf2</i> blunted the upregulation of renin in response to low-salt/captopril and the pressure-responsiveness to low and high perfusion.