PACSIN2 accelerates nephrin trafficking and is up-regulated in diabetic kidney disease

Vincent Dumont, Tuomas A. Tolvanen, Sara Kuusela, Hong Wang, Tuula A. Nyman, Sonja Lindfors, Jukka Tienari, Harry Nisén, Shiro Suetsugu, Markus Plomann, Hiroshi Kawachi, Sanna Lehtonen

Research output: Contribution to journalArticleScientificpeer-review

Abstract

Nephrin is a core component of podocyte (glomerular epithelial cell) slit diaphragm and is required for kidney ultrafiltration. Down-regulation or mislocalization of nephrin has been observed in diabetic kidney disease (DKD), characterized by albuminuria. Here, we investigate the role of protein kinase C and casein kinase 2 substrate in neurons 2 (PACSIN2), a regulator of endocytosis and recycling, in the trafficking of nephrin and development of DKD. We observe that PACSIN2 is up-regulated and nephrin mislocalized in podocytes of obese Zucker Diabetic Fatty (ZDF) rats that have altered renal function. In cultured podocytes, PACSIN2 and nephrin colocalize and interact. We show that nephrin is endocytosed in PACSIN2-positive membrane regions and that PACSIN2 overexpression increases both nephrin endocytosis and recycling. We identify rabenosyn-5, which is involved in early endosome maturation and endosomal sorting, as a novel interaction partner of PACSIN2. Interestingly, rabenosyn-5 expression is increased in podocytes in obese ZDF rats, and, in vitro, its overexpression enhances the association of PACSIN2 and nephrin. We also show that palmitate, which is elevated in diabetes, enhances this association. Collectively, PACSIN2 is up-regulated and nephrin is abnormally localized in podocytes of diabetic ZDF rats. In vitro, PACSIN2 enhances nephrin turnover apparently via a mechanism involving rabenosyn-5. The data suggest that elevated PACSIN2 expression accelerates nephrin trafficking and associates with albuminuria.
Original languageEnglish
JournalFASEB Journal
Volume31
Number of pages18
ISSN0892-6638
DOIs
Publication statusPublished - Sep 2017
MoE publication typeA1 Journal article-refereed

Fields of Science

  • 3111 Biomedicine
  • 1182 Biochemistry, cell and molecular biology

Cite this

Dumont, Vincent ; Tolvanen, Tuomas A. ; Kuusela, Sara ; Wang, Hong ; Nyman, Tuula A. ; Lindfors, Sonja ; Tienari, Jukka ; Nisén, Harry ; Suetsugu, Shiro ; Plomann, Markus ; Kawachi, Hiroshi ; Lehtonen, Sanna. / PACSIN2 accelerates nephrin trafficking and is up-regulated in diabetic kidney disease. In: FASEB Journal. 2017 ; Vol. 31.
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abstract = "Nephrin is a core component of podocyte (glomerular epithelial cell) slit diaphragm and is required for kidney ultrafiltration. Down-regulation or mislocalization of nephrin has been observed in diabetic kidney disease (DKD), characterized by albuminuria. Here, we investigate the role of protein kinase C and casein kinase 2 substrate in neurons 2 (PACSIN2), a regulator of endocytosis and recycling, in the trafficking of nephrin and development of DKD. We observe that PACSIN2 is up-regulated and nephrin mislocalized in podocytes of obese Zucker Diabetic Fatty (ZDF) rats that have altered renal function. In cultured podocytes, PACSIN2 and nephrin colocalize and interact. We show that nephrin is endocytosed in PACSIN2-positive membrane regions and that PACSIN2 overexpression increases both nephrin endocytosis and recycling. We identify rabenosyn-5, which is involved in early endosome maturation and endosomal sorting, as a novel interaction partner of PACSIN2. Interestingly, rabenosyn-5 expression is increased in podocytes in obese ZDF rats, and, in vitro, its overexpression enhances the association of PACSIN2 and nephrin. We also show that palmitate, which is elevated in diabetes, enhances this association. Collectively, PACSIN2 is up-regulated and nephrin is abnormally localized in podocytes of diabetic ZDF rats. In vitro, PACSIN2 enhances nephrin turnover apparently via a mechanism involving rabenosyn-5. The data suggest that elevated PACSIN2 expression accelerates nephrin trafficking and associates with albuminuria.",
keywords = "3111 Biomedicine, 1182 Biochemistry, cell and molecular biology",
author = "Vincent Dumont and Tolvanen, {Tuomas A.} and Sara Kuusela and Hong Wang and Nyman, {Tuula A.} and Sonja Lindfors and Jukka Tienari and Harry Nis{\'e}n and Shiro Suetsugu and Markus Plomann and Hiroshi Kawachi and Sanna Lehtonen",
year = "2017",
month = "9",
doi = "10.1096/fj.201601265R",
language = "English",
volume = "31",
journal = "FASEB Journal",
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PACSIN2 accelerates nephrin trafficking and is up-regulated in diabetic kidney disease. / Dumont, Vincent; Tolvanen, Tuomas A.; Kuusela, Sara; Wang, Hong; Nyman, Tuula A.; Lindfors, Sonja; Tienari, Jukka; Nisén, Harry; Suetsugu, Shiro; Plomann, Markus; Kawachi, Hiroshi; Lehtonen, Sanna.

In: FASEB Journal, Vol. 31, 09.2017.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - PACSIN2 accelerates nephrin trafficking and is up-regulated in diabetic kidney disease

AU - Dumont, Vincent

AU - Tolvanen, Tuomas A.

AU - Kuusela, Sara

AU - Wang, Hong

AU - Nyman, Tuula A.

AU - Lindfors, Sonja

AU - Tienari, Jukka

AU - Nisén, Harry

AU - Suetsugu, Shiro

AU - Plomann, Markus

AU - Kawachi, Hiroshi

AU - Lehtonen, Sanna

PY - 2017/9

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N2 - Nephrin is a core component of podocyte (glomerular epithelial cell) slit diaphragm and is required for kidney ultrafiltration. Down-regulation or mislocalization of nephrin has been observed in diabetic kidney disease (DKD), characterized by albuminuria. Here, we investigate the role of protein kinase C and casein kinase 2 substrate in neurons 2 (PACSIN2), a regulator of endocytosis and recycling, in the trafficking of nephrin and development of DKD. We observe that PACSIN2 is up-regulated and nephrin mislocalized in podocytes of obese Zucker Diabetic Fatty (ZDF) rats that have altered renal function. In cultured podocytes, PACSIN2 and nephrin colocalize and interact. We show that nephrin is endocytosed in PACSIN2-positive membrane regions and that PACSIN2 overexpression increases both nephrin endocytosis and recycling. We identify rabenosyn-5, which is involved in early endosome maturation and endosomal sorting, as a novel interaction partner of PACSIN2. Interestingly, rabenosyn-5 expression is increased in podocytes in obese ZDF rats, and, in vitro, its overexpression enhances the association of PACSIN2 and nephrin. We also show that palmitate, which is elevated in diabetes, enhances this association. Collectively, PACSIN2 is up-regulated and nephrin is abnormally localized in podocytes of diabetic ZDF rats. In vitro, PACSIN2 enhances nephrin turnover apparently via a mechanism involving rabenosyn-5. The data suggest that elevated PACSIN2 expression accelerates nephrin trafficking and associates with albuminuria.

AB - Nephrin is a core component of podocyte (glomerular epithelial cell) slit diaphragm and is required for kidney ultrafiltration. Down-regulation or mislocalization of nephrin has been observed in diabetic kidney disease (DKD), characterized by albuminuria. Here, we investigate the role of protein kinase C and casein kinase 2 substrate in neurons 2 (PACSIN2), a regulator of endocytosis and recycling, in the trafficking of nephrin and development of DKD. We observe that PACSIN2 is up-regulated and nephrin mislocalized in podocytes of obese Zucker Diabetic Fatty (ZDF) rats that have altered renal function. In cultured podocytes, PACSIN2 and nephrin colocalize and interact. We show that nephrin is endocytosed in PACSIN2-positive membrane regions and that PACSIN2 overexpression increases both nephrin endocytosis and recycling. We identify rabenosyn-5, which is involved in early endosome maturation and endosomal sorting, as a novel interaction partner of PACSIN2. Interestingly, rabenosyn-5 expression is increased in podocytes in obese ZDF rats, and, in vitro, its overexpression enhances the association of PACSIN2 and nephrin. We also show that palmitate, which is elevated in diabetes, enhances this association. Collectively, PACSIN2 is up-regulated and nephrin is abnormally localized in podocytes of diabetic ZDF rats. In vitro, PACSIN2 enhances nephrin turnover apparently via a mechanism involving rabenosyn-5. The data suggest that elevated PACSIN2 expression accelerates nephrin trafficking and associates with albuminuria.

KW - 3111 Biomedicine

KW - 1182 Biochemistry, cell and molecular biology

U2 - 10.1096/fj.201601265R

DO - 10.1096/fj.201601265R

M3 - Article

VL - 31

JO - FASEB Journal

JF - FASEB Journal

SN - 0892-6638

ER -