We investigated the role of the PRR in the maintenance of podocyte function. Generation of podocyte-specific PRR knockout mice (cKO) with the help of cre-loxP technique and phenotypical analyses. Generation of podocyte-specific PRR knockout mice (cKO) resulted in death of the animals between 2–3 weeks after birth. Within 14 days, cKO 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. The findings indicated a functional block in autophagosome-lysosome fusion and overload of the proteasome protein degradation machinery, as supported by p62 accumulation. In vitro PRR knockdown and pharmacological v-ATPase activity blockade increased vesicular pH with accumulation of LC3-positive and LAMP2-positive vesicles and altered cytoskeleton. Our findings suggest that the PRR is essential for podocyte function and survival by maintaining autophagy and protein turnover machinery. PRR plays a pivotal role in lysosomal pH control, which is important for podocyte survival and cytoskeletal integrity.