Loss of decay-accelerating factor triggers podocyte injury and glomerulosclerosis

Abstract

Kidney glomerulosclerosis commonly progresses to end-stage kidney failure, but pathogenic mechanisms are still poorly understood. Here, we show that podocyte expression of decay-accelerating factor (DAF/CD55), a complement C3 convertase regulator, crucially controls disease in murine models of adriamycin (ADR)-induced focal and segmental glomerulosclerosis (FSGS) and streptozotocin (STZ)-induced diabetic glomerulosclerosis. ADR induces enzymatic cleavage of DAF from podocyte surfaces, leading to complement activation. C3 deficiency or prevention of C3a receptor (C3aR) signaling abrogates disease despite DAF deficiency, confirming complement dependence. Mechanistic studies show that C3a/C3aR ligations on podocytes initiate an autocrine IL-1β/IL-1R1 signaling loop that reduces nephrin expression, causing actin cytoskeleton rearrangement. Uncoupling IL-1β/IL-1R1 signaling prevents disease, providing a causal link. Glomeruli of patients with FSGS lack DAF and stain positive for C3d, and urinary C3a positively correlates with the degree of proteinuria. Together, our data indicate that the development and progression of glomerulosclerosis involve loss of podocyte DAF, triggering local, complement-dependent, IL-1β–induced podocyte injury, potentially identifying new therapeutic targets.

Complement, a Therapeutic Target in Diabetic Kidney Disease

“…This is the results of increased DAF cleavage by phospholipase, despite increased DAF mRNA levels. Importantly, we also found an association between urinary C3a with the progression of proteinuria ( 25 ). Our data not only established the link between immune dysregulation with FSGS but more importantly, future therapeutic approaches and available drug targets.…”

“…Therefore, both C5aR and C3aR propose an attractive target for renoprotection in diabetes. We hypothesized that DKD is associated with glomerular cleavage of the DAF, a key inhibitor of C3 convertase ( 25 ). After diabetes induction by streptozotocin, DAF deficient mice have augmented C3b glomerular deposition and manifested a more severe disease phenotype and aggravated histological lesions when compared to control diabetic wild-type mice ( Figure 1 ).…”

“…While the upregulation of complement regulatory transcripts may seem to contradict a previously noted downregulation of this protein in non-diabetic glomerular disease leading to uninhibited complement activation, we similarly saw an increase in CD55 mRNA in FSGS patients but a decrease in transmembrane CD55 staining in FSGS biopsies. This decrease in protein is likely due to cleavage of CD55 that can be found in the urine of Adriamycin treated mice and FSGS patients ( 25 ). A similar mechanism could be occurring in DKD.…”

Urinary complement proteins and risk of end-stage renal disease: quantitative urinary proteomics in patients with type 2 diabetes and biopsy-proven diabetic nephropathy

“…DAF is a glycophosphatidylinositol-anchored protein expressed both on podocytes and epithelial tubular cells [39] that regulates the C3 and C5 convertases of the classical and alternative pathways [40]. DAF accelerates decay and inhibits the reformation of surface-bound C3 convertases, together with retraining amplification of the cascade [39]. In streptozotocin-induced diabetic glomerulosclerosis, podocyte-specific deficiency of DAF activated C3a/C3aR signaling, causing actin cytoskeleton rearrangement and podocyte injury [39].…”

Regulation of Complement Activation by Heme Oxygenase-1 (HO-1) in Kidney Injury

“…The reasons for addressing the role of HO-1 in regulating DAF expression include: (a) the demonstration that HO-1 enhances vascular endothelial resistance to complement-mediated injury induced in vitro through the induction of DAF [ 62 ], (b) the demonstration that DAF confers protection against complement-mediated podocyte injury following the administration of anti-GBM antibody-mediated nephritis in mice (71), (c) the observation that in kidney biopsies from patients with focal segmental glomerulosclerosis (FSGS), complement (C3d) deposition in the glomeruli is paralleled by a reduction in DAF expression [ 104 ], and (d) the demonstration that the distribution of DAF in the rat kidney is restricted to the apical surface of glomerular podocytes [ 72 ] where the loss of DAF promotes complement (C3b) deposition and the development of podocytopathy resembling human FSGS [ 73 , 74 ].…”