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Abstract
Podoplanin (PDPN) is intensely expressed on the podocyte membrane in an evolutionally conserved manner. CLEC-2, the endogenous ligand of PDPN, is highly expressed in platelets and also exists in a soluble form in plasma. Normally, podocytes are sequestered from CLEC-2, but when the glomerular barrier is injured, podocytes gain access to CLEC-2. We tested the effects of CLEC-2 in podocytes in vitro and in vivo. Cultured podocytes treated with Fc-CLEC-2 demonstrated that CLEC-2 induced the dephosphorylation of ezrin, radixin, and moesin (ERM) proteins. Podocytes treated with Fc-CLEC-2 also showed the dissociation of F-actin filaments from PDPN, F-actin degradation, detachment, and round morphology. Next, we perfused normal mouse kidney in vivo with FLAG-CLEC-2. CLEC-2 induced dephosphorylation of ERM and widening of the foot processes of podocytes. Platelets were detected by immunostaining for CD41 in the urine of mice with podocyte injury, indicating that podocytes can encounter platelets when glomeruli are injured. Collectively, these observations suggest that when platelets leak through the injured glomeruli, CLEC-2 from the platelets acts on PDPN in podocytes and induces morphological change and detachment, which may further aggravate podocyte injury. Thus, PDPN on podocytes may work as a leaked-platelet sensor.
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1 Tokai University School of Medicine, Departments of Basic Medicine, Isehara, Japan (GRID:grid.265061.6) (ISNI:0000 0001 1516 6626); Okayama University Hospital, Division of Kidney, Diabetes and Endocrine Diseases, Okayama, Japan (GRID:grid.412342.2) (ISNI:0000 0004 0631 9477)
2 Tokai University School of Medicine, Molecular Life Science, Isehara, Japan (GRID:grid.265061.6) (ISNI:0000 0001 1516 6626)
3 Tokai University School of Medicine, Emergency and Critical Care Medicine, Isehara, Japan (GRID:grid.265061.6) (ISNI:0000 0001 1516 6626)
4 Tokai University School of Medicine, Support Center for Medical Research and Education, Isehara, Japan (GRID:grid.265061.6) (ISNI:0000 0001 1516 6626)
5 National Cancer Institute, NIH, Laboratory of Molecular Biology, Center for Cancer Research, Bethesda, USA (GRID:grid.48336.3a) (ISNI:0000 0004 1936 8075)
6 Tokai University School of Medicine, Internal Medicine, Isehara, Japan (GRID:grid.265061.6) (ISNI:0000 0001 1516 6626)
7 Tokai University School of Medicine, Departments of Basic Medicine, Isehara, Japan (GRID:grid.265061.6) (ISNI:0000 0001 1516 6626)