Albumin-associated free fatty acids induce macropinocytosis in podocytes.
Podocytes are specialized epithelial cells in the kidney glomerulus that play important structural and functional roles in maintaining the filtration barrier. Nephrotic syndrome results from a breakdown of the kidney filtration barrier and is associated with proteinuria, hyperlipidemia, and edema. Additionally, podocytes undergo changes in morphology and internalize plasma proteins in response to this disorder. Here, we used fluid-phase tracers in murine models and determined that podocytes actively internalize fluid from the plasma and that the rate of internalization is increased when the filtration barrier is disrupted. In cultured podocytes, the presence of free fatty acids (FFAs) associated with serum albumin stimulated macropinocytosis through a pathway that involves FFA receptors, the Gβ/Gγ complex, and RAC1. Moreover, mice with elevated levels of plasma FFAs as the result of a high-fat diet were more susceptible to Adriamycin-induced proteinuria than were animals on standard chow. Together, these results support a model in which podocytes sense the disruption of the filtration barrier via FFAs bound to albumin and respond by enhancing fluid-phase uptake. The response to FFAs may function in the development of nephrotic syndrome by amplifying the effects of proteinuria.
Jun-Jae
JJ
Chung
Tobias B
TB
Huber
Markus
M
Gödel
George
G
Jarad
Björn
B
Hartleben
Christopher
C
Kwoh
Alexander
A
Keil
Aleksey
A
Karpitskiy
Jiancheng
J
Hu
Christine J
CJ
Huh
Marina
M
Cella
Richard W
RW
Gross
Jeffrey H
JH
Miner
Andrey S
AS
Shaw
D000418:Albumins / Q000378:metabolism*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000494:pharmacology; D002461:Cell Line, Transformed; D004041:Dietary Fats / Q000009:adverse effects / Q000494:pharmacology; D004317:Doxorubicin / Q000009:adverse effects / Q000494:pharmacology; D005227:Fatty Acids / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009404:Nephrotic Syndrome / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D010873:Pinocytosis; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology; D011507:Proteinuria / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
D000418:Albumins; D000903:Antibiotics, Antineoplastic; D004041:Dietary Fats; D005227:Fatty Acids; D009479:Neuropeptides; C484602:Rac1 protein, mouse; D004317:Doxorubicin; D020830:rac1 GTP-Binding Protein