Podocyte-specific knockout of the neonatal Fc receptor (FcRn) results in differential protection depending on the model of glomerulonephritis

Abstract

Podocytes have been proposed to be antigen presenting cells (APCs). In traditional APCs, the neonatal Fc receptor (FcRn) is required for antigen presentation and global knockout of FcRn protects against glomerulonephritis. Since podocytes express FcRn, we sought to determine whether the absence of podocyte FcRn ameliorates immune-mediated disease. We examined MHCII and costimulatory markers expression in cultured wild type (WT) and FcRn knockout (KO) podocytes. Interferon gamma (IFNγ) induced MHCII expression in both WT and KO podocytes but did not change CD80 expression. Neither WT nor KO expressed CD86 or inducible costimulatory ligand (ICOSL) at baseline or with IFNγ. Using an antigen presentation assay, WT podocytes but not KO treated with immune complexes induced a modest increase in IL-2. Induction of the anti-glomerular basement membrane (anti-GBM) model resulted in a significant decrease in glomerular crescents in podocyte-specific FcRn knockout mouse (podFcRn KO) versus controls but the overall percentage of crescents was low. To examine the effects of the podocyte-specific FcRn knockout in a model with a longer autologous phase, we used the nephrotoxic serum nephritis (NTS) model. We found that the podFcRn KO mice had significantly reduced crescent formation and glomerulosclerosis compared to control mice. This study demonstrates that lack of podocyte FcRn is protective in immune mediated kidney disease that is dependent on an autologous phase. This study also highlights the difference between the anti-GBM model and NTS model of disease.

The therapeutic age of the neonatal Fc receptor

“…In mice immunized with the non-collagenous domain of the α3 chain of type IV collagen, subepithelial ICs caused glomerular pathology and proteinuria, and an FcRn-inhibitor peptide was able to effectively limit disease 164 . Podocyte-specific FcRn promoted glomerulosclerosis and glomerular crescents in a nephrotoxic serum nephritis model, whereas it did not affect disease in an acute anti-glomerular basement membrane nephritis model 165 . Serum from patients with lupus nephritis or transplant glomerulopathy 166 , but not from healthy donors, induced expression of calcium/calmodulin-dependent protein kinase 4 and CD86 in human podocytes in vitro, and this activation pathway was confirmed to cause lupus nephritis-associated damage and proteinuria in vivo 167 , 168 , in an FcRn-dependent manner.…”

Potential biomarkers of chronic kidney disease progression among kidney-derived proteins; a review

“…The role of FcRn provides a mechanistic link between B2M and albumin. FcRn expressed in the kidney (in podocytes, (4). Further investigations are required to confirm whether FcRn-mediated albumin absorption is a possible novel mechanism linking the activation of the renin-angiotensin system, oxidative stress, and the progression of kidney disease.…”

A Putative Role for TRPC6 in Immune-Mediated Kidney Injury

“…Immune cell infiltration I/R, UUO, PAN-induced nephrosis, DN [42][43][44][45][46] Tubulointerstitial inflammation DN, PAN-induced nephrosis, I/R [25,41,42,[114][115][116][117][118] Antigen presentation by podocytes I/R, DN [16,[119][120][121][122][123][124] ROS-induced overexpression of TRPC6 CKD [31,49,50,[125][126][127][128] Platelet hyperactivation and subsequent NOX-independent NET formation LN [69,70,[129][130][131][132][133][134][135][136][137] CKD; chronic kidney disease DN; diabetic kidney disease, I/R; Ischemia/reperfusion injury, LN; lupus nephritis, PAN; Puromycin aminonucleoside, UUO; unilateral ureteral obstruction. CKD; chronic kidney disease DN; diabetic kidney disease, I/R; Ischemia/reperfusion injury, LN; lupus nephritis, PAN; Puromycin aminonucleoside, UUO; unilateral ureteral obstruction.…”

“…Notably, FcRn can contribute to antigen presentation by the most efficient professional antigen-presenting cells, i.e., dendritic cells [120]. Podocyte-specific FcRn knockout decreased interleukin-6 (IL-6) production in podocytes and reduced disease progression in a nephrotoxic seruminduced nephritis disease model [121,122]. TRPC6 might be involved in the process of antigen presentation in podocytes via STIM1.…”