A hypomorphic renin allele in Ren1c-T2A knock-in mice caused chronic renin deficiency, driving progressive renal arteriolar remodeling, hypotension, and functional decline.
Does chronic renin deficiency drive renal arteriolar remodeling and functional decline in a mouse model?
This study demonstrates that chronic renin deficiency is sufficient to drive progressive renal vascular remodeling and functional decline, providing a mechanistic framework for the long-term consequences of RAAS inhibition.
Chronic inhibition of the renin-angiotensin-aldosterone system (RAAS) causes progressive renal vascular disease characterized by concentric arterial and arteriolar hypertrophy (CAAH), driven by sustained activation of renin-producing cells. 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 this model as a platform for investigating the long-term consequences of RAAS inhibition and pathogenic renin variants.
Medrano et al. (Fri,) conducted a other in Progressive renal vascular disease. Ren1c-T2A knock-in (hypomorphic renin allele) was evaluated on Development of concentric arterial and arteriolar hypertrophy (CAAH), hypotension, and renal dysfunction. A hypomorphic renin allele in Ren1c-T2A knock-in mice caused chronic renin deficiency, driving progressive renal arteriolar remodeling, hypotension, and functional decline.