Renal Fibroblasts and Myofibroblasts in Chronic Kidney Disease

Abstract

Fibroblasts and myofibroblasts are believed to be the key effector cells in renal fibrogenesis responsible for the synthesis and deposition of extracellular matrix components. In an editorial written 15 yr ago, Gown claimed to have the mysteries of the fibroblast (partially) unmasked (1). Unfortunately, 15 yr later many mysteries of the fibroblast and myofibroblasts remain intact and we are only beginning to solve the riddle this cell poses. This manuscript summarizes current understanding of the origin, phenotypic heterogeneity, and function of renal (myo)fibroblasts. Renal interstitial fibrosis is considered the hallmark of progressive renal disease. In particular, many studies have determined that the extent of tubulointerstitial involvement correlates better with renal function deterioration than glomerular changes do, thus the extent of damaged tubulointerstitial area in any given renal biopsy has important implications for the renal prognosis of the patient (summarized in [2]). Tubulointerstitial fibrosis is characterized by the accumulation of extracellular matrix (ECM) components including collagen types I, III, and IV, as well as proteoglycans and fibronectin. Fibroblasts are considered the primary matrix-producing cells in the kidney and hence they are clinically relevant as principal mediators of renal fibrosis associated with progressive renal failure. Fibroblasts in the Kidney Originally, resident interstitial fibroblasts were described as contractile cellular elements being the sole source of ECM (3). Today, interstitial fibroblasts can be best defined as the nonvascular, nonepithelial, noninflammatory cells of the interstitium (and of connective tissue in general), and they are its principal cellular component (4). Fibroblasts synthesize many of the constituents of the fibrillar ECM, such as fibronectin and types I, III, and V collagen (5,6), and they are also a major source of ECM-degrading proteases such as matrix metalloproteinases (MMP), underscoring their crucial role in maintaining an ECM homeostasis via regulation of ECM turnover (7,8). Fibroblasts are considered mesenchymal cells that display a spindle-shaped morphology (9). However, due to the relative lack of specific markers, it can be challenging to distinguish fibroblasts from other cells of mesenchymal origin, such as pericytes, vascular smooth muscle cells (VSMC), or mesenchymal stem cells in the kidney (Table 1), and thus renal fibroblasts have remained relatively poorly characterized in molecular terms. What Is the Myofibroblast? The term “myofibroblast” is used for fibroblasts that possess unique contractile properties (6). Myofibroblasts were originally identified as the cells being responsible for wound contraction (10). In the setting of renal fibrosis, myofibroblasts are considered to represent an activated fibroblast phenotype, which is mainly responsible for ECM deposition in tubulointerstitial fibrosis (11). Myofibroblasts are large cells with long processes resembling fibroblasts and VSMC (12). In addition, they are characterized by bundled microfilaments, a well-developed rough endoplasmatic reticulum, hemidesmosomes, and other intercellular attachments (11). In the absence of electron microscopy validation, myofibroblasts are commonly identified by their expression of α-smooth muscle actin (α-SMA) (6,13). Identification of myofibroblasts based on the expression of α-SMA can be challenging, however, because α-SMA is also expressed by other cells of mesenchymal lineage such as VSMC and pericytes (1,4) (Table 1). Traditionally, myofibroblasts in the kidney have been considered to represent an activated population of resident fibroblasts (14). However, recent studies questioned whether the increase in the number of α-SMA–positive cells is the result of residual proliferating smooth muscle cells, proliferation of the few fibroblasts constitutively expressing the protein, or by de novo expression of formerly nonexpressing cells. This issue is further complicated by the observation that in anti–glomerular basement membrane antibody-induced nephritis (15), as well as in periglomerular areas in a study by the same group (16), early expansion of α-SMA–positive myofibroblasts is observed in perivascular regions similar to what had been described Wiggins et al. (15), suggesting that shedding of VSMC and pericytes contributes to the population of α-SMA–positive cells in the fibrotic interstitium. Furthermore, at least for some fibroblasts, activation is not associated with de novo expression of α-SMA (17). Ru and colleagues described that even among so-called myofibroblasts a higher degree of variability and complexity due to different levels of α-SMA expression may exist (18). In summary, all these studies support the notion that fibroblasts from kidneys with interstitial fibrosis differ from fibroblasts in normal kidneys. Myofibroblasts and Nonmyofibroblasts De novo expression of α-SMA is not the only change during the transi