Heparin/heparan sulphate interactions with complement--a possible target for reduction of renal function loss?

Abstract

Current management of end-stage renal failure is based on renal replacement therapy by dialysis or transplantation. Increased occurrence of renal failure in both native and transplanted kidneys indicates a need for novel therapies to stop or limit the progression of the disease. Acute kidney injury and proteinuria are major risk factors in the development of renal failure. In this regard, innate immunity plays an important role in the pathogenesis of renal diseases in both native and transplanted kidneys. The complement system is a major humoral part of innate defense. Next to the well-known complement activators, quite a number of the complement factors react with proteoglycans (PGs) both on cellular membranes and in the extracellular compartment. Therefore, these interactions might serve as targets for intervention. In this review, the current knowledge of interactions between PGs and complement is reviewed, and additionally the options for interference in the progression of renal disease are discussed.

Pharmacology of Heparin and Related Drugs

“…It is therefore of interest in the regulation of the inflammatory response that many complement proteins are capable of binding to heparin, and a survey of the relative affinities of such proteins for a heparin-coated surface has been carried out, leading to an estimate that complement proteins in the circulation may well be bound to heparin to a significant extent at therapeutic heparin concentrations (Yu et al, 2005a). The ability of heparin (exogenous and presumably endogenous) and its mimetics to influence the complement system may also, in time, lead to new therapies for diseases involving complement activation, such as in the treatment of renal failure (Zaferani et al, 2014).…”

The emerging role of coagulation proteases in kidney disease

“…However, the implications of downstream cellular injury mediated by activated coagulation protease signalling remains unexplored in these settings. Anticoagulation with heparin might modulate complement system activity, reflecting the close interaction of the complement and coagulation systems and suggesting that it might be possible to pharmaceutically target and utilize these systems in AKI 167 .…”

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] .…”

“…Specifically, in the case of acute PON, the pathogenesis of tubu lointerstitial injury is C5b9independent and the tubular filtration of excess albumin, growth factors and microtubular proteincast obstruction are likely to be more critical [37] . Further studies to understand the role of complement system will be helpful in defining new therapies for the generic treatment of kidney diseases characterized by chronic proteinuria [29] .…”