Urinary properdin excretion is associated with intrarenal complement activation and poor renal function

Journal of Biological Chemistry

et al. 2012

Section: Discussionmentioning

confidence: 95%

Factor H and Properdin Recognize Different Epitopes on Renal Tubular Epithelial Heparan Sulfate

Zaferani

Vivès

Journal of Biological Chemistry

et al. 2012

“…The importance of complement activation in tubulointerstitial toxicity was already demonstrated years ago (13,36,37). In vitro and in vivo studies have implicated activation of the AP of complement on tubular epithelial cells and its linkage to renal fibrosis (3, 5, 38, 39).…”

Section: Discussionmentioning

confidence: 99%

“…In proteinuria, properdin is found in the urine and may bind to proximal tubular cells. In vitro it was demonstrated that this properdin activates the AP on renal cells (6,13). Furthermore, the excretion of properdin in urine is correlated with increased urinary levels of the terminal complement cascade complex C5b-9 and with poor renal function (6,13).…”

mentioning

confidence: 99%

Identification of Tubular Heparan Sulfate as a Docking Platform for the Alternative Complement Component Properdin in Proteinuric Renal Disease

Zaferani

Vivès

Journal of Biological Chemistry

et al. 2011

Properdin binds to proximal tubular epithelial cells (PTEC)and activates the complement system via the alternative pathway in vitro. Cellular ligands for properdin in the kidney have not yet been identified. Because properdin interacts with solidphase heparin, we investigated whether heparan sulfate proteoglycans (HSPG) could be the physiological ligands of properdin. Kidneys from proteinuric rats showed colocalization of syndecan-1, a major epithelial HSPG, and properdin in the apical membranes of PTEC, which was not seen in control renal tissue. In vitro, PTEC did not constitutively express properdin. However, exogenous properdin binds to these cells in a dose-dependent fashion. Properdin binding was prevented by heparitinase pretreatment of the cells and was dose-dependently inhibited by exogenous heparin. ELISA and surface plasmon resonance spectroscopy (BIAcore) showed a strong dose-dependent interaction between heparan sulfate (HS) and properdin (K d ‫؍‬ 128 nM). Pretreatment of HSPG with heparitinase abolished this interaction in ELISA. Competition assays, using a library of HS-like polysaccharides, showed that sulfation pattern, chain length, and backbone composition determine the interaction of properdin with glycosaminoglycans. Interestingly, two nonanticoagulant heparin derivatives inhibited properdin-HS interaction in ELISA and BIAcore. Incubation of PTEC with human serum as complement source led to complement activation and deposition of C3 on the cells. This C3 deposition is dependent on the binding of properdin to HS as shown by heparitinase pretreatment of the cells. Our data identify tubular HS as a novel docking platform for alternative pathway activation via properdin, which might play a role in proteinuric renal damage. Our study also suggests nonanticoagulant heparinoids may provide renoprotection in complement-dependent renal diseases.The complement system plays an important role in glomerular injury and the development of tubulointerstitial scarring in several progressive renal diseases (1, 2). One of the three complement activation pathways is the alternative pathway (AP), 2 and there is growing evidence of activation of AP on renal tubular cells in proteinuric renal diseases (3-7).The AP is controlled by a number of inhibitory regulators, but there is only one known positive regulator, properdin (8 -10). This protein was first discovered in 1954 but received renewed interest in the 1970s (9). Properdin is a highly positively charged protein. It is composed of identical subunits that associate together to make dimers, trimers, tetramers, and even higher oligomers. Properdin oligomerization is known to be essential for its function (9). AP activation can be amplified following formation of the C3 convertase complex (C3bBb). Nascent C3bBb is known to be unstable in plasma. Properdin can bind to this complex and stabilizes it 5-10-fold, protecting the complex partially from inhibition by factors I and H (8 -10). Recent data indicate that extending the half-life of the C3bBb complex is not th...

“…A previous study (40) in patients with kidney disease demonstrated the presence of properdin in their urine, which was associated with higher levels of urinary soluble C5b-9 and worse renal function. Properdin bound to HK2 cells can induce the generation of C5b-9 on its surface, as previously shown (14).…”

Section: Properdin-directed C3 Deposition On Viable Hk2 Cells Is Inhimentioning

confidence: 87%

“…Heparan sulphate on the surface of PTECs acted as a binding site for properdin, binding that can be inhibited by heparinoids (46,47). In addition, excretion of properdin in urine was associated with complement activation products and worse renal outcome in patients with at least 1 g/day of proteinuria in diabetic nephropathy and glomerular disease cases (40).…”

mentioning

confidence: 99%

Monomeric C-reactive protein inhibits renal cell-directed complement activation mediated by properdin

O'flynn

American Journal of Physiology-Renal Physiology

Dixon

et al. 2016