Prorenin receptor is essential for podocyte autophagy and survival
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Prorenin receptor is essential for podocyte autophagy and survival. / Riediger, Fabian; Quack, Ivo; Qadri, Fatimunnisa; Hartleben, Björn; Park, Joon-Keun; Potthoff, Sebastian A; Sohn, Dennis; Sihn, Gabin; Rousselle, Anthony; Fokuhl, Verena; Maschke, Ulrike; Purfürst, Bettina; Schneider, Wolfgang; Rump, Lars C; Luft, Friedrich C; Dechend, Ralf; Bader, Michael; Huber, Tobias B; Nguyen, Genevieve; Muller, Dominik N.
in: J AM SOC NEPHROL, Jahrgang 22, Nr. 12, 12.2011, S. 2193-202.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Prorenin receptor is essential for podocyte autophagy and survival
AU - Riediger, Fabian
AU - Quack, Ivo
AU - Qadri, Fatimunnisa
AU - Hartleben, Björn
AU - Park, Joon-Keun
AU - Potthoff, Sebastian A
AU - Sohn, Dennis
AU - Sihn, Gabin
AU - Rousselle, Anthony
AU - Fokuhl, Verena
AU - Maschke, Ulrike
AU - Purfürst, Bettina
AU - Schneider, Wolfgang
AU - Rump, Lars C
AU - Luft, Friedrich C
AU - Dechend, Ralf
AU - Bader, Michael
AU - Huber, Tobias B
AU - Nguyen, Genevieve
AU - Muller, Dominik N
PY - 2011/12
Y1 - 2011/12
N2 - 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.
AB - 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.
KW - Animals
KW - Autophagy
KW - Cell Survival
KW - Female
KW - Mice
KW - Podocytes
KW - Receptors, Cell Surface
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1681/ASN.2011020200
DO - 10.1681/ASN.2011020200
M3 - SCORING: Journal article
C2 - 22034640
VL - 22
SP - 2193
EP - 2202
JO - J AM SOC NEPHROL
JF - J AM SOC NEPHROL
SN - 1046-6673
IS - 12
ER -
