Impaired biogenesis of renin granules in juxtaglomerular cells of Vps33a (D251E) mutant mice

Renin is mainly stored in the renin granules (RGs) of juxtaglomerular cells (JGCs). RGs are a type of lysosome-related organelle (LRO), and knowledge on the underlying mechanism of RG biogenesis is limited. Hermansky-Pudlak syndrome (HPS) is characterized by multiple LRO defects. Whether there are RG defects in HPS is unknown. Using different mouse models of HPS, we found that the active renin content was reduced in the kidneys of buff (bf) mice, which carry a homozygous point mutation (D251E) of Vps33a, a subunit of the HOPS complex. We observed that bf mice exhibited smaller RGs than did heterozygous mice. Knockdown of Vps33a, Snap23, Stx11 and Vamp8 in As4.1 cells impaired the biogenesis of RGs. Interaction between mutant Vps33aD251E and Stx11 was enhanced. We concluded that Vps33a is likely to be involved in the fusion process during RG biogenesis, which is regulated by the SNARE complex (Snap23-Stx11-Vamp8). The enhanced interaction of Vps33aD251E-Stx11 might impair the function of the SNARE complex, which is required for RG biogenesis. This highlights that defects in RG biogenesis can lead to hyporeninemia.