LECT2–renin complexes

Hypertension, a major contributor to cardiovascular diseases, is primarily regulated by the renin-angiotensin-aldosterone system (RAAS). The rate-limiting step in RAAS activation is the conversion of angiotensinogen (AGT) to angiotensin I (Ang I) by renin. However, an endogenous renin inhibitor remains unidentified. Here, we identify leukocyte cell-derived chemotaxin 2 (LECT2) as an endogenous renin inhibitor that competitively disrupts the renin-AGT catalytic complex, thereby suppressing Ang I production and RAAS activity to reduce blood pressure. Recombinant human LECT2-Fc protein (hLECT2-Fc) has been developed as a therapeutic agent for spontaneously hypertensive rats (SHR). In comparison with conventional antihypertensive therapies (aliskiren, captopril, and losartan), hLECT2-Fc demonstrates equivalent antihypertensive efficacy coupled with organ-protective benefits. The translational potential of this approach was further validated in a mouse transverse aortic constriction (TAC) model, where hLECT2-Fc administration markedly attenuated cardiac hypertrophy and heart failure. Our study suggests that LECT2 represents a promising therapeutic candidate for the control of hypertension and its associated end-organ damage.