Role In Development Of Fibrosis Research Articles

Fibrostricturing Crohn's Disease Is Marked by an Increase in Active Eosinophils in the Deeper Layers.

Approximately 50% of patients with Crohn's disease (CD) develop intestinal strictures necessitating surgery. The immune cell distribution in these strictures remains uncharacterized. We aimed to identify the immune cells in intestinal strictures of patients with CD. During ileocolonic resections, transmural sections of terminal ileum were sampled from 25 patients with CD and 10 non-inflammatory bowel disease controls. Macroscopically unaffected, fibrostenotic, and inflamed ileum was collected and analyzed for immune cell distribution (flow cytometry) and protein expression. Collagen deposition was assessed through a Masson Trichrome staining. Eosinophil and fibroblast colocalization was assessed through immunohistochemistry. The Masson Trichrome staining confirmed augmented collagen deposition in both the fibrotic and the inflamed regions, though with a significant increased collagen deposition in the fibrotic compared with inflamed tissue. Distinct Th1, Th2, regulatory T cells, dendritic cells, and monocytes were identified in fibrotic and inflamed CD ileum compared with unaffected ileum of patients with CD as non-inflammatory bowel disease controls. Only minor differences were observed between fibrotic and inflamed tissue, with more active eosinophils in fibrotic deeper layers and increased eosinophil cationic protein expression in inflamed deeper layers. Last, no differences in eosinophil and fibroblast colocalization were observed between the different regions. This study characterized immune cell distribution and protein expression in fibrotic and inflamed ileal tissue of patients with CD. Immunologic, proteomic, and histological data suggest inflammation and fibrosis are intertwined, with a large overlap between both tissue types. However strikingly, we did identify an increased presence of active eosinophils only in the fibrotic deeper layers, suggesting their potential role in fibrosis development.

Fibroblast Activation Protein Alpha (FAPα) in Fibrosis: Beyond a Perspective Marker for Activated Stromal Cells?

The development of tissue fibrosis is a complex process involving the interaction of multiple cell types, which makes the search for antifibrotic agents rather challenging. So far, myofibroblasts have been considered the key cell type that mediated the development of fibrosis and thus was the main target for therapy. However, current strategies aimed at inhibiting myofibroblast function or eliminating them fail to demonstrate sufficient effectiveness in clinical practice. Therefore, today, there is an unmet need to search for more reliable cellular targets to contribute to fibrosis resolution or the inhibition of its progression. Activated stromal cells, capable of active proliferation and invasive growth into healthy tissue, appear to be such a target population due to their more accessible localization in the tissue and their high susceptibility to various regulatory signals. This subpopulation is marked by fibroblast activation protein alpha (FAPα). For a long time, FAPα was considered exclusively a marker of cancer-associated fibroblasts. However, accumulating data are emerging on the diverse functions of FAPα, which suggests that this protein is not only a marker but also plays an important role in fibrosis development and progression. This review aims to summarize the current data on the expression, regulation, and function of FAPα regarding fibrosis development and identify promising advances in the area.

Fusion Protein of RBP and Albumin Domain III Reduces Lung Fibrosis by Inactivating Lung Stellate Cells.

Activated stellate cells play a role in fibrosis development in the liver, pancreas, and kidneys. The fusion protein R-III, which consists of retinol-binding protein and albumin domain III, has been demonstrated to attenuate liver and renal fibrosis by suppressing stellate cell activation. In this study, we investigated the efficacy of R-III against bleomycin-induced lung fibrosis in mice. R-III reduced lung fibrosis and primarily localized in autofluorescent cells in the lung tissue. Furthermore, we isolated lung stellate cells (LSCs) from rat lungs using the isolation protocol employed for hepatic stellate cells (HSCs). LSCs shared many characteristics with HSCs, including the presence of vitamin A-containing lipid droplets and the expression of alpha-smooth muscle actin and collagen type I, markers for activated HSCs/myofibroblasts. LSCs spontaneously transdifferentiated into myofibroblasts in in vitro culture, which was inhibited by R-III. These findings suggest that R-III may reduce lung fibrosis by inactivating LSCs and could be a promising treatment for extrahepatic fibrosis.

Do Semaphorins Play a Role in Development of Fibrosis in Patients with Nonalcoholic Fatty Liver Disease?

Nonalcoholic fatty liver disease (NAFLD) is associated with systemic changes in immune response linked with chronic low-grade inflammation and disease progression. Semaphorins, a large family of biological response modifiers, were recently recognized as one of the key regulators of immune responses, possibly also associated with chronic liver diseases. The aim of this study was to identify semaphorins associated with NAFLD and their relationship with steatosis and fibrosis stages. In this prospective, case-control study, serum semaphorin concentrations (SEMA3A, -3C, -4A, -4D, -5A and -7A) were measured in 95 NAFLD patients and 35 healthy controls. Significantly higher concentrations of SEMA3A, -3C and -4D and lower concentrations of SEAMA5A and -7A were found in NAFLD. While there was no difference according to steatosis grades, SEMA3C and SEMA4D significantly increased and SEMA3A significantly decreased with fibrosis stages and had better accuracy in predicting fibrosis compared to the FIB-4 score. Immunohistochemistry confirmed higher expression of SEMA4D in hepatocytes, endothelial cells and lymphocytes in NAFLD livers. The SEMA5A rs1319222 TT genotype was more frequent in the NAFLD group and was associated with higher liver stiffness measurements. In conclusion, we provide the first evidence of the association of semaphorins with fibrosis in patients with NAFLD.

SAMiRNA Targeting Amphiregulin Alleviate Total-Body-Irradiation-Induced Renal Fibrosis.

Fibrosis is a serious unintended side effect of radiation therapy. In this study, we aimed to investigate whether amphiregulin (AREG) plays a critical role in fibrosis development after total-body irradiation (TBI). We found that the expression of AREG and fibrotic markers, such as α-smooth muscle actin (α-SMA) and collagen type I alpha 1 (COL1α1), was elevated in the kidneys of 6 Gy TBI mice. Expression of AREG and α-SMA was mainly elevated in the proximal and distal tubules of the kidney in response to TBI, which was confirmed by immunofluorescence staining. Knockdown of Areg mRNA using self-assembled-micelle inhibitory RNA (SAMiRNA) significantly reduced the expression of fibrotic markers, including α-SMA and COL1α1, and inflammatory regulators. Finally, intravenous injections of SAMiRNA targeting mouse Areg mRNA (SAMiRNA-mAREG) diminished radiation-induced collagen accumulation in the renal cortex and medulla. Taken together, the results of the present study suggest that blocking of AREG signaling via SAMiRNA-mAREG treatment could be a promising therapeutic approach to alleviate radiation-induced kidney fibrosis.

Regulatory Immune Cells in Idiopathic Pulmonary Fibrosis: Friends or Foes?

The immune system is receiving increasing attention for interstitial lung diseases, as knowledge on its role in fibrosis development and response to therapies is expanding. Uncontrolled immune responses and unbalanced injury-inflammation-repair processes drive the initiation and progression of idiopathic pulmonary fibrosis. The regulatory immune system plays important roles in controlling pathogenic immune responses, regulating inflammation and modulating the transition of inflammation to fibrosis. This review aims to summarize and critically discuss the current knowledge on the potential role of regulatory immune cells, including mesenchymal stromal/stem cells, regulatory T cells, regulatory B cells, macrophages, dendritic cells and myeloid-derived suppressor cells in idiopathic pulmonary fibrosis. Furthermore, we review the emerging role of regulatory immune cells in anti-fibrotic therapy and lung transplantation. A comprehensive understanding of immune regulation could pave the way towards new therapeutic or preventive approaches in idiopathic pulmonary fibrosis.

Revisiting Cell Death Responses in Fibrotic Lung Disease: Crosstalk between Structured and Non-Structured Cells.

Fibrosis is a life-threatening disorder caused by excessive formation of connective tissue that can affect several critical organs. Innate immune cells are involved in the development of various disorders, including lung fibrosis. To date, several hematopoietic cell types have been implicated in fibrosis, including pro-fibrotic monocytes like fibrocytes and segregated-nucleus-containing atypical monocytes (SatMs), but the precise cellular and molecular mechanisms underlying its development remain unclear. Repetitive injury and subsequent cell death response are triggering events for lung fibrosis development. Crosstalk between lung structured and non-structured cells is known to regulate the key molecular event. We recently reported that RNA-binding motif protein 7 (RBM7) expression is highly upregulated in the fibrotic lung and plays fundamental roles in fibrosis development. RBM7 regulates nuclear degradation of NEAT1 non-coding RNA, resulting in sustained apoptosis in the lung epithelium and fibrosis. Apoptotic epithelial cells produce CXCL12, which leads to the recruitment of pro-fibrotic monocytes. Apoptosis is also the main source of autoantigens. Recent studies have revealed important functions for natural autoantibodies that react with specific sets of self-antigens and are unique to individual diseases. Here, we review recent insights into lung fibrosis development in association with crosstalk between structured cells like lung epithelial cells and non-structured cells like migrating immune cells, and discuss their relevance to acquired immunity through natural autoantibody production.

Identification and characterization of substrates crosslinked by transglutaminases in liver and kidney fibrosis.

The transglutaminase (TGase) family consists of eight isozymes that catalyze Ca2+-dependent crosslink formation between glutamine and lysine residues of proteins. In the pathogenesis of various chronic diseases, among the TGase isozymes, TG2 in particular is upregulated and contributes to a critical role in fibrosis development and progression via the stabilization of extracellular matrix proteins and activation of TGF-β. Although TG2 has been considered a key enzyme in fibrosis, the causative role of TG2 and involvement of other isozymes remain unclear. We have recently developed a comprehensive analysis method targeting the isozyme-specific substrates of TGase in liver and kidney fibrosis. In this review article, we introduce a previously developed method for determining the activity and tissue distribution of TGase and for the detecting and identification of TGase substrates in an isozyme-specific manner. Using our comprehensive analysis method, we newly characterized the overlapping profile data regarding potential substrates of TG1 and TG2 that have been identified in liver and kidney fibrosis to date. Our results obtained by comparing the specificity and similarity of potential TGase substrates between different tissue fibrosis models provide a deeper understanding regarding the specific and common pathways in disease pathogenesis and progression.

Exogenous Administration of Low-Dose Lipopolysaccharide Potentiates Liver Fibrosis in a Choline-Deficient l-Amino-Acid-Defined Diet-Induced Murine Steatohepatitis Model

Various rodent models have been proposed for basic research; however, the pathogenesis of human nonalcoholic steatohepatitis (NASH) is difficult to closely mimic. Lipopolysaccharide (LPS) has been reported to play a pivotal role in fibrosis development during NASH progression via activation of toll-like receptor 4 (TLR4) signaling. This study aimed to clarify the impact of low-dose LPS challenge on NASH pathological progression and to establish a novel murine NASH model. C57BL/6J mice were fed a choline-deficient l-amino-acid-defined (CDAA) diet to induce NASH, and low-dose LPS (0.5 mg/kg) was intraperitoneally injected thrice a week. CDAA-fed mice showed hepatic CD14 overexpression, and low-dose LPS challenge enhanced TLR4/NF-κB signaling activation in the liver of CDAA-fed mice. LPS challenge potentiated CDAA-diet-mediated insulin resistance, hepatic steatosis with upregulated lipogenic genes, and F4/80-positive macrophage infiltration with increased proinflammatory cytokines. It is noteworthy that LPS administration extensively boosted pericellular fibrosis with the activation of hepatic stellate cells in CDAA-fed mice. Exogenous LPS administration exacerbated pericellular fibrosis in CDAA-mediated steatohepatitis in mice. These findings suggest a key role for LPS/TLR4 signaling in NASH progression, and the authors therefore propose this as a suitable model to mimic human NASH.

Elevated interleukin-4 levels predicted advanced fibrosis in chronic hepatitis C.

Cytokine imbalance has been associated with chronic hepatitis C virus (HCV) infection. We hypothesized that cytokines have an important role in fibrosis development in HCV infection. Data of 92 patients were analyzed retrospectively. Fluorescent Bead immunoassay was used to measure the following serum cytokine levels: Interferon γ, tumor necrosis factor α, interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, and IL-12. Various statistical analyses were used as appropriate. Of the 92 HCV-infected patients, 49 (53.3%) were male, 23 (25%) patients had advanced (fibrosis grades 3-4) fibrosis, and the mean age of the study population was 51.9 ± 9.4 years. Elevation of baseline IL-4 level (>490 pg/mL) was associated with liver fibrosis grade by χ test (odds ratio [OR] = 2.99; 95%, CI = 1.02-8.78; p = 0.042) and multivariate logistic regression (OR = 4.26; 95% CI = 1.13-16.02; p = 0.032). Also, IL-4 had strong diagnostic value in advanced liver fibrosis by using area under receiver operating characteristics curve analysis. Assessment of fibrosis score was consequently developed from our findings and compared with other noninvasive serum markers to assess liver fibrosis. This study provides evidence that increased IL-4 expression predicted advanced liver fibrosis in treatment of naive HCV-infected patients. The newly developed "FIL4" score had good predictive value for advanced fibrosis before treatment and this value was even strong in HCV-genotype 1b patients.

The Role of Berberine in the Prevention of HIF-1α Activation to Alleviate Adipose Tissue Fibrosis in High-Fat-Diet-Induced Obese Mice.

Berberine (BBR) is the main active ingredient of a traditional Chinese herb Coptis chinensis. It has been reported to exhibit beneficial effects in treating diabetes and obesity. However, the underlying mechanism has not been fully elucidated. Adipose tissue fibrosis is a hallmark of obesity-associated adipose tissue dysfunction. HIF-1α plays a key role in adipose tissue fibrosis, which closely linked to metabolic dysfunction in obese state. We hypothesized that BBR may alleviate obesity-induced adipose tissue fibrosis and associated metabolic dysfunction through inhibition of HIF-1α. To test this hypothesis, we treated high fat diet (HFD) feeding mice with different dose of BBR (100 mg/kg, 200 mg/kg, and 300 mg/kg) for 8 weeks. We found that BBR treatment greatly decreased the body weight gain and reduced insulin resistance induced by HFD. Data also revealed that BBR improved histologic fibrous of epididymal white adipose tissue (eWAT) and was accompanied with inhibition of the abnormal synthesis and deposition of extracellular matrix (ECM) proteins, such as collagen and fibronectin. We also found that BBR treatment suppressed the expression of HIF-1α and decreased the mRNA expression of LOX in epididymal adipose tissue, which plays a key role in fibrosis development. Taken together, these results suggest that BBR can regulate metabolic homeostasis and suppress adipose tissue fibrosis through inhibiting the expression of HIF-1α.

PGC-1α Protects from Notch-Induced Kidney Fibrosis Development.

Kidney fibrosis is the histologic manifestation of CKD. Sustained activation of developmental pathways, such as Notch, in tubule epithelial cells has been shown to have a key role in fibrosis development. The molecular mechanism of Notch-induced fibrosis, however, remains poorly understood. Here, we show that, that expression of peroxisomal proliferation g-coactivator (PGC-1α) and fatty acid oxidation-related genes are lower in mice expressing active Notch1 in tubular epithelial cells (Pax8-rtTA/ICN1) compared to littermate controls. Chromatin immunoprecipitation assays revealed that the Notch target gene Hes1 directly binds to the regulatory region of PGC-1α Compared with Pax8-rtTA/ICN1 transgenic animals, Pax8-rtTA/ICN1/Ppargc1a transgenic mice showed improvement of renal structural alterations (on histology) and molecular defect (expression of profibrotic genes). Overexpression of PGC-1α restored mitochondrial content and reversed the fatty acid oxidation defect induced by Notch overexpression in vitro in tubule cells. Furthermore, compared with Pax8-rtTA/ICN1 mice, Pax8-rtTA/ICN1/Ppargc1a mice exhibited improvement in renal fatty acid oxidation gene expression and apoptosis. Our results show that metabolic dysregulation has a key role in kidney fibrosis induced by sustained activation of the Notch developmental pathway and can be ameliorated by PGC-1α.

Editorial: Liver Myofibroblasts.

Editorial: Liver Myofibroblasts.

Reactive oxygen species and fibrosis: further evidence of a significant liaison.

Age-related diseases such as obesity, diabetes, non-alcoholic fatty liver disease, chronic kidney disease and cardiomyopathy are frequently associated with fibrosis. Work within the last decade has improved our understanding of the pathophysiological mechanisms contributing to fibrosis development. In particular, oxidative stress and the antioxidant system appear to be crucial modulators of processes such as transforming growth factor-β1 (TGF-β1) signalling, metabolic homeostasis and chronic low-grade inflammation, all of which play important roles in fibrosis development and persistence. In the current review, we discuss the connections between reactive oxygen species, antioxidant enzymes and TGF-β1 signalling, together with functional consequences, reflecting a concept of redox-fibrosis that can be targeted in future therapies.Graphical abstractᅟ

Combined Inhibition of CTGF-Signaling and Radiation Therapy in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a strong desmoplastic reaction, tissue hypoxia and resistance to radiation therapy. Connective tissue growth factor (CTGF) plays a key role in development of fibrosis and tumor progression, therefore, representing an attractive therapeutic target for the treatment of PDAC. Particle therapy with carbon ions is less dependent on oxygen enhancement ratio (OER) and has produced encouraging phase 1/2 clinical data in PDAC. We aimed to investigate the effect of combined CTGF-inhibition and photon vs carbon radiation therapy.

Increased Plasma Tissue Inhibitors of Metalloproteinase Concentrations as Negative Predictors Associated With Deterioration of Kidney Allograft Function Upon Long-Term Observation

Chronic allograft injury (CAI) is the most frequent cause of progressive kidney allograft impairment and eventual loss, which is due to interstitial fibrosis and tubular atrophy (IF/TA). Mechanisms of CAI are not fully understood. Chemokines, cytokines, metalloproteinases (MMPs), and tissue inhibitors of metalloproteinases (TIMPs) play roles in fibrosis development. The aims of this study were to evaluate plasma and urine TIMPs (TIMP-1 and TIMP-2), MMPs (MMP-2 and MMP-9), proinflammatory interleukin-6 (IL-6), chemokine (C-C motif) ligand 2 (CCL2 chemokines previously known as monocyte chemoattractant protein-1 [MCP-1]) among 150 recipients beyond 1 year post–renal transplantations and to explore the usefulness of these potential biomarkers of ongoing allograft injury. Renal transplant recipients compared with healthy volunteers (control group) showed significantly increased plasma and urine IL-6, MMP-9, TIMP-1, and TIMP-2, as well as lower plasma MMP-2 and urine CCL2 concentrations. Compared with recipients showing good function those with impairments displayed higher plasma TIMP-1 (P < .001) and TIMP-2 (P = .003) concentrations. The recipient estimated glomerular filtration rate (eGFR) values negatively correlated with plasma TIMP-1 and TIMP-2 levels (r = −0.43; P < .0001 and rs = −0.42; P < .0001, respectively) and with urine IL-6 excretion (rs = −0.33; P < .0001). Multivariate and receiver operating characteristic (ROC) analyses showed TIMP-1 plasma level assessments to be useful estimates of allograft injury.

Fibrosis in non-alcoholic fatty liver disease: correlation with simple blood indices and association with tumor necrosis factor-alpha olymorphisms.

The study was conducted with an aim to evaluate the clinico-pathological profile, the correlation of AST: ALT ratio and APRI with histological fibrosis, and the frequency of two specific polymorphisms (-238, -308) in the TNF alpha promoter region in patients with NAFLD. The present study compared aspartate transaminase/alanine transaminase (AST/ALT) ratio and AST-to-platelet ratio index (APRI) with fibrosis score in 29 patients who underwent liver biopsy for NAFLD. Single nucleotide polymorphisms (SNP) in the tumor necrosis factor-alpha (TNF-alpha) promoter region at positions -308 and -238 were examined by polymerase chain reaction-restriction fragment length polymorphism. AST/ALT ratio correlated better than the APRI with liver fibrosis in patients with NAFLD (AUROC of 0.9 compared to 0.68). TNF-alpha promoter region SNPs were present in only a minority of patients, and did not correlate with fibrosis severity. AST/ALT ratio correlated well with liver fibrosis in Indian patients with NAFLD. The SNPs studied had no role in development of fibrosis in Indian patients with NAFLD.

Increased Plasma Timps Concentrations as the Negative Predictor Associated with Deterioration of Kidney Allograft Function in the Long-Term Observation

Introduction: Chronic allograft injury (CAI) is the most frequent cause of kidney graft loss, and presents with progressive graft impairment. Chemokines, cytokines and MMPs/TIMPs system play the role in fibrosis development. The aim of the study was to assess the importance of MMPs/TIMPs, IL-6 and CCL2 (previously MCP-1) in renal transplant recipients (RTR) with long-term allograft function (over 1 year) with impaired graft function Methods: 150 RTR (male 66%, aged 49,2 ± 11,5 y.), at mean 73,4 ± 41,2 months (range 12-240) after kidney transplantation and 37 healthy volunteers (male 54%, aged 48,4 ± 14,1 y.) as controls, were assessed for plasma and urine MMP-2, MMP-9, TIMP-1, TIMP-2, IL-6 and CCL2. Investigated factors were evaluated by ELISA, and urine concentrations were standardized to urine creatinine. Depending on allograft function 45 RTR had eGFR > 60 ml/min/1,73m2, and 104 RTR had eGFR < 60 ml/min/1,73m2, respectively. The data are presented as mean ± SD or median and 95% Cl for the median. The Mann-Whitney U test (for independent samples) was applied, and differences with p < 0,05 were considered statistically significant. Results: 1. RTR compared with controls had significantly lower eGFR (48 ± 16 and 73 ± 10 ml/min/1,73m2; p = 0,0001) and increased concentrations of plasma and urine IL-6 (p = 1,8e-0,5 and p = 0,0001), MMP-9 (p = 0,0015 and p = 0,003), TIMP-1 (p = 2,2e-16 and p=3,4e-05), TIMP-2 (p = 0,003 and p = 0,02), respectively, as well as lower plasma MMP-2 (p = 7,5e-06) and urine CCL2 (p = 3,3e-05) concentrations. 2. RTR with impaired graft function (eGFR < 60 ml/min/1,73m2) compared with RTR with preserved graft function (eGFR > 60 ml/min/1,73m2) had higher median plasma TIMP-1 (165 ng/ml, 95%Cl 151 - 171 ng/ml vs 124 ng/ml, 95%Cl: 115 - 141 ng/ml; p < 0,0001) and TIMP-2 (93 ng/ml, 95%Cl: 88 - 99 ng/ml vs 79 ng/ml, 95%Cl: 76 - 88 ng/ml; p = 0,0005) concentrations and trend to higher median urine IL-6 concentration (0,9 pg/ml, 95%Cl: 0,6- 1,3 pg/ml vs 0,4 pg/ml, 95%Cl: 0,3 - 0,9 pg/ml; p = 0,054). 3. There were no significant differences in plasma and urine CCL2, MMP-2, MMP-9 and plasma IL-6 concentrations between RTR with preserved and impaired graft function. Conclusion: RTR compared with healthy controls had significantly higher plasma and urine IL-6, urine CCL2 concentrations and unsettled MMPs/TIMPs system RTR with impaired graft function had significantly increased plasma TIMP-1, TIMP-2 and trend to increased urine IL-6 concentrations compared with RTR with preserved graft function.

Regulator of G protein signaling 2 is a functionally important negative regulator of angiotensin II-induced cardiac fibroblast responses

Cardiac fibroblasts play a key role in fibrosis development in response to stress and injury. Angiotensin II (ANG II) is a major profibrotic activator whose downstream effects (such as phospholipase Cβ activation, cell proliferation, and extracellular matrix secretion) are mainly mediated via G(q)-coupled AT(1) receptors. Regulators of G protein signaling (RGS), which accelerate termination of G protein signaling, are expressed in the myocardium. Among them, RGS2 has emerged as an important player in modulating G(q)-mediated hypertrophic remodeling in cardiac myocytes. To date, no information is available on RGS in cardiac fibroblasts. We tested the hypothesis that RGS2 is an important regulator of ANG II-induced signaling and function in ventricular fibroblasts. Using an in vitro model of fibroblast activation, we have demonstrated expression of several RGS isoforms, among which only RGS2 was transiently upregulated after short-term ANG II stimulation. Similar results were obtained in fibroblasts isolated from rat hearts after in vivo ANG II infusion via minipumps for 1 day. In contrast, prolonged ANG II stimulation (3-14 days) markedly downregulated RGS2 in vivo. To delineate the functional effects of RGS expression changes, we used gain- and loss-of-function approaches. Adenovirally infected RGS2 had a negative regulatory effect on ANG II-induced phospholipase Cβ activity, cell proliferation, and total collagen production, whereas RNA interference of endogenous RGS2 had opposite effects, despite the presence of several other RGS. Together, these data suggest that RGS2 is a functionally important negative regulator of ANG II-induced cardiac fibroblast responses that may play a role in ANG II-induced fibrosis development.

Epithelial Notch signaling regulates interstitial fibrosis development in the kidneys of mice and humans

Chronic kidney disease is a leading cause of death in the United States. Tubulointerstitial fibrosis (TIF) is considered the final common pathway leading to end-stage renal disease (ESRD). Here, we used pharmacologic, genetic, in vivo, and in vitro experiments to show that activation of the Notch pathway in tubular epithelial cells (TECs) in patients and in mouse models of TIF plays a role in TIF development. Expression of Notch in renal TECs was found to be both necessary and sufficient for TIF development. Genetic deletion of the Notch pathway in TECs reduced renal fibrosis. Consistent with this, TEC-specific expression of active Notch1 caused rapid development of TIF. Pharmacologic inhibition of Notch activation using a γ-secretase inhibitor ameliorated TIF. In summary, our experiments establish that epithelial injury and Notch signaling play key roles in fibrosis development and indicate that Notch blockade may be a therapeutic strategy to reduce fibrosis and ESRD development.