The many effects of complement C3- and C5-binding proteins in renal injury.

The complement system is an important component of the innate immune system and a modulator of adaptive immunity. The entire complement system is focused on C3 and C5. Thus, there are proteins that activate C3 and C5, those that regulate this activation, and those that transduce the effects of C3 and C5 activation products; each can affect the kidney in renal injury. The normal kidney has the inherent capacity to protect itself from complement activation through cellular expression of decay-accelerating factor, membrane cofactor protein (in human beings), and Crry (in rodents). In addition, plasma factor H protects vascular spaces in the kidney. Although the main function of these proteins is to limit complement activation, there is now considerable evidence that they can transduce signals on engagement in immune cells. The G-protein-coupled 7-span transmembrane receptors for C3a and C5a, and the integral membrane complement receptors (CR) for C3b, iC3b, and C3dg, are expressed outside the kidney, particularly in cells of hematopoietic and immune lineage. These are important in renal injury through their infiltration of the kidney and/or by affecting kidney-directed immune responses. There is mounting evidence that intrinsic glomerular and tubular cell C3aR and C5aR expression and activation also can affect renal injury. CR1 on podocytes and the beta2 integrins CR3 and CR4 in kidney dendritic cells have functions that remain poorly defined. Cells of the kidney also have the capacity to produce and activate their own complement proteins. Thus, intrinsic renal cells express decay-accelerating factor, membrane cofactor protein, Crry, C3aR, C5aR, CR1, CR3, and CR4. These can be engaged by C3 and C5 activation products derived from systemic and local pools in renal injury. Given their capacity to provide signals that influence kidney cellular behavior, their activation can have substantial effects in renal injury. Defining these in a cell- and disease-specific fashion is an exciting challenge for future research.