Abstract
CD40/CD40 ligand (CD40L) dyad, a co-stimulatory bi-molecular complex involved in the adaptive immune response, has also potent pro-inflammatory actions in haematopoietic and non-haematopoietic cells. We describe here a novel role for soluble CD40L (sCD40L) as modifier of glomerular permselectivity directly acting on glomerular epithelial cells (GECs). We found that stimulation of CD40, constitutively expressed on GEC cell membrane, by the sCD40L rapidly induced redistribution and loss of nephrin in GECs, and increased albumin permeability in isolated rat glomeruli. Pre-treatment with inhibitors of CD40-CD40L interaction completely prevented these effects. Furthermore, in vivo injection of sCD40L induced a significant reduction of nephrin and podocin expression in mouse glomeruli, although no significant increase of urine protein/creatinine ratio was observed after in vivo injection. The same effects were induced by plasma factors partially purified from post-transplant plasma exchange eluates of patients with focal segmental glomerulosclerosis (FSGS), and were blocked by CD40-CD40L inhibitors. Moreover, 17 and 34 kDa sCD40L isoforms were detected in the same plasmapheresis eluates by Western blotting. Finally, the levels of sCD40Lwere significantly increased in serum of children both with steroid-sensitive and steroid-resistant nephrotic syndrome (NS), and in adult patients with biopsy-proven FSGS, compared to healthy subjects, but neither in children with congenital NS nor in patients with membranous nephropathy.Our results demonstrate that sCD40L directly modifies nephrin and podocin distribution in GECs. Moreover, they suggest that sCD40L contained in plasmapheresis eluates from FSGS patients with post-transplant recurrence may contribute, presumably cooperating with other mediators, to FSGS pathogenesis by modulating glomerular permeability.
Highlights
The CD40/CD40 ligand (CD40L) dyad, a bi-molecular component of the tumor necrosis factor (TNF) gene superfamily, plays a critical role in the adaptive immune response [1,2,3,4]
CD40 expression by glomerular epithelial cells (GECs)/podocytes has been recently shown by several research groups [9, 14,15,16,17], little is known on its physiologic function in this cell-type, and on its involvement in the pathogenesis of podocytopathies, a distinct group of diseases characterized by a functional modification of renal permselectivity, with proteinuria and nephrotic syndrome as clinical hallmarks, and minimal or focal segmental glomerulosclerosis lesions (MCN or FSGS, respectively) as their pathology backgrounds
In cultured podocytes, the effect of CD40 stimulation by human recombinant soluble form of CD40L (sCD40L) on nephrin expression and cytoskeleton organization, phenomena that had been observed to be induced by other well-known proteinuric agents [35, 39]. sCD40L induced a significant reduction of nephrin expression on podocyte cell membrane (Fig 2, panels B and D), evident after only 15 minutes (Fig 2D, lower graph)
Summary
The CD40/CD40 ligand (CD40L) dyad, a bi-molecular component of the tumor necrosis factor (TNF) gene superfamily, plays a critical role in the adaptive immune response [1,2,3,4] Both molecules have widespread distribution: CD40L is preferentially expressed on activated CD4+ T lymphocytes and platelets, and CD40 on B lymphocytes, monocytes/macrophages, and dendritic cells. Post-transplant recurrence of proteinuria occurs in almost 50% of FSGS patients receiving a renal graft with a kinetic of proteinuria (frequently occurring within few minutes from transplant) that recalls the existence of a circulating plasmatic permeability factor This is an area of intense research that has produced so far inconsistent results [18,19,20,21,22,23,24,25,26,27,28,29]
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