Biphasic MIF and SDF1 expression during podocyte injury promote CD44-mediated glomerular parietal cell migration in focal segmental glomerulosclerosis

Abstract

Glomerular parietal epithelial cell (PEC) activation, as revealed by de novo expression of CD44 and cell migration toward the injured filtration barrier, is a hallmark of podocyte injury-driven focal segmental glomerulosclerosis (FSGS). However, the signaling pathway that mediates activation of PECs in response to podocyte injury is unknown. The present study focused on CD44 signaling, particularly the roles of two CD44-related chemokines, migration inhibitory factor (MIF) and stromal cell-derived factor 1 (SDF1), and their common receptor, chemokine (C-X-C motif) receptor 4 (CXCR4), in the NEP25/LMB2 mouse podocyte-toxin model of FSGS. In the early phase of the disease, CD44-positive PECs were locally evident on the opposite side of the intact glomerular tuft and subsequently increased in the vicinity of synechiae with podocyte loss. Expression of MIF and SDF1 was first increased in injured podocytes and subsequently transferred to activated PECs expressing CD44 and CXCR4. In an immortalized mouse PEC (mPEC) line, recombinant MIF and SDF1 (rMIF and rSDF1, respectively) individually increased CD44 and CXCR4 mRNA and protein levels. rMIF and rSDF1 stimulated endogenous MIF and SDF1 production. rMIF- and rSDF1-induced mPEC migration was suppressed by CD44 siRNA. However, MIF and SDF1 inhibitors failed to show any impact on proteinuria, podocyte number, and CD44 expression in NEP25/LMB2 mice. Our data suggest that injured podocytes upregulate MIF and SDF1 that stimulate CD44 expression and CD44-mediated migration, which is enhanced by endogenous MIF and SDF1 in PECs. This biphasic expression pattern of the chemokine-CD44 axis in podocytes and PECs may be a novel mechanism of “podocyte-PEC cross-talk” signaling underlying podocyte injury-driven FSGS.

The Pathology Lesion Patterns of Podocytopathies: How and why?

“…Consequently, the capillary loop may bulge toward the Bowman capsule and an early connection, tuft adhesion, forms between PECs and the uncovered glomerular basement membrane or between podocytes and PECs ( Löwen et al, 2021 ). As a response, PECs become focally activated, de novo express the specific markers CD9 and CD44 ( Okamoto et al, 2013 ; Lazareth et al, 2019 ; Ito et al, 2020 ), migrate to a visceral location and deposit matrix. Interestingly, the CD44 marker is scarcely expressed by PECs in human MC lesion and may represent a useful marker to distinguish the MC and FSGS lesions in human biopsies ( Smeets et al, 2014 ; Kuppe et al, 2015 ).…”

Bidirectional, non-necrotizing glomerular crescents are the critical pathology in X-linked Alport syndrome mouse model harboring nonsense mutation of human COL4A5

“…Instead, podocytes tended to invaginate their processes deeply into the thickened GBM, and are thus likely to resist detachment, as has been suggested in other models of podocyte injury 34,35 . Because injured podocyte synthesized chemokines which stimulated PEC activation via CXCR4 36 , podocyte injury in this model may also be involved in the crescentic formation, even without detachment. Thus, glomerular crescents produced by disruption of two functional barriers, but not FSGS caused by podocyte depletion, is the primary pathogenesis promoting kidney disease in our model.…”

CD44 impacts glomerular parietal epithelial cell changes in the aged mouse kidney

“…Fourth, aging in mice under controlled laboratory conditions are different to human aging. Finally, the mechanisms of glomerular scarring are likely multi-factorial, that might include the changes to PECs being secondary to other factors such as reduced podocyte number and increased single nephron glomerular filtration rate (Denic et al, 2017), and cross talk from podocytes to PECs as recently described by Ito, Sakamoto, Hikichi, Matsusaka, & Nagata (2020).…”