Interplay between extracellular matrix components and cellular and molecular mechanisms in kidney fibrosis

Abstract

Chronic kidney disease (CKD) is characterized by pathological accumulation of extracellular matrix (ECM) proteins in renal structures. Tubulointerstitial fibrosis is observed in glomerular diseases as well as in the regeneration failure of acute kidney injury (AKI). Therefore, finding antifibrotic therapies comprises an intensive research field in Nephrology. Nowadays, ECM is not only considered as a cellular scaffold, but also exerts important cellular functions. In this review, we describe the cellular and molecular mechanisms involved in kidney fibrosis, paying particular attention to ECM components, profibrotic factors and cell–matrix interactions. In response to kidney damage, activation of glomerular and/or tubular cells may induce aberrant phenotypes characterized by overproduction of proinflammatory and profibrotic factors, and thus contribute to CKD progression. Among ECM components, matricellular proteins can regulate cell–ECM interactions, as well as cellular phenotype changes. Regarding kidney fibrosis, one of the most studied matricellular proteins is cellular communication network-2 (CCN2), also called connective tissue growth factor (CTGF), currently considered as a fibrotic marker and a potential therapeutic target. Integrins connect the ECM proteins to the actin cytoskeleton and several downstream signaling pathways that enable cells to respond to external stimuli in a coordinated manner and maintain optimal tissue stiffness. In kidney fibrosis, there is an increase in ECM deposition, lower ECM degradation and ECM proteins cross-linking, leading to an alteration in the tissue mechanical properties and their responses to injurious stimuli. A better understanding of these complex cellular and molecular events could help us to improve the antifibrotic therapies for CKD.

CCN2 Increases TGF-β Receptor Type II Expression in Vascular Smooth Muscle Cells: Essential Role of CCN2 in the TGF-β Pathway Regulation

“…The regulation of the TGF-β pathway comprises a wide range of components and factors, which lead into the activation of a large list of genes [ 51 ]. Among the latter, CCN2 plays an essential role in the profibrotic response induced by TGF-β [ 52 , 53 ]. TGF-β pathway components levels have been described to be essential in the regulation of the TGF-β activation [ 48 ].…”

Molecular Mechanisms of Kidney Injury and Repair

“…Proximal tubular cells in CCA suffer profound changes in intracellular signaling, provoking phenotypic alterations characterized by an aberrant and detrimental secretome termed the senescence-associated secretory phenotype (SASP) [59,63]. Glomerular cells, such as podocytes and endothelial cells, may undergo senescence, leading to SASP, excessive ECM accumulation (Figure 2) and glomerulosclerosis [6]. Cells of the immune system can also become senescent.…”

“…An elegant study using chimeric mice and in vitro studies clearly demonstrated the role of TGF-β/Smad3 signaling in this phenotype transition [83]. CCN2 is a matricellular ECM protein that participates in diverse biological processes, including cell proliferation and migration, ECM remodeling and kidney fibrosis [3,6,84,85]. A key paradigm in fibrosis was to consider CCN2 a key downstream mediator of pro-fibrotic factors, including TGF-β1 and Angiotensin II [86,87].…”

“…CCN2 is widely used as a fibrotic marker in kidney tissue. CCN2 promotes partial EMT in tubular cells and ECM accumulation in cultured renal cells, and is considered a therapeutic target in kidney fibrosis [6]. SASP pro-fibrotic factors also upregulate ECM components in kidney parenchymal cells and promote partial EMT in tubular cells, contributing to the AKI-to-CKD transition or CKD progression, leading to kidney fibrosis [3,88].…”

“…The acute phase of AKI, characterized by cell death, is followed by a recovery phase, where there is an activation of protective and regenerative mechanisms in surviving cells to restore epithelial cell properties and functions [3,5]. However, failed resolution may result in partial epithelial-mesenchymal transition (EMT), cell senescence, G2/M cellcycle-arrest (CCA), activation of fibroblasts and immune cells and epigenetic modifications that perpetuate inflammation and release a profibrogenic secretome, contributing to the progressive decline of kidney function and fibrosis [3,5,6] (Figure 1). In this review, we examine key molecular and cellular mechanisms involved in both maladaptive responses and the endogenous repair mechanisms in the kidney, which offer an opportunity for the design of new therapeutic approaches.…”