PACSIN2 accelerates nephrin trafficking and is up-regulated in diabetic kidney disease.
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.-Dumont, V., Tolvanen, T. A., Kuusela, S., Wang, H., Nyman, T. A., Lindfors, S., Tienari, J., Nisen, H., Suetsugu, S., Plomann, M., Kawachi, H., Lehtonen, S. PACSIN2 accelerates nephrin trafficking and is up-regulated in diabetic kidney disease.
['Dumont|Vincent|V|', 'Tolvanen|Tuomas A|TA|', 'Kuusela|Sara|S|', 'Wang|Hong|H|', 'Nyman|Tuula A|TA|', 'Lindfors|Sonja|S|', 'Tienari|Jukka|J|', 'Nisen|Harry|H|', 'Suetsugu|Shiro|S|', 'Plomann|Markus|M|', 'Kawachi|Hiroshi|H|', 'Lehtonen|Sanna|S|']
D048868:Adaptor Proteins, Signal Transducing D000818:Animals D002352:Carrier Proteins D003598:Cytoskeletal Proteins D003920:Diabetes Mellitus D003928:Diabetic Nephropathies D005786:Gene Expression Regulation D006801:Humans D008565:Membrane Proteins D051379:Mice D009765:Obesity D050199:Podocytes D021381:Protein Transport D011506:Proteins D011924:Rats, Zucker D015854:Up-Regulation D033921:Vesicular Transport Proteins
podocyte endocytosis recycling rabenosyn-5 palmitate