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

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.

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Melanocortin therapy ameliorates podocytopathy and proteinuria in experimental focal segmental glomerulosclerosis involving a podocyte specific non-MC1R-mediated melanocortinergic signaling

Clinical Science ◽

10.1042/cs20200016 ◽

2020 ◽

Vol 134 (7) ◽

pp. 695-710

Author(s):

Yingjin Qiao ◽

Pei Wang ◽

Mingyang Chang ◽

Bohan Chen ◽

Yan Ge ◽

...

Keyword(s):

Beneficial Effect ◽

Focal Segmental Glomerulosclerosis ◽

De Novo ◽

Protective Action ◽

Clinical Effectiveness ◽

Podocyte Injury ◽

Segmental Glomerulosclerosis ◽

Foot Process

Abstract The clinical effectiveness of adrenocorticotropin in inducing remission of steroid-resistant nephrotic syndrome points to a steroidogenic-independent anti-proteinuric activity of melanocortins. However, which melanocortin receptors (MCR) convey this beneficial effect and if systemic or podocyte-specific mechanisms are involved remain uncertain. In vivo, wild-type (WT) mice developed heavy proteinuria and kidney dysfunction following Adriamycin insult, concomitant with focal segmental glomerulosclerosis (FSGS) and podocytopathy, marked by loss of podocin and synaptopodin, podocytopenia and extensive foot process effacement on electron microscopy. All these pathologic findings were prominently attenuated by NDP-MSH, a potent non-steroidogenic pan-MCR agonist. Surprisingly, MC1R deficiency in MC1R-null mice barely affected the severity of Adriamycin-elicited injury. Moreover, the beneficial effect of NDP-MSH was completely preserved in MC1R-null mice, suggesting that MC1R is likely non-essential for the protective action. A direct podocyte effect seems to contribute to the beneficial effect of NDP-MSH, because Adriamycin-inflicted cytopathic signs in primary podocytes prepared from WT mice were all mitigated by NDP-MSH, including apoptosis, loss of podocyte markers, de novo expression of the podocyte injury marker desmin, actin cytoskeleton derangement and podocyte hypermotility. Consistent with in vivo findings, the podoprotective activity of NDP-MSH was fully preserved in MC1R-null podocytes. Mechanistically, MC1R expression was predominantly distributed to glomerular endothelial cells in glomeruli but negligibly noted in podocytes in vivo and in vitro, suggesting that MC1R signaling is unlikely involved in direct podocyte protection. Ergo, melanocortin therapy protects against podocyte injury and ameliorates proteinuria and glomerulopathy in experimental FSGS, at least in part, via a podocyte-specific non-MC1R-mediated melanocortinergic signaling.

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Faculty Opinions recommendation of Janus kinase 2/signal transducer and activator of transcription 3 inhibitors attenuate the effect of cardiotrophin-like cytokine factor 1 and human focal segmental glomerulosclerosis serum on glomerular filtration barrier.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725428053.793530397 ◽

2017 ◽

Author(s):

Jochen Reiser

Keyword(s):

Glomerular Filtration ◽

Focal Segmental Glomerulosclerosis ◽

Janus Kinase ◽

Signal Transducer ◽

Janus Kinase 2 ◽

Glomerular Filtration Barrier ◽

Filtration Barrier ◽

Segmental Glomerulosclerosis ◽

Transcription 3

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Novel diagnostic and therapeutic techniques reveal changed metabolic profiles in recurrent focal segmental glomerulosclerosis

Scientific Reports ◽

10.1038/s41598-021-83883-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Janina Müller-Deile ◽

George Sarau ◽

Ahmed M. Kotb ◽

Christian Jaremenko ◽

Ulrike E. Rolle-Kampczyk ◽

...

Keyword(s):

Kidney Transplantation ◽

Raman Spectra ◽

Focal Segmental Glomerulosclerosis ◽

Disease Recurrence ◽

Early Recurrence ◽

Metabolome Analysis ◽

Novel Technologies ◽

Filtration Barrier ◽

Segmental Glomerulosclerosis ◽

Living Related

AbstractIdiopathic forms of Focal Segmental Glomerulosclerosis (FSGS) are caused by circulating permeability factors, which can lead to early recurrence of FSGS and kidney failure after kidney transplantation. In the past three decades, many research endeavors were undertaken to identify these unknown factors. Even though some potential candidates have been recently discussed in the literature, “the” actual factor remains elusive. Therefore, there is an increased demand in FSGS research for the use of novel technologies that allow us to study FSGS from a yet unexplored angle. Here, we report the successful treatment of recurrent FSGS in a patient after living-related kidney transplantation by removal of circulating factors with CytoSorb apheresis. Interestingly, the classical published circulating factors were all in normal range in this patient but early disease recurrence in the transplant kidney and immediate response to CytoSorb apheresis were still suggestive for pathogenic circulating factors. To proof the functional effects of the patient’s serum on podocytes and the glomerular filtration barrier we used a podocyte cell culture model and a proteinuria model in zebrafish to detect pathogenic effects on the podocytes actin cytoskeleton inducing a functional phenotype and podocyte effacement. We then performed Raman spectroscopy in the < 50 kDa serum fraction, on cultured podocytes treated with the FSGS serum and in kidney biopsies of the same patient at the time of transplantation and at the time of disease recurrence. The analysis revealed changes in podocyte metabolome induced by the FSGS serum as well as in focal glomerular and parietal epithelial cell regions in the FSGS biopsy. Several altered Raman spectra were identified in the fractionated serum and metabolome analysis by mass spectrometry detected lipid profiles in the FSGS serum, which were supported by disturbances in the Raman spectra. Our novel innovative analysis reveals changed lipid metabolome profiles associated with idiopathic FSGS that might reflect a new subtype of the disease.

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Mechanical challenges and cytoskeletal impairments in focal segmental glomerulosclerosis

AJP Renal Physiology ◽

10.1152/ajprenal.00641.2017 ◽

2018 ◽

Vol 314 (5) ◽

pp. F921-F925 ◽

Cited By ~ 5

Author(s):

Di Feng ◽

Clark DuMontier ◽

Martin R. Pollak

Keyword(s):

Blood Flow ◽

Focal Segmental Glomerulosclerosis ◽

Kidney Injury ◽

Future Research ◽

Disease States ◽

Filtration Barrier ◽

Segmental Glomerulosclerosis ◽

The Face ◽

Foot Process ◽

Future Research Directions

Focal segmental glomerulosclerosis (FSGS) is a histologically defined form of kidney injury typically mediated by podocyte dysfunction. Podocytes rely on their intricate actin-based cytoskeleton to maintain the glomerular filtration barrier in the face of mechanical challenges resulting from pulsatile blood flow and filtration of this blood flow. This review summarizes the mechanical challenges faced by podocytes in the form of stretch and shear stress, both of which may play a role in the progression of podocyte dysfunction and detachment. It also reviews how podocytes respond to these mechanical challenges in dynamic fashion through rearranging their cytoskeleton, triggering various biochemical pathways, and, in some disease states, altering their morphology in the form of foot process effacement. Furthermore, this review highlights the growing body of evidence identifying several mutations of important cytoskeleton proteins as causes of FSGS. Lastly, it synthesizes the above evidence to show that a better understanding of how these mutations leave podocytes vulnerable to the mechanical challenges they face is essential to better understanding the mechanisms by which they lead to disease. The review concludes with future research directions to fill this gap and some novel techniques with which to pursue these directions.

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The long noncoding RNA LOC105374325 causes podocyte injury in individuals with focal segmental glomerulosclerosis

Journal of Biological Chemistry ◽

10.1074/jbc.ra118.005579 ◽

2018 ◽

Vol 293 (52) ◽

pp. 20227-20239 ◽

Cited By ~ 8

Author(s):

Shuai Hu ◽

Runhong Han ◽

Jingsong Shi ◽

Xiaodong Zhu ◽

Weisong Qin ◽

...

Keyword(s):

Focal Segmental Glomerulosclerosis ◽

Long Noncoding Rna ◽

Noncoding Rna ◽

Podocyte Injury ◽

Segmental Glomerulosclerosis

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De Novo Focal Segmental Glomerulosclerosis

Diagnostic Pathology: Kidney Diseases ◽

10.1016/b978-0-323-37707-2.50238-x ◽

2016 ◽

pp. 988-989

Keyword(s):

Focal Segmental Glomerulosclerosis ◽

De Novo ◽

Segmental Glomerulosclerosis

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Focal segmental glomerulosclerosis and mild intellectual disability in a patient with a novel de novo truncating TRIM8 mutation

European Journal of Medical Genetics ◽

10.1016/j.ejmg.2020.103972 ◽

2020 ◽

Vol 63 (9) ◽

pp. 103972

Author(s):

Martin A. McClatchey ◽

Zachary D. du Toit ◽

Rhys Vaughan ◽

Sharon D. Whatley ◽

Sara Martins ◽

...

Keyword(s):

Intellectual Disability ◽

Focal Segmental Glomerulosclerosis ◽

De Novo ◽

Mild Intellectual Disability ◽

Segmental Glomerulosclerosis

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Progesterone reduces the migration of mast cells toward the chemokine stromal cell-derived factor-1/CXCL12 with an accompanying decrease in CXCR4 receptors

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00286.2006 ◽

2007 ◽

Vol 292 (5) ◽

pp. E1410-E1417 ◽

Cited By ~ 15

Author(s):

Marie-Pierre Belot ◽

Latifa Abdennebi-Najar ◽

Françoise Gaudin ◽

Michèle Lieberherr ◽

Véronique Godot ◽

...

Keyword(s):

Mast Cell ◽

Cell Migration ◽

Mast Cells ◽

Vitro Assay ◽

Akt Phosphorylation ◽

Cxcr4 Mrna ◽

Microenvironmental Factors ◽

Membrane Bound ◽

Stromal Cell Derived Factor

Mast cell recruitment is implicated in many physiological functions and several diseases. It depends on microenvironmental factors, including hormones. We have investigated the effect of progesterone on the migration of HMC-1560 mast cells toward CXCL12, a chemokine that controls the migration of mast cells into tissues. HMC-1560 mast cells were incubated with 1 nM to 1 μM progesterone for 24 h. Controls were run without progesterone. Cell migration toward CXCL12 was monitored with an in vitro assay, and statistical analysis of repeated experiments revealed that progesterone significantly reduced cell migration without increasing the number of apoptotic cells ( P = 0.0084, n = 7). Differences between progesterone-treated and untreated cells were significant at 1 μM ( P < 0.01, n = 7). Cells incubated with 1 μM progesterone showed no rearrangment of actin filaments in response to CXCL12. Progesterone also reduced the calcium response to CXCL12 and Akt phosphorylation. Cells incubated with progesterone had one-half the control concentrations of CXCR4 (mRNA, total protein, and membrane-bound protein). Progesterone also inhibited the migration of HMC-1560 cells transfected with hPR-B-pSG5 plasmid, which contained 2.5 times as much PR-B as the control. These transfected cells responded differently ( P < 0.05, n = 5) from untreated cells to 1 nM progesterone. We conclude that progesterone reduces mast cell migration toward CXCL12 and that CXCR4 may be a progesterone target in mast cells.

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