Role of local complement activation in kidney fibrosis and repair

Abstract

The complement system is an important component of the innate immune system involved in host defense and maintaining homeostasis. While the liver is the main source of complement proteins in the bloodstream, recent research has shown that various tissues, including the kidneys, can produce complement components locally in response to both acute and chronic inflammation. This Review highlights evidence from animal models of glomerular and tubulointerstitial kidney disease showing increased expression of intracellular complement in the kidneys. Studies using knockout mice for complement and complement receptors, along with complement inhibitors, have demonstrated that reduced complement activation in animal models of kidney fibrosis led to reduced inflammation and fibrosis, thereby supporting the pathogenic role of complement activation. Data from single-cell RNA-sequencing, spatial transcriptomics, and proteomics studies further demonstrate that alterations in local complement levels contribute to the fibrotic microenvironment observed in these models. Additionally, kidney biopsy results from patients with acute kidney injury and chronic kidney disease (CKD) indicate an increased expression of intracellular complement components as disease progresses. Developing drugs aimed at diminishing the expression and activation of local complement in glomerular and tubulointerstitial kidney disease could provide a novel approach to managing CKD.

Figure 1. Overview of complement activation.

The three complement activation pathways — classical, lectin, and alternative — converge at C3 convertase formation. C3 convertase cleaves C3 into C3a (inflammatory mediator) and C3b (opsonin), which participates in C5 convertase formation. C5 convertase cleaves C5 into C5a (inflammatory mediator) and C5b, which initiates the membrane attack complex (MAC) by recruiting C6, C7, C8, and C9. Regulatory proteins like factor H (FH) and factor I (FI) control excessive complement activation. The complement system enhances immune defense through inflammation, opsonization, and direct cell lysis via MAC formation. MASP, mannose-binding lectin-associated serine protease.

Figure 2. C3 expression dynamics correspond to failed repair in proximal tubules.

(A) Temporal kinetics of murine C3 expression during tubular repair following AKI (bilateral ischemia). Smoothed expression trajectories of C3 in proximal tubular cells (PTCs) during kidney injury and repair. Murine data (from datasets published in ref. 59) indicate a biphasic induction of C3 expression, with markedly increased and sustained expression in failed-repair PTCs compared with adaptive-repair PTCs. To represent the patterns of expression, dynamics were modeled using spline interpolation across six time points (0 hour, 4 hours, 12 hours, 2 days, 12 days, and 48 days) following injury. (B) Enhanced C3 gene activity in maladaptive proximal tubular states in human kidney disease. Relative C3 gene activity across proximal tubular subsets derived from human kidney single-cell sequencing data in healthy controls, AKI, and CKD (see ref. ; datasets available from the KPMP, https://www.kpmp.org, and analyzed here with permission). Proximal tubular cells (PTs) from healthy kidneys exhibit minimal C3 activity, whereas C3 expression is substantially elevated in maladaptive repair PTs across both AKI and CKD settings. Bar height reflects relative gene activity.

Figure 3. Cellular response of PTCs to injury.

Ischemic or nephrotoxic insult activates pathways leading to either adaptive or maladaptive repair. Adaptive repair is characterized by dedifferentiation, proliferation, and redifferentiation, facilitating functional recovery. In contrast, maladaptive repair is marked by prolonged cell cycle arrest, and upregulation of VCAM1, C3, NF-κB, and TGF-β, among others, leading to epithelial-mesenchymal transition (EMT), senescence, fibrosis, and inflammation. The maladaptive response is further exacerbated by pro-inflammatory macrophage activation via C3AR1, contributing to sustained inflammation and ECM deposition. This model underscores the dichotomy between successful tubular regeneration and progressive kidney fibrosis, implicating C3-driven immune modulation in maladaptive repair.