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Review
. 2013 Apr 1;304(7):C591-603.
doi: 10.1152/ajpcell.00414.2012. Epub 2013 Jan 16.

Cellular mechanisms of tissue fibrosis. 3. Novel mechanisms of kidney fibrosis

Gabriela Campanholle  1 , Giovanni Ligresti, Sina A Gharib, Jeremy S Duffield
Affiliations
Review

Cellular mechanisms of tissue fibrosis. 3. Novel mechanisms of kidney fibrosis

Gabriela Campanholle et al. Am J Physiol Cell Physiol. .

Abstract

Chronic kidney disease, defined as loss of kidney function for more than three months, is characterized pathologically by glomerulosclerosis, interstitial fibrosis, tubular atrophy, peritubular capillary rarefaction, and inflammation. Recent studies have identified a previously poorly appreciated, yet extensive population of mesenchymal cells, called either pericytes when attached to peritubular capillaries or resident fibroblasts when embedded in matrix, as the progenitors of scar-forming cells known as myofibroblasts. In response to sustained kidney injury, pericytes detach from the vasculature and differentiate into myofibroblasts, a process not only causing fibrosis, but also directly contributing to capillary rarefaction and inflammation. The interrelationship of these three detrimental processes makes myofibroblasts and their pericyte progenitors an attractive target in chronic kidney disease. In this review, we describe current understanding of the mechanisms of pericyte-to-myofibroblast differentiation during chronic kidney disease, draw parallels with disease processes in the glomerulus, and highlight promising new therapeutic strategies that target pericytes or myofibroblasts. In addition, we describe the critical paracrine roles of epithelial, endothelial, and innate immune cells in the fibrogenic process.

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Figures

Fig. 1.
Fig. 1.
Characterization of cells that generate fibrillar collagen-Iα1 protein in models of kidney disease. A: split panel low-power confocal image of kidney cortex from Coll-GFPTg mouse d10 after ureteral obstruction to model inflammation and fibrosis, showing green fluorescent protein (GFP) nuclear and cytoplasm fluorescence of cells that are making collagen, colabeled with directly Cy3-conjugated anti-α-smooth muscle actin (α-SMA) antibodies. Note almost complete overlap (a, arteriole; g, glomerulus). B and C: high-power images of diseased kidney cortex from Coll-GFPTg mouse showing CD45+ leukocytes or S100A4+ cells. Note there is no overlap with collagen-producing cells. D: high-power image of single cells from a digested fibrotic Coll-GFPTg kidney showing that >99.9% of CD45+ cells do not generate collagen-Iα1 protein whereas a minority (<0.1%) do generate this protein weakly. E and F: images and graphs relating to bone marrow chimera mice in which only bone marrow cells harbor the Coll-GFPTg. E: diseased kidneys from these mice show rare bone marrow-derived cells restricted to perivenular sites that generate collagen protein (i.e., “circulating fibrocytes”) and lack the myofibroblast marker αSMA. F: number of fibrocytes/whole sagittal section (top) in mice with kidney disease in spleen and kidney, ± systemic injection of LPS (6 μg/g body wt). Percentage fibrocytes compared with leukocytes or myofibroblasts (bottom) in diseased kidney sections. Note that kidney circulating fibrocytes are exceptionally rare and are not increased after LPS whereas splenic fibrocytes are also rare, but more abundant and increased by LPS treatment. Bars, 25 μm.
Fig. 2.
Fig. 2.
Pericytes generate collagen-Iα1 in normal kidney, and their fate in interstitial kidney disease is mapped using the developmental transcription factor FOXD1. A: normal human kidney cortex showing relationship of peritubular capillaries and perivascular cells. Pericytes were labeled with anti-αSMA, and endothelium was labeled with anti-CD34. B: normal kidney cortex from Coll-GFPTg mouse showing relationship of pericytes to capillary basement membrane (CBM) with processes passing through duplication/splits in CBM (arrows). C: split panel images of cortex and medulla from mice expressing tdTomato in cells derived from FOXD1+ metanephric mesenchyme during embryogenesis. Note complete overlap with pericytes expressing Coll-GFP (arrowheads) but that vascular smooth muscle cells do not express Coll-GFP (arrow). D: 10 days after induction of interstitial kidney disease (UUO model), FOXD1+-derived cells have expanded and all now coexpress αSMA and have therefore become myofibroblasts. E: in normal glomeruli of Coll-GFPTg mice, podocin+ podocytes produce collagen protein, but αSMA-negative mesangial cells (arrows) do not produce collagen. F: 21 days after induction of nephrotoxic serum nephritis (NTN), there is glomerular injury and most surviving podocytes continue to express Coll-GFP and therefore produce collagen-Iα1 protein (arrowheads, top); a minority no longer express Coll-GFP (arrows, top); mesangial cells now activate αSMA but nevertheless do not express Coll-GFP (arrows, bottom). Bars, 25 μm.
Fig. 3.
Fig. 3.
Transcriptomic analysis of pericytes in kidney disease. A: pericyte transdifferentiation into myofibroblasts during kidney injury is characterized by profound changes in gene expression with over 860 differentially regulated genes (false discovery rate <0.01, 549 upregulated, 313 downregulated). Normalized gene expression values are depicted as pericytes (day 0) become myofibroblasts (days 2 and 7), with the bulk of the transcriptional changes occurring by day 2. These temporal expression patterns are highly enriched in distinct functional pathways, most prominently, those involved in immunity (P value 3 × 10−48) and inflammatory response (P value 7 × 10−26) among others. Furthermore, many of the differentially expressed genes share common, overrepresented transcription factor (TF) binding sites (Bonferroni-adjusted enrichment P < 0.01), implying coordinated regulation by a limited repertoire of TFs. B: our global computational approach is amenable to more detailed data-mining analyses. For example, the cytokine interleukin-6 (Il-6) is highly upregulated when pericytes transdifferentiate into myofibroblasts, functionally maps to immune and inflammatory pathways, and has a Rela (NF-κB p65) binding site upstream of its transcription start site. Interestingly, Rela expression itself doubles when pericytes become myofibroblasts in this animal model of kidney injury.
Fig. 4.
Fig. 4.
Schema showing candidate receptors and pathways involved in pericyte differentiation into myofibroblasts. Endothelial cell is shown in red and pericyte is shown in green. Factors in orange promote myofibroblast differentiation and activation, whereas factors in shades of blue inhibit differentiation and activation. PPAR, peroxisome proliferator-activated receptor; FA, fatty acid; ROS, reactive oxygen species; miRNA, microRNA; MAPK, mitogen-activated protein kinase; JNK, c-Jun NH2-terminal kinase; ADAMTS1, a disintegrin and metalloproteinase with thrombospondin motif; TIMP3, metalloproteinase inhibitor 3; VEGFA, vascular endothelial growth factor A; VEGFR2, vascular endothelial growth factor receptor; EphB, ephrin receptor B; Gli, glioma-associated oncogene homolog; LRP, low-density lipoprotein receptor-related protein; WNT, wingless/int1; CTGF, connective tissue growth factor; TGF-βR, transforming growth factor-β receptor; PDGFR, platelet-derived growth factor receptors.
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