Transforming growth factor-β (TGF-β) is a key driver of fibrosis in chronic kidney disease, acting via canonical and non-canonical signalling pathways to activate myofibroblasts and induce the production of extracellular matrix. This Review describes the mechanisms by which TGF-β promotes renal fibrosis, the pathways that modulate TGF-β signalling, and new therapeutic opportunities for the inhibition of TGF-β-driven renal fibrosis
Fibrosis: mechanisms and targets
Fibrosis is characterized by the excess accumulation of extracellular matrix components, leading to disrupted tissue function in affected organs. Fibrosis can develop in nearly every part of the body, and is an important driver of end-stage organ failure and death in a variety of chronic diseases. The high proportion of individuals affected by organ fibrosis and the associated morbidity and mortality of fibrotic disease has led to ongoing efforts to understand the mechanisms involved in the activation of fibroblasts and abnormal deposition of extracellular matrix, with the aim of developing new therapeutic strategies to prevent or treat fibrotic disease. The goal of this collection is to highlight the latest developments in this field and provide insights into the pathological processes of fibrosis and efforts to identify therapeutic avenues.
The collection consists of Reviews and Research articles from several Nature journals, describing the latest advances in fibrosis research in various organs, including the liver, kidney, heart, skin and lung. It also includes relevant News and Opinion articles and additional content, including a selection of peer-reviewed procedures from Nature Protocols, and a PrimeView, which summarizes the main features of systemic sclerosis.
In liver diseases, inflammasome activation is a major contributor to hepatocyte damage, immune cell activation and amplification of inflammation. This Review provides a detailed account of the different types of inflammasomes that are involved, their activation and biological functions in the context of liver injury and disease progression.
Renal fibrosis is caused by renal inflammation, although the underlying mechanisms are unclear. Here, the authors discuss the function of tubular epithelial cells and specific leukocytes—including macrophages, CD4+T cells and mast cells—in the progression from inflammation to fibrosis, as well as the prevention of fibrosis.
Fibrosis is characterized by excessive accumulation of connective tissue components in organs or tissues and is a critical, and potentially lethal, component of systemic sclerosis (SSc). Here, the authors describe the pathological role of fibrosis in the development of SSc, outlining the crucial triggers of fibrosis (including endothelium, aberrant immune responses and endoplasmic reticulum stress, among others).
Fibrosis is a reactive process that develops in response to excessive epithelial injury and inflammation. Here, Katalin Susztak and colleagues discuss the reactivation of three key developmental signalling pathways — Notch, Wnt and Hedgehog — in response to injury, and describe the roles of these pathways in the development of renal fibrosis.
During stress or injury-induced cardiac remodelling, fibroblasts increase production of extracellular matrix proteins, which leads to fibrosis formation, and consequently, heart failure. In this Review, Thomas Thum describes the contribution of noncoding RNAs to this process, with a specific focus on microRNAs that might be used as future therapeutic targets or biomarkers for cardiac fibrosis.
Systemic sclerosis is an autoimmune disease characterized by vasculopathy-induced fibrosis of the skin and organs that can be life-threatening. Varga and colleagues describe the current views of pathogenesis and treatment, and present an outlook for the future.
The notion that chronic kidney disease (CKD) can be repaired has spurred intense research over the past decade and has focused on antifibrotic therapies, with numerous strategies being explored preclinically and clinically. In this Review, the authors describe the therapeutic concepts and molecular targets under investigation to inhibit or even reverse CKD.
Fibrosis is a common but often debilitating pathological process involved in diseases of different tissues. Here, Macdonald and colleagues describe the common features and pathophysiological processes that lead to fibrosis of different organs, and present a 'fibrosis toolbox': a collection of small molecules that can be used to further dissect the pathogenesis of tissue fibrosis.
Primary biliary cirrhosis (PBC) leads to progressive cholestasis, biliary fibrosis and cirrhosis and characteristic symptoms with a marked effect on quality of life. Evolution in our understanding of disease mechanisms in PBC is rapidly leading to the advent of new and re-purposed therapeutic agents targeting key processes. This Review provides a current perspective on potential approaches to PBC treatment, and highlights the challenges faced in evaluating and implementing those treatments.
Transforming growth factor-β (TGF-β), a key component in altered vascular and connective tissue homeostasis, is often linked with the pathogenesis of fibrotic diseases such as systemic sclerosis (SSc). In this Review, Lafyatis highlights the known mechanisms ofin situTGF-β activation and summarizes the evidence that place TGF-β at the centre of SSc pathogenesis.
The persistent production of extracellular matrix during fibrosis leads to impaired organ function. Myofibroblasts are considered the predominant effector cell during fibrosis; however, the exact origin of myofibroblasts during kidney disease is widely debated. Here, the authors describe the evidence supporting the various potential origins of renal myofibroblasts as well as the techniques used to trace and identify these progenitor cells. They discuss the therapeutic methods that might prevent the transition of precursors to a myofibroblast phenotype, thereby inhibiting fibrosis.
Mendelian conditions, which are caused by dysfunction of a single gene, illustrate how the availability of the human genome sequence and tools for interrogating individual genomes can provide insights into disease. In this Review, cystic fibrosis is presented as an example of how genetics can continuously inform clinical research and practice.
Cardiac MRI is a noninvasive phenotyping tool that allows for accurate and easy detection and quantification of myocardial fibrosis in myocardial tissue. In this Review, Ambale-Venkatesh and Lima focus on late-gadolinium enhancement and T1 mapping strategies, and explore the different prognostic applications of this technique.
Chronic kidney disease (CKD) is becoming a worldwide epidemic, largely due to the increased prevalence of obesity and diabetes in the general population. As a consequence, new targets and treatments are urgently required to reduce the burden of CKD and the need for renal replacement therapy in affected patients. Here, the authors discuss new insights into the fibrotic and inflammatory pathways that lead to CKD and highlight novel targets for potential disease-arresting therapies.
The WNT pathway has a vast array of functions and aberrant WNT signalling is correspondingly implicated in numerous diseases, including cancer, fibrosis and nervous system disorders. Kahn discusses our understanding of this developmentally important pathway, the complexities associated with safely targeting it therapeutically and WNT-modulating agents that are currently being investigated.
Podocytes are susceptible to injury and undergo a series of adaptive, maladaptive or catastrophic responses depending on the severity and duration of the insult. Emerging evidence indicates a central role for Wnt/β-catenin signalling in mediating podocyte dysfunction and the development of proteinuria. Here, Lili Zhou and Youhua Liu describe advances in current understanding of the pathomechanisms of Wnt/β-catenin signalling in mediating podocyte injury and discuss the therapeutic potential of targeting this pathway for the treatment of proteinuric kidney disease.
Thyroid-associated ophthalmopathy (TAO) is an orbital manifestation of Graves disease. The pathogenesis of TAO is still not well understood and effective therapies for TAO are lacking. Here, Terry Smith reviews the processes that underlie autoimmunity and inflammation in the orbit of patients with TAO, with a focus on the role of infiltrating fibrocytes expressing the TSH receptor. Therapeutic implications are also discussed.
Progression of kidney disease is characterized by the sustained release of proinflammatory and profibrotic cytokines and growth factors, leading to renal fibrosis. TGF-β is considered to be one of the main regulators of fibrosis, but preclinical studies have revealed important synergistic roles for other growth factors, including CTGF, EGF and PDGF, in this process. Here, the authors discuss the roles of these growth factors in kidney fibrosis, as well as the evidence supporting their qualification as additional targets for novel antifibrotic therapies.
Cells within the microvascular compartment, particularly leukocytes, can affect angiogenesis, inflammation and fibrosis. Kreuger and Phillipson discuss how to target these cells therapeutically, focusing on ways to interfere with intracellular communication and reprogramme leukocytes, which could have applications in the design of drugs and their delivery systems.
Acute kidney injury (AKI) is associated with high levels of mortality and an increased risk of progressive chronic kidney disease. Here, David Ferenbach and Joseph Bonventre describe the mechanisms involved in the initiation and propagation of AKI. They discuss the prototypic mechanisms employed by the damaged kidney to repair, and how the adaptive processes of repair can become maladaptive, leading to the development of progressive fibrotic kidney disease and a state that can be considered accelerated kidney ageing.
The renin–angiotensin–aldosterone system (RAAS) regulates blood pressure homeostasis via multiple mechanisms that act on a variety of organs. The development of drugs that target RAAS components is an active area of research. The authors of this Review discuss current and future therapeutic manipulation of the RAAS and its promise in improving the care of patients with hypertension.
IgG4-related disease can affect any organ system, including the kidney. Renal involvement is an indication for prompt treatment, owing to an increased risk of chronic kidney disease. In this Review, Frank Cortazar and John Stone provide an overview of systemic IgG4-related disease before describing in detail the renal manifestations of IgG4-related tubulointerstitial nephritis and membranous glomerulonephropathy secondary to IgG4-related disease. They consider the pathophysiology, as well as current and future treatment options.
Emerging evidence implicates autophagy in the maintenance of energy homeostasis, both at the cellular level and within the organism as a whole. The authors of this Review discuss the control of cellular autophagy by nutrients, the regulation of energy metabolism by autophagy and the consequences of autophagy dysfunction and modulation in metabolic disease.
Diabetic kidney disease remains the most common cause of end-stage renal disease, indicating the need for additional therapeutic approaches beyond renin–angiotensin system blockade. Here, the authors review developments in renoprotective therapy in the past decade and critically analyse failed randomized controlled trials. They also discuss novel approaches to diabetic kidney disease that have shown promise in animal models or are currently being investigated in clinical studies.
In the past decade considerable advances have been made in understanding the physiology and pathophysiology of coagulation proteases, their regulators and receptors in renal disease. In this Review, Berend Isermann and colleagues discuss the haemostatic and non-haemostatic functions of coagulation regulators and receptors in the kidney, the roles of coagulation proteases in acute kidney injury, chronic kidney disease and renal transplantation, and the potential for translating these insights into targeted therapies.
Diabetic cardiomyopathy is a major cause of morbidity and mortality, and its prevalence is increasing. This Review discusses the latest research in diabetic cardiomyopathy, summarizes current understanding of the molecular mechanisms underpinning this condition and explores potential preventive and therapeutic strategies.
Targeting of the pulmonary capillary vascular niche promotes lung alveolar repair and ameliorates fibrosis
Pulmonary fibrosis induced by repetitive chemical injury in mice involves cross talk among macrophages, endothelial cells and fibroblasts. Macrophages induce expression of the Notch ligand Jag1 in pulmonary capillary endothelial cells, leading to Notch pathway activation in perivascular fibroblasts and fibrosis.
Shahin Rafii and colleagues show that the balance between two stromal-derived factor-1 receptors, CXCR7 and CXCR4, determines whether liver injury results in a regenerative or fibrotic response in liver sinusoidal endothelial cells (LSECs). Activation of a pro-regenerative CXCR7/Id1 pathway predominates after acute injury, whereas chronic liver injury induces sustained activation of FGFR1 in LSECs, which augments expression of CXCR4, interfering with protective CXCR7 signalling and shifting the response towards fibrogenesis. These results suggest possible strategies for developing therapeutics that facilitate the promotion of liver repair without provoking fibrosis.
Tissue fibrosis is a major contributor to mortality in the developed world. Here, the authors identify a genetic variant in the intronic region of interferon-λ4 that is a strong predictor of hepatic inflammation and fibrosis, independent of liver disease aetiology
Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology
Myofibroblasts drive fibrogenesis in the liver but their cellular origins remain unclear. Here Mederacke et al. use the Lratgene to label hepatic stellate cells (HSCs) in transgenic mice and reveal HSCs as the major source of myofibroblasts in models of toxic, biliary and fatty liver fibrosis.
TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease
Non-alcoholic fatty liver disease (NAFLD) is characterized by increased hepatic triglyceride content (HTGC) in the absence of high alcohol consumption. Here the authors show that a genetic variant in TM6SF2, which is known to be associated with HTGC, is a clinically relevant modifier of hepatic fibrogenesis and increases the risk of progressive NAFLD.
Liver fibrosis involves the activation of hepatic stellate cells (HSCs). Here the authors show that the guanine exchange factor GIV is specifically upregulated in HSCs, and that it serves as an integrator of multi-receptor driven pro-fibrotic signalling in the liver via its ability to activate G proteins.
Chronic pancreatitis is an inflammatory disease accompanied by fibrosis. Here the authors show that pancreatic stellate cells produce IL-4 and IL-13 that trigger alternative activation of macrophages, and that genetic or pharmacological inhibition of IL-4/IL-13 signaling ameliorates the disease.
Epithelial-to-mesenchymal transition induces cell cycle arrest and parenchymal damage in renal fibrosis
During renal fibrosis epithelial cells undergo a partial epithelial-to-mesenchymal transition that can be targeted to reverse established disease.
Snail1-induced partial epithelial-to-mesenchymal transition drives renal fibrosis in mice and can be targeted to reverse established disease
During renal fibrosis, epithelial cells undergo a partial epithelial-to-mesenchymal transition that can be targeted to reverse established disease.
Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development
A new study shows that reduced fat metabolism in renal tubule cells contributes to kidney fibrosis.
High-efficiency reprogramming of fibroblasts into cardiomyocytes requires suppression of pro-fibrotic signalling
Direct reprogramming of cardiac fibroblasts into cardiomyocytes is an attractive strategy for heart regeneration, but it is hampered by the low efficiency of the process. Here the authors show that mouse fibroblasts can be reprogrammed with high efficiency into functional cardiomyocytes when pro-fibrotic signaling is inhibited.
Nilotinib reduces muscle fibrosis in chronic muscle injury by promoting TNF-mediated apoptosis of fibro/adipogenic progenitors
Tgf-β1 contributes to fibrosis during chronic injury by abrogating Tnf-directed apoptosis of fibro/adipogenic progenitor cells during muscle regeneration
Systemic sclerosis (SSc) is an incurable disease of unknown cause, characterized by vasculopathy, autoimmunity and fibrosis. Here the authors show that simultaneous decrease in two transcription factors, KLF5 and Fli1, underlies SSc development in mice and represents a signature trait of SSc patients.
The protein Mincle can sense pathogens and molecules associated with cell death. Here the authors show that Mincle expressed in macrophages is a mediator of obesity-induced fibrosis and inflammation of adipose tissue, and that Mincle knockout mice are protected from diet-induced metabolic dysfunction.
The adipokine endotrophin promotes tumour inflammation and angiogenesis, but its effects on adipose tissue are unclear. Here, Sun et al.show that endotrophin promotes adipose tissue inflammation and fibrosis, and that injections of an anti-endotrophin antibody improve metabolic parameters of mice on a high-fat diet.
NR4A1 is shown to be an endogenous inhibitor of TGF-β-induced fibrosis and represents a therapeutic target for this condition.