Cellular and molecular mechanisms in kidney fibrosis

Abstract

Fibrosis is a characteristic feature of all forms of chronic kidney disease. Deposition of pathological matrix in the interstitial space and within the walls of glomerular capillaries as well as the cellular processes resulting in this deposition are increasingly recognized as important factors amplifying kidney injury and accelerating nephron demise. Recent insights into the cellular and molecular mechanisms of fibrogenesis herald the promise of new therapies to slow kidney disease progression. This review focuses on new findings that enhance understanding of cellular and molecular mechanisms of fibrosis, the characteristics of myofibroblasts, their progenitors, and molecular pathways regulating both fibrogenesis and its resolution.

Figure 1. Photomicrographs showing fibrosis in the interstitium and glomerulus of a patient with moderate (stage III) diabetic CKD.

Silver methenamine-stained sections show fibrosis and basement membranes (black) in a glomerulus (top) and in the cortical interstitium (bottom). Glomerular mesangial matrix expansion (thin arrow) predominates, whereas glomerulosclerosis, which includes obliteration of capillary loops, can be seen (arrowhead). Injured tubules are widespread (asterisks) and interstitial matrix (thick arrows) is extensive in areas where peritubular capillaries normally exist, as is extensive tubular basement membrane thickening. Scale bar: 50 μm.

Figure 2. Results of fate-mapping studies of kidney myofibroblast progenitors.

OSR1⁺ intermediate mesoderm progenitors give rise to FOXD1⁺ progenitors and progenitors of the collecting duct (CD), epithelium, and endothelium. This patterning occurs by 9.5 dpc in mouse embryos. FOXD1⁺ progenitors established by this time self-renew to give rise to stroma and mural cells of the kidney. Potentially, a second population of progenitors expresses P0 in the neural crest, which then migrates to the cortical nephrogenic stroma and contributes to FOXD1⁺ stromal progenitors at 13.5 dpc. FOXD1 progeny give rise to mural cells and resident fibroblasts. In disease settings, FOXD1-lineage cells become the vast majority of myofibroblasts in models of kidney disease.

Figure 3. Factors regulating and perpetuating FOXD1-lineage differentiation to myofibroblasts.

Shown is the initiation of the fibrogenic process, the mechanisms that perpetuate the fibrogenic state, and the consequences of myofibroblast persistence. FOXD1-lineage fibroblasts and pericytes in the interstitial space or attached to endothelium, respectively, respond to signals of endothelial or epithelial injury in a bidirectional manner, including PDGFR-β and -α engagement, which triggers detachment, spreading, migration, and differentiation to myofibroblasts. This process can resolve, but the extent of reversion or other mechanisms of myofibroblast disappearance remain unclear. Some studies propose that a circulating leukocyte also contributes to myofibroblasts, but it remains poorly characterized. Myofibroblasts respond to growth factors, plasma factors, and environmental cues to proliferate, deposit fibrillar matrix, and contract. Expression of metalloproteinases, including ADAMTS family members and their regulators, coordinates detachment, migration, formation of collagen fibrils; factors regulating matrix turnover and degradation including FAP and CTHRC1 favor matrix accumulation. Myofibroblasts are a potent source of cytokines and chemokines and metabolic products, which regulate the inflammatory response. As injury persists, myofibroblasts undergo transcriptional and miRNA reprogramming that contributes to their persistence in an activated state. A subpopulation of myofibroblasts may utilize Endo180 to degrade and resorb pathological matrix, which promotes resolution. The fate of myofibroblasts is currently unclear, but resolution of fibrosis may involve reversion, cell death, or possibly senescence.