Brief Report - (2025) Volume 15, Issue 3
Received: 01-May-2025, Manuscript No. jnt-26-178931;
Editor assigned: 05-May-2025, Pre QC No. P-178931;
Reviewed: 19-May-2025, QC No. Q-178931;
Revised: 22-May-2025, Manuscript No. R-178931;
Published:
29-May-2025
, DOI: 10.37421/2161-0959.2025.15.561
Citation: Wei-Lun, Chen. ”Targeting Cellular Mechanisms of Renal Fibrosis Progression.” J Nephrol Ther 15 (2025):561.
Copyright: © 2025 Wei-Lun C. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.
Renal fibrosis, a universal consequence of chronic kidney diseases, signifies an excessive accumulation of extracellular matrix (ECM) within the kidney parenchyma [1].
This pathological process underlies the progression of kidney dysfunction and eventual organ failure, making its understanding crucial for developing effective therapeutic interventions. This review aims to consolidate current knowledge on the cellular and molecular mechanisms that drive renal fibrosis. We will delve into the distinct contributions of various cell types and signaling pathways that orchestrate the fibrotic response in the kidney. Understanding these complex interactions is paramount for identifying novel targets and strategies to halt or reverse kidney damage. The review will cover the critical roles of resident kidney cells, such as renal fibroblasts and tubular epithelial cells, in this process. Furthermore, the involvement of infiltrating immune cells, particularly macrophages, will be thoroughly examined for their significant impact on fibrogenesis. The intricate interplay between these cellular components, mediated through paracrine signaling and direct matrix deposition, will be elucidated to provide a comprehensive view of the fibrotic cascade. Additionally, we will explore emerging therapeutic avenues that aim to modulate these identified cellular pathways. These include antifibrotic drugs targeting key growth factors like TGF-β, anti-inflammatory agents designed to dampen the immune response, and innovative cell-based therapies with regenerative potential. The overarching goal is to foster a deeper comprehension of the cellular underpinnings of renal fibrosis to pave the way for the development of more effective and targeted treatments for patients suffering from kidney diseases [1].
The pathogenesis of renal fibrosis involves the differentiation and activation of specific cell types that contribute to excessive ECM deposition [2].
Myofibroblasts are recognized as key effector cells in this process, and their origins are diverse, arising from activated fibroblasts, epithelial cells undergoing epithelial-to-mesenchymal transition (EMT), and endothelial cells undergoing endothelial-to-mesenchymal transition (EndoMT) [2].
The signaling pathways that govern this transformation are complex, with TGF-β and Wnt signaling playing prominent roles in promoting myofibroblast differentiation and subsequent matrix production [2].
Understanding these differentiation pathways is essential for developing targeted therapies. The therapeutic implications stemming from this knowledge are significant, focusing on strategies to inhibit myofibroblast activation and differentiation. This approach offers promising avenues for treating various fibrotic kidney diseases by addressing a central cellular component of the fibrotic process [2].
Furthermore, the intricate involvement of the immune system, particularly macrophages, has been increasingly recognized as a critical factor in the development and progression of renal fibrosis [3].
Macrophages exhibit remarkable phenotypic plasticity, undergoing polarization into distinct subtypes, such as pro-inflammatory (M1) and pro-fibrotic (M2) macrophages [3].
It is the M2 subtype that significantly promotes fibrosis by secreting growth factors and matrix-remodeling enzymes, thereby exacerbating tissue damage and scar formation [3].
Consequently, therapeutic strategies are being explored to modulate macrophage function, including repolarization techniques to shift them away from a pro-fibrotic phenotype or depletion of these pro-fibrotic macrophages [3].
This cellular perspective on immune cell involvement provides a vital angle for developing treatments for kidney fibrosis [3].
In parallel, tubular epithelial cells (TECs) play a pivotal role in the initiation and advancement of renal fibrosis [4].
Under various stress conditions, TECs can undergo EMT, a process by which they lose their epithelial characteristics and acquire mesenchymal traits, contributing to the pool of myofibroblasts and releasing pro-fibrotic factors [4].
The mechanisms by which TECs sense and respond to renal injury are complex and lead to interstitial inflammation and subsequent fibrosis [4].
Therefore, protecting TECs from injury and preventing EMT are identified as crucial therapeutic targets for mitigating renal fibrosis [4].
The intricate relationship between resident renal fibroblasts and the extracellular matrix (ECM) is another cornerstone of the fibrotic process [5].
Quiescent fibroblasts can be activated into proliferative and contractile myofibroblasts, which are the primary producers of collagen and other ECM components that accumulate in fibrotic kidneys [5].
The behavior of these fibroblasts is influenced by mechanical forces and soluble mediators present in the renal microenvironment [5].
Targeting fibroblast activation pathways, such as inhibiting key signaling cascades or modulating ECM turnover, holds significant therapeutic potential for managing renal fibrosis [5].
Transforming growth factor-beta (TGF-β) has emerged as a central mediator in the pathogenesis of renal fibrosis [6].
This potent cytokine activates signaling pathways that profoundly influence myofibroblast differentiation, extracellular matrix synthesis, and the inflammatory milieu within the kidney [6].
Consequently, current and emerging therapeutic strategies are critically assessing methods to target the TGF-β pathway. These interventions include small molecule inhibitors and antibody-based therapies, all aimed at counteracting the fibrotic effects of excessive TGF-β signaling [6].
Beyond growth factors, the renin-angiotensin-aldosterone system (RAAS) has been implicated as a significant driver of renal fibrosis [7].
Activation of RAAS leads to increased inflammation, oxidative stress, and subsequent deposition of extracellular matrix in the kidney [7].
Inhibiting RAAS components, such as through the use of ACE inhibitors and angiotensin receptor blockers, has been shown to attenuate renal fibrosis [7].
Furthermore, emerging therapies are exploring ways to target specific RAAS components or their downstream effects to provide more nuanced interventions [7].
The Wnt/β-catenin signaling pathway represents another critical area of therapeutic interest in the context of renal fibrosis [8].
Aberrant activation of this pathway has been demonstrated to promote myofibroblast differentiation and the subsequent accumulation of extracellular matrix, thereby contributing to fibrotic kidney disease [8].
Various strategies are being investigated for their potential to inhibit Wnt signaling, including the use of small molecule antagonists and other modulators, positioning this pathway as a promising target for future treatments [8].
Oxidative stress also plays a substantial role in the development and progression of renal fibrosis [9].
Reactive oxygen species (ROS) can inflict damage on kidney cells and activate pro-fibrotic signaling pathways, thus exacerbating the fibrotic process [9].
Therapeutic interventions are being explored to mitigate the effects of oxidative stress, including antioxidant therapies and agents designed to bolster endogenous antioxidant defenses, offering potential treatments for fibrotic kidney disease [9].
Finally, targeting inflammasomes and chronic inflammation presents a compelling therapeutic strategy for renal fibrosis [10].
Inflammasome activation can trigger inflammatory cascades that contribute to tissue damage and fibrosis within the kidney [10].
Emerging therapies that modulate inflammasome activity, such as NLRP3 inhibitors, are under investigation for their potential to curb the progression of renal fibrosis [10].
Renal fibrosis, a common pathological outcome of chronic kidney diseases, is characterized by the excessive deposition of extracellular matrix (ECM) within the renal interstitium. This process ultimately leads to impaired kidney function and progression to end-stage renal disease [1].
Understanding the cellular and molecular underpinnings of this complex phenomenon is paramount for the development of effective therapeutic strategies. A central aspect of renal fibrosis involves the activation and differentiation of myofibroblasts, which are the primary producers of ECM components [2].
These myofibroblasts can arise from diverse cellular sources, including resident renal fibroblasts, activated tubular epithelial cells undergoing epithelial-to-mesenchymal transition (EMT), and endothelial cells undergoing endothelial-to-mesenchymal transition (EndoMT) [2].
The signaling pathways that regulate these transitions, such as the transforming growth factor-beta (TGF-β) and Wnt/β-catenin pathways, are critical targets for therapeutic intervention [2, 6, 8]. The role of immune cells, particularly macrophages, in driving renal fibrosis is also a significant area of research [3].
Macrophages exhibit plasticity and can polarize into different functional phenotypes, with the M2 subset being particularly implicated in promoting fibrosis through the secretion of pro-fibrotic mediators and matrix-remodeling enzymes [3].
Therapeutic strategies aimed at modulating macrophage polarization or depleting pro-fibrotic macrophages are being explored to mitigate renal fibrosis [3].
Tubular epithelial cells (TECs) themselves contribute to fibrosis by undergoing EMT in response to injury, thereby generating myofibroblasts and releasing pro-fibrotic factors [4].
Consequently, protecting TECs from damage and preventing EMT are considered vital for preventing or slowing fibrotic progression [4].
Resident renal fibroblasts are also key players, transforming into activated myofibroblasts that deposit excessive ECM [5].
Beyond cellular mechanisms, systemic factors contribute significantly to renal fibrosis. The renin-angiotensin-aldosterone system (RAAS) is a major driver, with its activation leading to increased inflammation, oxidative stress, and ECM deposition [7].
Inhibiting RAAS components has proven beneficial in attenuating renal fibrosis [7].
Oxidative stress, driven by reactive oxygen species (ROS), also damages kidney cells and activates pro-fibrotic pathways, making antioxidant therapies a potential treatment strategy [9].
Furthermore, chronic inflammation, often mediated by inflammasome activation, perpetuates tissue damage and fibrosis [10].
Targeting inflammasomes, such as with NLRP3 inhibitors, offers a promising avenue for managing renal fibrotic diseases [10].
This comprehensive understanding of cellular and systemic contributors to renal fibrosis highlights the multifactorial nature of this condition and underscores the need for multifaceted therapeutic approaches.
Renal fibrosis, a common pathway leading to chronic kidney disease, is characterized by the excessive accumulation of extracellular matrix (ECM) within the kidney [1].
This pathological process results in progressive loss of kidney function and eventual organ failure. The review delves into the intricate cellular mechanisms that drive this fibrotic response. It highlights the critical roles of resident kidney cells, including renal fibroblasts and tubular epithelial cells, as well as infiltrating immune cells, with a particular focus on macrophages [1].
These cellular components interact through paracrine signaling and direct matrix deposition, contributing significantly to the fibrotic cascade [1].
Furthermore, the article discusses emerging therapeutic targets that aim to modulate these cellular pathways. These include antifibrotic drugs designed to inhibit growth factors such as TGF-β, anti-inflammatory agents to dampen the immune response, and novel cell-based therapies offering regenerative potential [1].
The primary goal is to deepen the understanding of the cellular underpinnings of renal fibrosis to facilitate the development of more effective interventions. Central to the pathogenesis of renal fibrosis is the role of myofibroblasts, which are identified as key effector cells responsible for excessive ECM deposition [2].
This review elucidates the diverse origins of these myofibroblasts, noting their derivation from activated fibroblasts, epithelial cells undergoing epithelial-to-mesenchymal transition (EMT), and endothelial cells undergoing endothelial-to-mesenchymal transition (EndoMT) [2].
The signaling pathways that orchestrate this myofibroblast differentiation, such as TGF-β and Wnt signaling, are critically examined for their role in promoting the fibrotic process [2].
The therapeutic implications of this research are significant, focusing on strategies that inhibit myofibroblast activation and differentiation as potential treatments for fibrotic kidney diseases [2].
Furthermore, the contribution of immune cells, particularly macrophages, to the development and progression of renal fibrosis is thoroughly investigated [3].
Macrophages possess remarkable phenotypic plasticity, allowing them to polarize into distinct subtypes, including pro-inflammatory (M1) and pro-fibrotic (M2) macrophages [3].
It is the M2 subtype that significantly promotes fibrosis by secreting growth factors and matrix-remodeling enzymes, thereby exacerbating tissue damage and scar formation [3].
Consequently, therapeutic approaches are being explored to modulate macrophage function, such as repolarization strategies or the depletion of pro-fibrotic macrophages, offering a cellular perspective on treating kidney fibrosis [3].
Tubular epithelial cells (TECs) are also implicated as crucial drivers in the initiation and progression of renal fibrosis [4].
Under conditions of stress or injury, TECs can undergo EMT, a process that contributes to the myofibroblast population and the release of pro-fibrotic factors [4].
The mechanisms by which TECs sense and respond to injury, leading to interstitial inflammation and subsequent fibrosis, are explored [4].
Therefore, protecting TECs from injury and preventing EMT are highlighted as essential therapeutic targets for mitigating renal fibrosis [4].
Moreover, the complex interplay between resident renal fibroblasts and the extracellular matrix (ECM) in the fibrotic process is dissected [5].
This article details how quiescent fibroblasts are activated into proliferative and contractile myofibroblasts, which are the principal producers of collagen and other ECM components that accumulate in fibrotic kidneys [5].
The influence of mechanical forces and soluble mediators on fibroblast behavior is also examined [5].
The therapeutic potential of targeting fibroblast activation pathways, such as inhibiting key signaling cascades or modulating ECM turnover, is considered [5].
Transforming growth factor-beta (TGF-β) is recognized as a central mediator in the pathogenesis of renal fibrosis [6].
This potent cytokine activates signaling pathways that profoundly influence myofibroblast differentiation, extracellular matrix synthesis, and the inflammatory milieu within the kidney [6].
Consequently, current and emerging therapeutic strategies critically assess methods to target the TGF-β pathway, including the use of small molecule inhibitors and antibody-based therapies, all aimed at counteracting its fibrotic effects [6].
Beyond growth factors, the renin-angiotensin-aldosterone system (RAAS) is identified as a significant driver of renal fibrosis [7].
Activation of RAAS leads to increased inflammation, oxidative stress, and subsequent deposition of extracellular matrix in the kidney [7].
Inhibiting RAAS components, such as through ACE inhibitors and angiotensin receptor blockers, has been demonstrated to attenuate renal fibrosis [7].
Emerging therapies are also exploring ways to target specific RAAS components or their downstream effects for more refined interventions [7].
The Wnt/β-catenin signaling pathway represents another critical area of therapeutic interest in the context of renal fibrosis [8].
Aberrant activation of this pathway promotes myofibroblast differentiation and the accumulation of extracellular matrix, thus contributing to fibrotic kidney disease [8].
Various strategies for inhibiting Wnt signaling are being investigated, including the use of small molecule antagonists and other modulators, positioning this pathway as a promising target for future treatments [8].
Oxidative stress also plays a substantial role in the development and progression of renal fibrosis [9].
Reactive oxygen species (ROS) can inflict damage on kidney cells and activate pro-fibrotic signaling pathways, thereby exacerbating the fibrotic process [9].
Therapeutic interventions are being explored to mitigate the effects of oxidative stress, including antioxidant therapies and agents designed to bolster endogenous antioxidant defenses, offering potential treatments for fibrotic kidney disease [9].
Finally, targeting inflammasomes and chronic inflammation presents a compelling therapeutic strategy for renal fibrosis [10].
Inflammasome activation can trigger inflammatory cascades that contribute to tissue damage and fibrosis within the kidney [10].
Emerging therapies that modulate inflammasome activity, such as NLRP3 inhibitors, are under investigation for their potential to curb the progression of renal fibrosis [10].
The cellular and molecular mechanisms underlying renal fibrosis are multifaceted, involving a complex interplay of resident kidney cells, immune cells, and various signaling pathways. Renal fibroblasts are activated into myofibroblasts, which are the primary producers of extracellular matrix, leading to its excessive accumulation [5].
Tubular epithelial cells (TECs) also contribute to fibrosis through epithelial-to-mesenchymal transition (EMT), a process that generates myofibroblasts and releases pro-fibrotic factors [4].
Immune cells, particularly macrophages, play a significant role through their polarization into pro-fibrotic (M2) subtypes that secrete growth factors and matrix-remodeling enzymes [3].
The epithelial-to-mesenchymal transition (EMT) and endothelial-to-mesenchymal transition (EndoMT) are key pathways that lead to myofibroblast differentiation [2].
Signaling pathways such as TGF-β and Wnt/β-catenin are central to these cellular transformations [2, 6, 8]. Systemic factors like the renin-angiotensin-aldosterone system (RAAS) also contribute to fibrosis by promoting inflammation, oxidative stress, and ECM deposition [7].
Oxidative stress itself is a significant contributor, damaging kidney cells and activating pro-fibrotic pathways [9].
Chronic inflammation, often mediated by inflammasome activation, further exacerbates tissue damage and fibrosis [10].
Understanding these diverse contributors is crucial for developing effective therapeutic strategies that target specific cellular pathways, immune responses, and systemic factors involved in renal fibrogenesis.
Renal fibrosis, a common endpoint for chronic kidney diseases, involves excessive extracellular matrix accumulation driven by various cellular mechanisms. Resident kidney cells like fibroblasts and tubular epithelial cells, along with infiltrating immune cells such as macrophages, play critical roles through paracrine signaling and direct matrix deposition. Myofibroblasts, derived from activated fibroblasts, TECs via EMT, and endothelial cells via EndoMT, are key effector cells. Signaling pathways like TGF-β and Wnt are central to myofibroblast differentiation. Therapeutic strategies focus on targeting these cellular pathways, including inhibiting TGF-β, modulating macrophage function, protecting TECs, and inhibiting Wnt signaling. Systemic factors like RAAS activation and oxidative stress also contribute significantly, making antifibrotic drugs, anti-inflammatory agents, and antioxidant therapies potential interventions. Targeting inflammasomes and chronic inflammation is another promising therapeutic avenue.
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