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

Renin is mainly stored in the renin granules (RGs) of juxtaglomerular cells (JGCs). Being a type of lysosome-related organelles (LROs), the underlying mechanism of RG biogenesis is very limited. Hermansky-Pudlak syndrome (HPS) is characterized by multiple LRO defects. Whether there exist RG defects in HPS is unknown. Using different kinds of HPS mice, 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 (vacuole protein sorting 33a), a subunit of the homotypic fusion and protein sorting complex (HOPS). We observed that bf mice exhibited smaller RGs. Knockdown of Vps33a, synaptosome associated protein 23 (Snap23), syntaxin 11 (Stx11), and vesicle-associated membrane protein 8 (Vamp8) in As4.1 cells impaired the biogenesis of RGs. The interaction between mutant Vps33aD251E and Stx11 was enhanced. We concluded that Vps33a is likely involved in the fusion process during RG biogenesis which is regulated by the SNARE complex (Snap23-Stx11-Vamp8). The enhanced interaction of Vps33aD251E-Stx11 may impair the function of the SNARE complex required for RG biogenesis. This highlights that defects in RG biogenesis may lead to hyporeninemia.