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However, the mechanisms linking impaired RAAS signaling to vascular remodeling remain unclear. Using a Ren1c-T2A knock-in mouse, we identified a mechanistic link between defective renin function and progressive vascular disease. The T2A insertion generates a hypomorphic renin allele, and homozygous mice develop progressive CAAH accompanied by markedly reduced levels of enzymatically active renin in the circulation. In response to reduced renin activity, mice activate a robust compensatory program characterized by increased Ren1 mRNA expression, depletion of renal renin stores, accumulation of catalytically impaired renin in the circulation, and extensive recruitment of renin-lineage cells along the renal arteriolar tree. Despite this response, RAAS activity remains insufficient, and homozygous mice develop progressive hypotension and renal dysfunction following the onset of CAAH. To define the basis of impaired renin function, molecular dynamics simulations revealed that the C-terminal T2A peptide alters the renin catalytic pocket, disrupting key aspartate residues and electrostatic interactions required for efficient angiotensinogen cleavage. These findings demonstrate that chronic renin deficiency is sufficient to drive renal arteriolar remodeling and functional decline in the absence of overt glomerular injury. Our results provide a mechanistic framework linking chronic RAAS suppression to progressive renal vascular disease and establish the present model as a platform for investigating the long-term consequences of RAAS inhibition and pathogenic renin variants.<\/jats:p>","DOI":"10.1042\/cs20261291","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T05:55:58Z","timestamp":1783922158000},"page":"1741-1759","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Translational uncoupling of renin synthesis and activity reveals a mechanism of kidney vascular remodeling"],"prefix":"10.1042","volume":"140","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8516-0788","authenticated-orcid":false,"given":"Silvia","family":"Medrano","sequence":"first","affiliation":[{"name":"1Child Health Research Center Department of Pediatrics, University of Virginia, Charlottesville, VA, 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