Renal Inflammation and Fibrosis: A Double-edged Sword

Abstract

Renal tissue injury initiates inflammatory and fibrotic processes that occur to promote regeneration and repair. After renal injury, damaged tissue releases cytokines and chemokines, which stimulate activation and infiltration of inflammatory cells to the kidney. Normal tissue repair processes occur simultaneously with activation of myofibroblasts, collagen deposition, and wound healing responses; however, prolonged activation of pro-inflammatory and pro-fibrotic cell types causes excess extracellular matrix deposition. This review focuses on the physiological and pathophysiological roles of specialized cell types, cytokines/chemokines, and growth factors, and their implications in recovery or exacerbation of acute kidney injury.

Keywords: acute kidney injury; cellular transdifferentiation; chemokines; chronic kidney disease; cytokines; extracellular matrix; fibrosis; growth factors; transforming growth factor-β.

Figure 1.

Distinct cell types, signaling proteins, and growth factors contribute to renal inflammation and fibrosis. Renal injury induces inflammation, which drives fibrosis. Coordination of a multitude of cell types, cytokines and chemokines, antioxidants, growth factors, and regulatory mechanisms modulates these responses. Meticulous control of these factors can drive repair of damaged tissue; however, if dysregulated, injury is exacerbated. Abbreviations: Mɸ, macrophage; NK cells, natural killer cells; TNF-α, tumor necrosis factor-α; IL, interleukin; SDF-1, stromal cell-derived factor-1; MCP-1, monocyte chemoattractant protein-1; CCL2, chemokine (C-C motif) ligand 2; HO-1, heme oxygenase-1; CTGF, connective tissue growth factor; PDGF, platelet-derived growth factor; EGF, epidermal growth factor; BMP-7, bone morphogenic protein-7; CXCL10, C-X-C motif chemokine 10; TGF-β, transforming growth factor-β.

Figure 2.

Neutrophil and macrophage interaction with injured kidney epithelium and interstitial cells. Neutrophils infiltrate into the injured tissue within hours of the event and express pro-inflammatory cytokines and enzymes for degrading extracellular matrix, providing space for activity of macrophages in clearance of debris. Infiltrative macrophages migrate from the blood stream into the kidney interstitium and are short-lived. Their numbers often peak within 1 to 3 days after injury and decline with resolution of acute inflammation. Few of these infiltrative macrophages differentiate into tissue resident macrophages. Infiltrative macrophages express chemokine and growth factor receptors, including CX3CR1, CCR2, and colony stimulating factor-1 receptor (CSF-1R). They express secreted proteins, including transforming growth factor-β (TGF-β), monocyte chemoattractant protein-1 (MCP-1/CCL2), Wnt ligands, and complement proteins. Tissue resident macrophages, in contrast to infiltrative, renew by in situ proliferation. Their numbers remain relatively constant after ischemia-reperfusion–acute kidney injury (IR-AKI). They express receptors including CX3CR1, CSF-1R, and Fc γ receptor 4 (FCGR4). They express secreted proteins including TGF-β, CCL2, Wnt ligands, and complement proteins. Certain Wnt ligands are differentially expressed by kidney resident macrophages compared with infiltrative. For example, Wnt4 is expressed at higher levels by resident macrophages. TGF-β secreted by both infiltrative and tissue resident macrophages can be trophic for fibroblast to myofibroblast differentiation. Myofibroblasts are critical pro-fibrotic cells in the kidney interstitium that secrete collagens and ECM proteins that promote interstitial fibrosis. Epithelial cell death and damage results in expression of complement proteins, CX3CL1 (fractalkine), CSF-1, and high mobility group box-1 (HMGB1). Each of these molecules are recognized by and can activate leukocytes. Also, the epithelium expresses receptors for signaling molecules produced by leukocytes, including Fzd/Lrp (Wnt ligand receptors), and TGF-βR. Fzd, frizzled (Wnt receptor); Lrp, low density lipoprotein receptor (Wnt co-receptor); IFN-γ, interferon-γ; Wnt, wingless-related integration site.

Figure 3.

Origins of myofibroblasts in renal fibrosis. Many renal cell types can differentiate into myofibroblasts during fibrosis in response to various stimuli, including fibroblasts, pericytes, fibrocytes, endothelial cells, macrophages, and tubular cells. Abbreviations: TGF-β, transforming growth factor-β; Hh/Gli, Hedgehog/GLI signaling pathway; CTGF, connective tissue growth factor; PDGF, platelet-derived growth factor; EndoMT, endothelial-to-mesenchymal transition; MMT, macrophage-to-myofibroblast transition; EMT, epithelial-to-mesenchymal transition; α-SMA, α-smooth muscle actin.