Prorenin Receptor Is Essential for Podocyte Autophagy and Survival
Prorenin Receptor Is Essential for Podocyte Autophagy and Survival
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DOI：
10.1681/asn.2011020200
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发表时间：
2011-12-01
影响因子：
13.6
通讯作者：
Muller, Dominik N.
中科院分区：
文献类型：
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作者：
Riediger, Fabian;Quack, Ivo;Muller, Dominik N.
前肾素受体（PRR）在足细胞中高度表达，但其在维持足细胞功能中的作用尚不清楚。在这里，我们产生了足细胞特异性的PRR-knockout小鼠，发现这些动物在出生后2至3周死亡。在14天内，PRR-knockout小鼠发展为肾病综合征，伴有足细胞足突融合的蛋白尿和细胞骨架变化。足细胞特异性PRR缺失还导致多泡体的加工紊乱和自噬体（LC 3）和溶酶体（LAMP 2）标记物的富集，表明自噬体-溶酶体融合的功能阻滞和蛋白酶体蛋白降解机制的过载。在体外，PRR敲除和空泡H+-ATP酶的药理学阻断，与PRR相关，增加囊泡pH，导致LC 3阳性和LAMP 2阳性囊泡的积累，并改变细胞骨架。总之，这些结果表明，PRR是必不可少的足细胞的功能和生存，通过维持自噬和蛋白质周转机制。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。
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.