Properdin has an ascendancy over factor H regulation in complement-mediated renal tubular damage

Abstract

BackgroundUrinary (U)-complement components have been detected in patients with proteinuric renal diseases, and complement activation via the alternative pathway (AP) is believed to play a role in renal tubular damage. The present study aimed to examine the regulation of complement AP activation in patients with renal tubular damage by focusing on the balance between properdin (P) and factor H (fH).MethodsIn the in vivo studies, U concentrations of P, fH and membrane attack complex (MAC) were measured in patients with renal diseases using an enzyme-linked immunosorbent assay (ELISA), and their relationships with the clinical data were evaluated. In the in vitro studies, human proximal tubular epithelial cells (PTECs) were incubated with normal human serum (NHS), P-depleted serum (PDS), purified P and/or fH. Changes in cell morphology and phenotype were assessed by microscopy, real-time polymerase chain reaction (PCR), immunostaining and a cell viability assay.ResultsThe U-P, fH and MAC concentrations were significantly higher in patients with renal disease than in normal controls and correlated with the U-protein and tubular damage markers. Furthermore, multivariate analysis revealed a relationship between P levels and tubular damage markers. There were no significant changes in morphology and mRNA expression in the AP components (P, fH, fB, C3, C5 and C9) after the addition of up to 25% NHS. Dose-dependent depositions of P or fH were observed after the addition of P or fH on PTECs. Depositions of P were not inhibited by fH in a mixture of a fixed concentration of P and a variable concentration of fH, and vice versa. Preincubation with the fixed concentration of P before the addition of NHS or PDS increased the depositions of P, C3 and MAC compared with incubation with intact NHS or intact PDS only; the depositions of C3 and MAC showed a serum-dependent trend. Preincubation with P before NHS addition significantly suppressed cell viability without causing morphological changes.ConclusionsIn the pathogenesis of renal tubular damage, P can directly bind to PTECs and may accelerate AP activation by surpassing fH regulation.

High levels of urinary complement proteins are associated with chronic renal damage and proximal tubule dysfunction in immunoglobulin A nephropathy

“…Previous studies have shown an association between urinary complement proteins and tubular damage markers, including β2‐microglobulin, in IgAN as well as other types of proteinuric renal diseases . In line with this, we found significant correlations between the three complement proteins (CFH, MBL and C5b‐9) in urine and the tubular damage markers, urinary RBP and α1‐MG, both known to be ligands to the endocytic receptor megalin .…”

Serum properdin consumption as a biomarker of C5 convertase dysregulation in C3 glomerulopathy

“…Zaferani and colleagues identified that tubular heparan sulphate proteoglycan (HSPG) served as a docking platform for P in proteinuric renal disease . P participation in PDP on the cell surface of PTECs enhances C3b and C5b‐9 deposition, leads to tubulointerstitial damage and worsens renal function . In connection with these evidences, serum P consumption in our patients can be explained by the deposition of P on altered renal tubules.…”

“…This situation promotes its interaction with heparan sulphate proteoglycan (HSPG) present on the extracellular matrix of PTECs, acting as a focal point for AP activation . Recent results confirmed that deposited P via HSPG on PTECs seems to be involved in complement activation, as it can increase the deposition of C3 and C5b‐9 in cellular surface in vitro . Moreover, urinary P levels were associated with higher urinary levels of soluble C5b‐9 (sC5b‐9) and with worse renal function .…”

C5b-9 does not mediate tubulointerstitial injury in experimental acute glomerular disease characterized by selective proteinuria

“…Second, further studies are required to confirm and define the mechanisms underlying the absence of luminal C5b9 formation in acute PON. In this regard, the urinary excretion of C5b9 as well as other complement regulatory proteins (particularly properdin and Factor H) [29,30,59] in PON could be compared to other chronic proteinuric and nonproteinuric models of chronic kidney disease as well as different types of proteinuric diseases in humans, in future studies. Finally, the present study has only examined the acute stages of PON, and different mechanisms of C5b9mediated injury could be involved if it is combined with renal mass reduction and/or if the injections of BSA are continued for a longer duration [14] .…”