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Renal fibrosis, characterized by glomerulosclerosis and tubulointerstitial fibrosis, is the final common manifestation of a wide variety of chronic kidney diseases (CKD). Irrespective of the initial causes, progressive CKD often results in widespread tissue scarring that leads to the complete destruction of kidney parenchyma and end-stage renal failure, a devastating condition that requires dialysis or kidney replacement.
The pathogenesis of renal fibrosis is, in essence, a monotonous process that is characterized by an excessive accumulation and deposition of extracellular matrix (ECM) components. In this context, the fundamental questions are what types of cells produce a large amount of ECM proteins under pathologic conditions, and how are they regulated. A better understanding of these issues is not only imperative for elucidating the pathogenic mechanism of CKD, but may also provide novel insights into developing new therapeutic strategies. Over the past several years, significant progress has been made in our understanding of the cellular and molecular mechanisms of renal fibrosis.
In this article, I attempt to provide a concise review of recent advances on several issues in the pathogenesis and therapeutics of chronic renal fibrosis.
Cellular Events in Renal Fibrogenesis: It Takes a Village
The pathologic findings of renal fibrosis are often described as glomerulosclerosis, tubulo-interstitial fibrosis, inflammatory infiltration, and loss of renal parenchyma characterized by tubular atrophy, capillary loss, and podocyte depletion. The underlying cellular events leading to these histologic presentations are even more complicated; they include mesangial and fibroblast activation, tubular epithelial to mesenchymal transition (EMT), monocyte/macrophage, and T-cell infiltration, and cell apoptosis. Although many in vitro studies emphasize the importance of one particular cellular event such as fibroblast activation, it should be kept in mind that no single type of cell in isolation is capable of initiating and sustaining a full scale of renal fibrosis. Renal fibrogenesis clearly necessitates the participation and interaction of many types of kidney resident and infiltrated cells. In this sense, it takes a ‘village’ to develop fibrotic lesions in an otherwise healthy kidney.
The current model of renal fibrogenesis is one similar to the wound-healing response to injury.
After the initial injury, the affected kidney tissues undergo a series of events in an attempt to repair and recover from the damage. These processes include kidney resident cell activation, which leads to the production and secretion of proinflammatory cytokines. The gradients of chemotactic cytokines provide a directional signal for guiding the infiltration of inflammatory monocytes/macrophages and T cells to the injured sites. Depending on the etiology of renal injury, glomerular or interstitial infiltrated inflammatory cells become activated, and produce injurious molecules such as reactive oxygen species, as well as fibrogenic and inflammatory cytokines. These, in turn, stimulate mesangial cells, fibroblasts, and tubular epithelial cells to undergo phenotypic activation or transition and produce a large amount of extra cellular matrix (ECM) components. Normal and novel forms of ECM proteins are then deposited in the extracellular compartment, and they are often crosslinked and become resistant to degradation. Continuous deposition of ECM results in fibrous scars and distorts the fine architecture of kidney tissues, leading to the collapse of renal parenchyma and the loss of kidney function. According to the sequence of these destructive events, the pathogenesis of renal fibrosis can be divided into several distinctive phases.
However, it should be stressed that renal fibrogenesis is a dynamic process in which many of these events occur simultaneously, often in a mutually stimulating fashion.
In view of its direct relevance to matrix accumulation, activation of the matrix-producing effector cells is generally regarded as a central event in renal fibrogenesis. Reliant on the nature and sites of injury, glomerular mesangial cells, interstitial fibroblasts, and tubular epithelial cells are the major fibrogenic cells in the injured kidney, although other cells, including bone marrow-derived cells, also play a role.
Myofibroblastic activation of mesangial cells and fibroblasts is an early fibrogenic response after injury, whereas tubular EMT often occurs in a delayed fashion. Recently, the pathologic significance of tubular EMT in renal fibrosis has become increasingly recognized.
The hallmarks of mesangial and fibroblast activation, as well as tubular EMT, are denovo expression of α-smooth muscle actin, a contractile protein normally restricted to perivascular smooth muscle cells in vivo, and overproduction of the interstitial matrix components such as type I and type III collagen and fibronectin.
What causes the difference between a healthy wound-healing and fibrotic response remains a fascinating question. One obvious distinction is the duration of the injury. An acute, transient renal injury may trigger similar responses to those in CKD, including inflammatory infiltration, secretion of fibrogenic factors, and fibroblast activation, but the damage is eventually repaired via tubular regeneration and matrix remodeling, and tissue structure and function are finally restored. As the duration of injury prolongs, wounded tissues react in an imprudent way, leading to a maladaptation that is characterized by the overproduction of the ECM that causes fibrous scar. It is ambiguous why the same tissue interprets the injurious signal differently in acute versus chronic conditions. One potential explanation could be that in the chronic situation after repeated injury, the fibrogenic signal is continuously present and increasingly amplified, owing to the progressive loss of the Smad antagonists.
The intensified fibrogenic signal not only stimulates fibroblast activation in a manner akin to wound-healing, but also initiates tubular EMT, a critical event that leads to the destruction of renal parenchyma, with no way to return when left untreated. In this sense, tubular EMT is a unique cellular event that distinguishes a fibrogenic consequence in CKD from a reparative injury response after acute insult, and thereby determines the divergent fates of the kidney when afflicted with a transient or sustained injury.
Endogenous Antifibrotic Factors and Fibrosis Therapy: It is all about the balances
Ancient Chinese medicine has taught us that a healthy state in human body depends on the delicate balance between Yin and Yang. Departure from this balance will lead to disastrous consequences and illness. Guided by this principle, the presence of fibrogenic factors almost certainly predicts that there have to be some antagonists that counteract their action. Indeed, recent studies have identified endogenous antifibrotic factors, particularly hepatocyte growth factor (HGF) and bone morphogenetic protein-7 (BMP-7), which can precisely antagonize the fibrogenic action of TGF-β. Therefore, restoration of the balance between pro- and antifibrotic signaling could serve as a guiding principle for designing rational therapeutic strategies. In this regard, inhibition of profibrotic TGF-β/Smad signaling is only half the equation. Another approach is to increase the antifibrotic factors in the diseased kidney.
HGF has recently emerged as a potent antifibrotic factor in the kidney, as well as in other organs. It possesses a remarkable ability to promote tissue repair and regeneration after various injuries. In many aspects, the effects of HGF and TGF-β on kidney cells are exactly opposite. In vitro, HGF effectively inhibits the TGF-β-mediated myofibroblastic activation from glomerular mesangial cells and interstitial fibroblasts, and blocks tubular EMT.
Dissection of the signal pathways has provided novel insights into the molecular mechanisms of HGF action. We demonstrate that HGF blocks Smad2/3 nuclear translocation in interstitial fibroblasts, upregulates Smad transcriptional corepressor TGIF via protein stabilization in mesangial cells, and induces SnoN expression in tubular epithelial cells.
Therefore, albeit initially divergent, HGF signaling in different kidney cells is converged to a common pathway that specifically targets Smad signaling. Consistently, administration of exogenous HGF or its gene ameliorates renal fibrosis and preserves kidney functions in a wide variety of animal models of CKD, including obstructive nephropathy, remnant kidney, diabetic nephropathy, and chronic allograft nephropathy.
BMP-7 is a member of the TGF-β superfamily that counteracts the fibrogenic action of TGF-β. Its expression is often downregulated in the fibrotic kidney. Supplementation with exogenous BMP-7 suppresses renal fibrosis in experimental renal diseases. In vitro, BMP-7 antagonizes TGF-β and inhibits tubular EMT.
Although the molecular details remain to be elucidated, inhibition of the fibrogenic Smad signaling is believed to play a central role in mediating the antifibrotic action of BMP-7.
Despite the remarkable therapeutic efficacy of HGF and BMP-7 in animal models, translation of these promising results into humans is waiting to happen. At this stage, it appears that there are sufficient preclinical data to warrant clinical trials to test the safety and efficacy of the antifibrotic factors on patients with chronic renal insufficiency. In spite of many challenges, these clinical trials will offer exciting opportunities for the ultimate test of the usefulness and efficacy of antifibrotic factors in the treatment of human CKD.
Induction of endogenous antifibrotic factor expression could be another strategy in combating renal fibrosis. In this respect, we have recently found that many renoprotective agents, such as peroxisome proliferator-activated receptor-γ agonists, 9-cis-retinoic acid, and 1,25-dihydroxyvitamin D3, induce HGF gene expression in mesangial cells and interstitial fibroblasts. Therefore, induction of antifibrotic HGF expression may be a convergent pathway leading to renal protection.
Consistent with this notion, ablation of HGF receptor in mesangial cells abolishes the antifibrotic effects of these renoprotective agents. Hence, as an alternative path to direct administration of HGF itself, upregulation of endogenous HGF expression by small molecule inducers may offer a practically attractive strategy for the treatment of renal fibrosis in clinical setting.
Conclusion
The process of renal fibrosis, in which multiple cellular events and molecular mediators participate and interact in concert, is enormously complicated. Despite these complexities, several important issues have recently come to light. In comparison to healthy wound healing, tubular EMT is a unique event that occurs in the fibrotic tissue after chronic injury, which may set the injured kidney in motion to scar formation. It also becomes apparent that induction and activation of TGF-β/Smad signaling are critical for initiating a fibrogenic response; and equally important is the loss of the Smad antagonists, which could render the fibrogenic signaling out of control. Finally, the identification of endogenous antifibrotic factors has provided us with unprecedented opportunities for therapeutic interventions of renal fibrosis. In view of the impressive efficacy of antifibrotic factors in attenuating experimental renal fibrosis, it is hoped that the translation of these studies into humans will result in improved therapeutics for patients with chronic renal insufficiency.