Prorenin receptor is essential for podocyte autophagy and survival.
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.
Nikolaus-Fiebiger-Center for Molecular Medicine, Glückstrasse 6, 91054 Erlangen, Germany.
Fabian
F
Riediger
Ivo
I
Quack
Fatimunnisa
F
Qadri
Björn
B
Hartleben
Joon-Keun
JK
Park
Sebastian A
SA
Potthoff
Dennis
D
Sohn
Gabin
G
Sihn
Anthony
A
Rousselle
Verena
V
Fokuhl
Ulrike
U
Maschke
Bettina
B
Purfürst
Wolfgang
W
Schneider
Lars C
LC
Rump
Friedrich C
FC
Luft
Ralf
R
Dechend
Michael
M
Bader
Tobias B
TB
Huber
Genevieve
G
Nguyen
Dominik N
DN
Muller
D000818:Animals; D001343:Autophagy / Q000502:physiology*; D002470:Cell Survival; D005260:Female; D051379:Mice; D050199:Podocytes / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000502:physiology*; D000093342:Prorenin Receptor
D011956:Receptors, Cell Surface; D000093342:Prorenin Receptor