Hypertension is a major risk factor for human morbidity and mortality, and the junctional protein paracingulin (CGNL1, JACOP) is required for development of hypertension in a Dahl salt-sensitive rat model and is linked to human hypertension in genome-wide association studies. However, the mechanism through which CGNL1 may regulate hypertension is unknown. Here we address this question using a mouse model, where hypertension is induced by unilateral nephrectomy and angiotensin II infusion (N+A model). Although untreated WT and CGNL1-KO mice showed similar blood pressure, the N+A protocol induced hypertension in WT mice but not in CGNL1-KO mice. We show by immunolocalization and transcriptomic analysis that CGNL1 is expressed throughout the kidney tubules and in endothelium of blood vessels, but not in smooth muscle. The (N+A) protocol induced decreased potassium urinary excretion in wild-type (WT), but not CGNL1-KO mice. Immunoblot analysis shows that the KO of CGNL1 blunted the (N+A)-induced changes in the expression levels and activation of tubular ion transporters, including the Na/H exchanger 3 (NHE3) and the thiazide-sensitive Na-Cl cotransporter (NCC), and blunted the angiotensin II-dependent changes in the levels and/or activation of AMP38 activated protein kinase (AMPK), ERK and myosin light chain. In contrast, myography showed comparable vascular reactivity in thoracic aortas and mesenteric arteries isolated from WT or CGNL1-KO mice. Together, these results suggest the KO of CGNL1 attenuates hypertension by uncoupling angiotensin II signaling in kidney tubule cells, indicating a novel pathway of regulation of signaling by a junctional protein.