A new perspective on the pathophysiology of kidney diseases: the intracellular complement system- “complosome”

The complement cascade is a vital component of the innate immune system. It consists of around 50 proteins, including circulating complement proteins and membrane-bound receptors. It operates through three main activation pathways: classical, lectin, and alternative. Dysregulation of the complement system is implicated in several kidney diseases, such as complement-mediated thrombotic microangiopathy, lupus nephritis (LN), C3 glomerulopathy and kidney transplantation. The complement system also extends beyond immune responses, influencing cellular processes through the “complosome” — an intracellular system that regulates metabolism, autophagy, and gene expression. This intracellular complement activity has been linked to kidney diseases, including glomerular and tubular injuries and renal cancer. As research progresses, targeting both extracellular and intracellular complement components holds promise for more effective treatments in complement -driven diseases. In this mini review, the role of the complement system in immune defense, the impact of the alternative pathway in kidney diseases, and the relationship between intracellular complement activity -complosome- and cellular functions have been discussed. Additionally, new approaches for the treatment of complement dysregulation have been explored.