Nikolaus-Fiebiger-Center for Molecular Medicine, Glückstrasse 6, 91054 Erlangen, Germany.
J Am Soc Nephrol. 2011 Dec;22(12):2193-202. doi: 10.1681/ASN.2011020200. Epub 2011 Oct 27.
The prorenin receptor (PRR) is highly expressed in podocytes, but its role in the maintenance of podocyte function is unknown. Here we generated podocyte-specific PRR-knockout mice and found that these animals died between 2 to 3 wk after birth. Within 14 d, PRR-knockout mice developed nephrotic syndrome, albuminuria with podocyte foot-process fusion, and cytoskeletal changes. Podocyte-specific PRR deletion also led to disturbed processing of multivesicular bodies and enrichment of autophagosomal (LC3) and lysosomal (LAMP2) markers, indicating a functional block in autophagosome-lysosome fusion and an overload of the proteasomal protein-degradation machinery. In vitro, PRR knockdown and pharmacologic blockade of vacuolar H(+)-ATPases, which associate with the PRR, increased vesicular pH, led to accumulation of LC3-positive and LAMP2-positive vesicles and altered the cytoskeleton. Taken together, these results suggest that the PRR is essential for podocyte function and survival by maintaining autophagy and protein-turnover machinery. Furthermore, PRR contributes to the control of lysosomal pH, which is important for podocyte survival and cytoskeletal integrity.
原肾素受体（PRR）在足细胞中高度表达，但它在维持足细胞功能中的作用尚不清楚。在这里，我们生成了足细胞特异性 PRR 敲除小鼠，并发现这些动物在出生后 2 至 3 周内死亡。在 14 天内，PRR 敲除小鼠发生肾病综合征，出现足细胞足突融合的蛋白尿和细胞骨架改变。足细胞特异性 PRR 缺失也导致多泡体的处理紊乱，自噬体（LC3）和溶酶体（LAMP2）标志物富集，表明自噬体-溶酶体融合功能障碍和蛋白酶体蛋白降解机制过载。在体外，PRR 敲低和液泡 H（+）-ATP 酶的药理学阻断（与 PRR 相关）增加了囊泡 pH，导致 LC3 阳性和 LAMP2 阳性囊泡的积累，并改变了细胞骨架。总之，这些结果表明，PRR 通过维持自噬和蛋白质周转机制对足细胞功能和存活至关重要。此外，PRR 有助于控制溶酶体 pH，这对足细胞存活和细胞骨架完整性很重要。
