VAMP8 knockout mice show enhanced renin release and content, kidney damage and salt sensitivity (860.5)

Abstract

The vesicle fusion SNARE protein VAMP8 mediates trafficking of aquaporin 2 in kidney collecting ducts. Gene deletion of VAMP8 in mice (V8‐KO) resulted in polyuria and enhanced plasma renin. Renin is stored in granules in juxtaglomerular (JG) cells and its release is mediated by SNARE proteins. In other endocrine cells, VAMP8 mediates granule maturation and constitutive exocytosis. We found that VAMP8 is expressed in JG cells. However, it is not known whether VAMP8 regulates renin release from JG cells or the enhanced plasma renin in V8‐KO is due to compensation for volume loss. We hypothesized that VAMP8 mediates renin granule maturation and constitutive renin release from JG cells. Primary cultures of JG cells from V8‐KO showed enhanced renin and pro‐renin protein expression compared to wild type (WT) (n=5). Baseline renin release from JG cells was 5‐fold higher in V8‐KO than WT (WT=0.06±0.01; KO=0.3±0.05 μgAngI/hr/mg prot.; p<0.05). Immunolabeling of renin and confocal imaging showed enlarged granules and vacuoles in JG cells from V8‐KO. Similar results were observed in V8‐KO JG cells by electron microscopy. Kidney histology showed enhanced renal fibrosis and glomerular sclerosis in V8‐KO (n=4). Despite the higher release of renin and kidney damage, baseline blood pressure in V8‐KO was similar to WT (mmHg: WT=122±3.4; V8‐KO=121±4.5). A high salt diet (1% NaCl drinking water) increased blood pressure in V8‐KO mice by 16±5 mmHg (p<0.05) but not in age matched WT controls. We concluded that VAMP8 plays an inhibitory role in renin release, most likely by mediating normal granule maturation. VAMP8 may regulate blood pressure by inhibiting renin release during a high salt diet. VAMP8 is protective against kidney damage, but the mechanism is unclear.Grant Funding Source: Supported by AHA and NIH