Background: Collectrin (Tmem27), an ACE2 homologue, is a chaperone of amino acid transporters in the kidney and endothelium. Global collectrin knockout (KO) mice have hypertension, endothelial dysfunction, exaggerated salt sensitivity, and diminished renal blood flow. This phenotype is associated with altered nitric oxide and superoxide balance, and increased proximal tubule NHE3 expression. Collectrin is located on the X chromosome where genome wide association population studies have largely been excluded. Methods: We generated proximal tubule specific collectrin KO (PT KO) mice to determine the precise contribution of proximal tubule collectrin in blood pressure homeostasis. We also examined the association of human TMEM27 single nucleotide polymorphisms (SNPs) with blood pressure traits in 11,926 HCHS/SOL Hispanic/Latino participants, Results: PT KO mice exhibited hypertension, and this was associated with increased baseline NHE3 expression and diminished lithium excretion. However, PT KO mice did not display exaggerated salt sensitivity nor reduction in renal blood flow, compared to control mice. Furthermore, PT KO mice exhibited enhanced endothelium-mediated dilation, suggesting a compensatory response to systemic hypertension induced by deficiency of collectrin in the PT. In HCHS/SOL participants, we observed sex-specific SNP associations with diastolic blood pressure. Conclusion: Loss of collectrin in the PT is sufficient to induce hypertension, at least in part, through activation of NHE3. Importantly, our model supports the notion that altered renal blood flow may be a determining factor for salt sensitivity. Further studies are needed to investigate the role of the TMEM27 locus on BP and salt-sensitivity in humans.