The origin of renal fibroblasts/myofibroblasts and the signals that trigger fibrosis

Abstract

Renal fibrosis is a common characteristic of chronic kidney disease (CKD). Aberrant and excessive depositions of extracellular matrix (ECM) proteins in both glomeruli and interstitial regions are typical hallmarks of renal fibrosis and amplify the severity of kidney injury. To date, an approved therapy specifically targeted to renal fibrosis is needed to mitigate or even retard renal fibrosis. Recent findings have identified a unique population of myofibroblasts as a primary source of ECM in scar tissue formation. However, the origin of myofibroblasts in renal fibrosis remains the subject of controversial debates. The advancement in lineage tracing and immunofluorescent microscopy technologies have suggested that myofibroblasts may arise from a number of sources such as activated renal fibroblasts, pericytes, epithelial-to-mesenchymal transition (EMT), endothelial-to-mesenchymal transition (EndoMT), bone marrow derived cells and fibrocytes. Recent studies also indicate that multiple ligands of TGF-β/Smads are the direct mediators for renal fibrosis. Consistently, inhibition of the TGF-β/Smads signaling pathway using various strategies significantly reduce renal fibrotic lesions and ameliorate kidney injury, suggesting that targeting the TGF-β/Smads signaling pathway could be a new strategy for effective therapies. In this review, we will briefly discuss the diverse origins of myofibroblasts and molecular pathways triggering renal fibrosis. Prospective therapeutic approaches based on those molecular mechanisms will hopefully offer exciting insights in the development of new therapeutic interventions for patients in the near future.

Introduction

The epidemic of chronic kidney disease (CKD) has been rising significantly over the past few decades and become a major health problem imposing enormous socioeconomic challenges to society. The causes of CKD can be secondary to diseases such as diabetes, hypertension, HIV infection and obesity, or due to primary kidney injury such as focal segmental glomerulosclerosis (FSGS) and acute kidney injury (AKI) (Mikulak and Singhal, 2010, Quigley et al., 2009, Venkatachalam et al., 2015, Nakagawa et al., 2007, Gasser et al., 2013, Sarafidis, 2008). All these pathological events cause normal kidney parenchymal destruction with progressive scar tissue formation, eventually leading to renal fibrosis, which is a common characteristic of end-stage renal disease. Fibrosis is marked by excessive and pathological accumulation of extracellular matrix (ECM) consisting of collagen I, III and IV, fibronectin, laminin, heparan and perlecan. Such aberrant ECM accumulation can result in destruction of an organ accompanied with compromised organ function. glomerulosclerosis and tubulointerstitial fibrosis are the common hallmarks of CKD. Fibrotic lesions in the glomerular tuft consist mainly of collagen I and IV and fibronectin, resulting in loss of blood flow and reduced filtration. ECM accumulation in the region between tubules and peritubular capillaries impede tubular normal function involving the removal of toxins and mediating cellular transport. As the fibrosis expands to the surrounding capillaries and the entire nephron, the kidney loses its structural support and a decrease in kidney volume results in loss of renal function. Currently, the common therapeutic strategy for treating non-diabetic CKD is the control of systemic blood pressure by blocking the angiotensin-aldosterone system (RAAS) to reduce proteinuria and slow the progression of CKD (Thethi et al., 2012, Choudhury et al., 2010). To date, an approved therapy specifically targeted to renal fibrosis is not available, even though extensive research has been performed to investigate the primary molecular mediators of fibrosis. Research involving animal models of kidney disease has identified myofibroblasts as major matrix producing cells contributing to fibrosis after injury.

Myofibroblasts can be characterized by being α-smooth muscle actin (α-SMA) positive, are mainly located in the renal interstitium and to a lesser extent in glomeruli in various animal models of renal fibrosis. The percentage of myofibroblasts is proportionally correlated with severity of renal fibrosis. However, the diverse origin and mixed phenotypic heterogeneity of myofibroblasts makes them a difficult therapeutic target. Therefore, delineating the origin of myofibroblasts and their molecular signaling pathways would provide valuable information for designing effective therapies to stop or even reverse renal fibrosis.