Universität zu Köln

Dumont, Vincent ORCID: 0000-0002-2893-5479, Tolvanen, Tuomas A., Kuusela, Sara, Wang, Hong ORCID: 0000-0001-5700-6786, Nyman, Tuula A., Lindfors, Sonja, Tienari, Jukka, Nisen, Harry, Suetsugu, Shiro ORCID: 0000-0002-4612-0628, Plomann, Markus, Kawachi, Hiroshi and Lehtonen, Sanna ORCID: 0000-0003-4189-2415 (2017). PACSIN2 accelerates nephrin trafficking and is up-regulated in diabetic kidney disease. Faseb J., 31 (9). S. 3978 - 3991. BETHESDA: FEDERATION AMER SOC EXP BIOL. ISSN 1530-6860

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Dumont, Vincent UNSPECIFIED orcid.org/0000-0002-2893-5479 UNSPECIFIED Tolvanen, Tuomas A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kuusela, Sara UNSPECIFIED UNSPECIFIED UNSPECIFIED Wang, Hong UNSPECIFIED orcid.org/0000-0001-5700-6786 UNSPECIFIED Nyman, Tuula A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lindfors, Sonja UNSPECIFIED UNSPECIFIED UNSPECIFIED Tienari, Jukka UNSPECIFIED UNSPECIFIED UNSPECIFIED Nisen, Harry UNSPECIFIED UNSPECIFIED UNSPECIFIED Suetsugu, Shiro UNSPECIFIED orcid.org/0000-0002-4612-0628 UNSPECIFIED Plomann, Markus UNSPECIFIED UNSPECIFIED UNSPECIFIED Kawachi, Hiroshi UNSPECIFIED UNSPECIFIED UNSPECIFIED Lehtonen, Sanna UNSPECIFIED orcid.org/0000-0003-4189-2415 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-220710
DOI:	10.1096/fj.201601265R
Journal or Publication Title:	Faseb J.
Volume:	31
Number:	9
Page Range:	S. 3978 - 3991
Date:	2017
Publisher:	FEDERATION AMER SOC EXP BIOL
Place of Publication:	BETHESDA
ISSN:	1530-6860
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SLIT DIAPHRAGM; MEMBRANE-TRAFFICKING; FATTY-ACIDS; PROTEIN; NEPHROPATHY; PODOCYTES; COMPLEX; INJURY; GENE; ORGANIZATION Multiple languages Biochemistry & Molecular Biology; Biology; Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/22071