Can A Kidney Repair Itself

Fibrogenesis Tissue Repair. 2009; ii: 3.

Possible mechanisms of kidney repair

Paola Romagnani

¹Excellence Center for Research, Transfer and High Educational activity DENOthe, University of Florence, Florence, Italy

³Department of Medicine, Harvard Medical School, Partition of Matrix Biology, Department of Medicine Beth Israel Deaconess Medical Center, Boston, Massachusetts, U.s.a.

Raghu Kalluri

ⁱⁱBeth State of israel Deaconess Medical Eye, Boston, Massachusetts, USA

Received 2009 Jan two; Accepted 2009 Jun 26.

Abstract

In most adult epithelia the process of replacing damaged or dead cells is maintained through the presence of stem/progenitor cells, which allow epithelial tissues to be repaired post-obit injury. Existing prove strongly supports the presence of stem cells in the adult kidney. Indeed, recent findings provide evidence in favour of a office for intrinsic renal cells and against a physiological role for bone marrow-derived stem cells in the regeneration of renal epithelial cells. In improver, recent studies have identified a subset of CD24⁺CD133⁺renal progenitors within the Bowman's capsule of adult human kidney, which provides regenerative potential for injured renal epithelial cells. Intriguingly, CD24⁺CD133⁺renal progenitors also represent common progenitors of tubular cells and podocytes during renal development. Chronic injury causes dysfunction of the tubular epithelial cells, which triggers the release of fibrogenic cytokines and recruitment of inflammatory cells to injured kidneys. The rapid interposition of scar tissue probably confers a survival advantage by preventing infectious microorganisms from invading the wound, but prevents subsequent tissue regeneration. Nevertheless, the existence of renal epithelial progenitors in the kidney suggests a possible explanation for the regression of renal lesions which has been observed in experimental animals and even in humans. Thus, manipulation of the wound repair process in gild to shift information technology towards regeneration will probably require the power to slow the rapid fibrotic response so that renal progenitor cells can let tissue regeneration rather than scar formation.

Background

Most epithelia need to constantly supplant damaged or dead cells throughout life. The procedure of continual cell replacement is critical for the maintenance of adult tissues and is typically maintained through the presence of stem cells. Stalk cells are functionally defined by their ability to self-renew and to differentiate into the jail cell lineages of their tissue of origin [1]. In one case activated, epithelial stalk cells tin can generate proliferating progeny, which are oftentimes referred to as transiently amplifying cells. In their normal environment, transiently amplifying cells will divide actively for a restricted period of time, expanding the cellular pool that will then differentiate along a particular cell lineage to brand the tissue. The physiological replacement of cells varies substantially among different epithelia. The epithelium of the intestine completely self-renews within effectually 5 days. Past contrast, interfollicular epidermis takes approximately 4 weeks to renew, whereas the lung epithelium can take as long every bit six months to be replaced. In add-on some epithelia, such as pilus follicles, present a cyclic manner of cell replacement [ane]. Similarly, the mammary gland proceeds through cycles of growth and degeneration during and following pregnancy [one]. In improver, stalk cells are critically involved in regeneration upon wounding. Unless the epithelial stalk/progenitor cells are permanently damaged, most epithelia are able to repair their tissues following injury [1]; when epithelial stalk cells are depleted, fibrotic responses occur [1].

Practise renal stalk/progenitor cells exist in the adult kidney?

The understanding of kidney repair is withal in its infancy despite the rapid advances fabricated in recent years. The kidney is one of the few organs that undergo mesenchymal-epithelial transition during development [ii]. Moreover, structures present in the adult kidney arise from reciprocal interactions between ii detached embryonic appendages, namely the ureteric bud (UB) and metanephric mesenchyme (MM) [2]. The developed kidney contains more than 24 mature cell types arranged in distinct vascular, interstitial, glomerular and tubular compartments [two]. This unique organogenesis and structural complexity of the adult kidney has presented many challenges to the identification and characterization of kidney stem cells [2,3]. Attempts to identify adult kidney stem cells were made on the basis of the broad principles of stalk cell biological science, such equally prolonged jail cell-cycling fourth dimension (label-retaining cells), ability to extrude Hoechst dye (side population cells), by restrictive jail cell culture conditions, or past using markers expressed by other stalk cells or developing kidney [3]. Existing prove strongly supports the presence of stem cells in the developed kidney. Indeed, remission of affliction and regression of renal lesions have been observed in experimental animals and even in humans [4]. Identification and knowledge of renal stem jail cell biology might help to unlock latent regenerative pathways in human kidney, which would have the potential to change medical practice as much equally the introduction of dialysis did in the twentieth century.

The origin of the cells that supercede injured tubular epithelia is non known [3,5], although several lines of evidence suggest an intrarenal source [6,seven]. Recently, putative adult kidney stem cells accept been isolated, with some show indicating that they may enable epithelial repair after injury [eight-xviii]. Several studies have suggested the existence of an interstitial renal stem cell. Ane fashion of looking for stalk cells in solid organs was a pulse of bromodeoxyuridine (BrdU) followed by a long chase menses. The quiescent stem cells, which do not divide, maintain the high levels of BrdU deposited in their genomes, whereas the dividing, more differentiated stem cells steadily dilute the BrdU incorporated into their genomes as they proliferate. Maeshima et al. [12,xiii] identified BrdU-labelled cells, which they termed renal progenitor-similar tubular cells, in the renal tubules. Oliver et al. [fourteen] identified a population of BrdU-label-retaining cells inside the interstitium of renal papilla in the rat kidney. However, the use of BrdU labelling does not seem to be a specific method for identification of stem cells [sixteen].

Other studies have identified a rare population of developed interstitial cells in rat or human being kidney [8,9], and such cells have been proposed to engraft into tubules of either developing or injured kidney tissue [8,9], suggesting that extratubular cells can traverse the basement membrane and contribute to epithelium [14]. Although intriguing, this hypothesis has recently been questioned by a study past Humphreys et al. who have developed a method for distinguishing the source of kidney tubular regeneration based on studies in transgenic rodents for the homeodomain transcriptional regulator Six2 [xviii]. In this model, the Six2 promoter drives a fusion protein of green fluorescent protein (GFP) and Cre recombinase, which is expressed transiently in renal epithelial precursors during the developmental period of active nephrogenesis [18]. GFPCre expression is not present in the adult, and this expression is non observed after injury. When Six2-GFPCre mice are crossed with a floxed STOP reporter strain, Cre-dependent removal of the stop sequence in progeny leads to constitutive and heritable expression of a marker cistron such that all mesenchyme-derived renal epithelial cells, from the Bowman'due south capsule to the junction of the connecting segment and collecting duct, are heritably labelled [xviii]. In contrast, the unabridged interstitial compartment is unlabelled [eighteen]. Thus, the maintenance of labelled tubules mail service-injury would support a model of epithelial tubule repair due to surviving tubular epithelial cells or stalk/progenitor cells localized inside the labelled nephron, while label dilution would implicate an unlabelled, interstitial stem cell in the repair process. These findings indicate that papillary interstitial cells [14] or other types of interstitial stem/progenitor cells [viii,9] do not direct contribute to renal epithelial cells regeneration. These observations likewise betoken that repair of injured nephrons is predominantly accomplished past intrinsic, surviving tubular epithelial cells or a subset of stem/progenitor cells localized inside the nephron [18].

Recent studies identified a subset of renal stem/progenitor cells inside the Bowman's capsule of adult homo kidney [15]. These renal progenitors were identified through the cess of the presence of both CD24, a surface molecule that has been used to place different types of human stalk cells [19,xx] and CD133, a marker of several types of adult tissue stem cells [21,22]. The results showed that both markers were co-expressed past a subset of parietal epithelial cells selectively localized at the urinary pole of the Bowman'southward capsule [xv] (Figure 1). Once isolated, CD24⁺CD133⁺renal progenitors were found to lack lineage-specific markers; to express transcription factors that are characteristic of multipotent stem cells, and to exhibit self-renewal, high clonogenic efficiency, and multidifferentiation potential [15]. When injected intravenously in SCID mice that had acute renal failure (ARF), CD24⁺CD133⁺renal progenitors regenerated tubular structures in different portions of the nephron and as well reduced the morphological and functional kidney harm [fifteen]. The identification of CD24⁺CD133⁺renal progenitors is in agreement with results obtained in transgenic mice, which suggests that endogenous cells of the nephron are responsible for repair of injured tubular epithelium [18], and allows the hypothesis that, from the urinary pole of the Bowman's capsule, CD24⁺CD133⁺renal progenitors might initiate the replacement and regeneration of tubular epithelial cells in adult human being kidney [15] (Figure 2).

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CD24⁺CD133⁺renal progenitors localize at the urinary pole of the Bowman'south capsule in adult human kidneys. (A) Triple-label immunofluorescence for CD133, (green), CD24 (red) and β1 integrin (blue) showing that in a mature glomerulus, co-expression of CD133 and CD24 characterizes a subset of cells in the Bowman's capsule (white) localized at the urinary pole (Upwards). AA = afferent arteriola. Objective 20×. (B) High power magnification of a triple-label immunofluorescence for CD133, (green), CD24 (red) and CD106 (blue) in a subset of cells in the Bowman's sheathing (white). Sections were stained as previously reported [15].

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Hypothetical diagram for kidney regeneration by dissimilar types of renal and extrarenal progenitors. CD24+CD133+ renal progenitors (ruby) are localized at the urinary pole and are in close contiguity with podocytes (green) at one extremity (the vascular stalk) and with tubular renal cells (xanthous) at the other extremity. A transitional cell population (red/dark-green) displays features of either renal progenitors (ruddy) or podocytes (green) and localizes between the urinary pole and the vascular pole. At the vascular stalk of the glomerulus, the transitional cells are localized in shut continuity with cells that lack progenitor markers, only exhibit the podocyte markers and the phenotypic features of differentiated podocytes (green). On the opposite side, at the urinary pole, transitional cells (scarlet/xanthous) with a mixed phenotype between tubular cells (yellow) and progenitor cells (red). The directions of differentiation is indicated by the arrows (modified from [24]).

Is there a unique renal progenitor common to renal evolution and the repair of adult kidney?

Regenerative biological science draws on the understanding of normal developmental processes. It is generally believed that developed stem/progenitor cells stand for a rest population straight derived from the organ-specific embryonic progenitor that is involved in organogenesis during fetal life [23-25]. This prompted united states to evaluate whether co-expression of CD133 and CD24 might be useful to track down multipotent kidney stem/progenitor cells during human being embryonic life.

Nephrons, the basic functional units of the kidney, are generated repetitively during kidney organogenesis from a mesenchymal progenitor population. Development of the mature mammalian kidney results from reciprocal signalling betwixt the branching UB tips and the undifferentiated MM. This leads to the assemblage and condensation of renal epithelia progenitor cells to grade the renal vesicle, which so undergoes transformation in the S-shaped body [2]. At this phase, the proximal end of the S-shaped body becomes invaded past claret vessels, differentiates into podocytes and parietal epithelial cells, and then generates glomeruli. Simultaneously, the middle and the distal segments of the S-shaped body brainstorm to express proteins that are characteristic of tubular epithelia [2]. The existence of renal embryonic progenitors in the MM is supported by the ascertainment that some MM-derived cells display multidifferentiation potential [two,26-28]. Accordingly, in embryonic human kidneys, co-expression of CD133 and CD24 characterizes a subset of cells in the cap mesenchyme, renal vesicles and S-shaped bodies that brandish self-renewal and multidifferentiation potential (Figure 1).

Interestingly, during nephron development, co-expression of CD133 and CD24 remained selectively localized to cells of the urinary pole of the Bowman's capsule [28]. Accordingly, CD24⁺CD133⁺renal embryonic progenitors progressively decreased during gestation and represented < ii% of whole cells in developed kidneys [15,28]. When injected into mice with ARF, CD24⁺CD133⁺renal embryonic progenitors regenerated cells of different portions of the nephron, reduced tissue necrosis and fibrosis, and significantly improved renal part [28]. In agreement with the putative nature of stem/progenitor cells, CD24⁺CD133⁺renal embryonic progenitors expressed high levels of the stem cell-specific transcription factor BmI-one [29,30] and could generate tubular cells of different portions of the nephron in a model of acute tubular necrosis [28]. The existence of a putative MM cell with stem jail cell properties was already suggested past studies performed by the group of Reisner [31], who demonstrated that functioning renal tissue tin be reconstituted by MM derived from kidneys of 8 weeks of gestation [31]. Indeed, fetal kidney tissue obtained from 10 to 14 weeks of gestation maintains the property to generate de novo functional nephrons, only generates a smaller number of mature glomeruli and tubuli than kidneys of 8 weeks of gestation [31]. Accordingly, CD24⁺CD133⁺renal embryonic progenitors are enriched in kidneys of 8 to 9 weeks of gestation, essentially subtract during 10 to 14 weeks of gestation, and represent < 2% of whole renal cells in adults.

Information technology is interesting that in both fetal and adult kidney, CD24⁺CD133⁺progenitors persist as parietal epithelial cells localized at the urinary pole of the Bowman'southward capsule, supporting the concept that CD24⁺CD133⁺progenitors might correspond a subpopulation of renal embryonic progenitors preserved from the early on stages of nephrogenesis, and the urinary pole of the Bowman's sheathing may stand for stem cell niche, which is a specific site in adult tissues where stem cells reside (Figure 1) [32]. In agreement with this hypothesis, embryonic stem cells, in one case differentiated toward renal tubular cells, selectively migrated to the tubuloglomerular junction after injection into developing kidneys [17]. More recently, studies performed in transgenic rodents for the homeodomain transcriptional regulator Six2 have confirmed the being in the cap mesenchyme of a multipotent nephron progenitor population [33]. Indeed, Six2-expressing cells give rising to all cell types of the main body of the nephron during all stages of nephrogenesis [34]. Pulse labeling of Six2-expressing nephron progenitors at the onset of kidney development suggests that the Six2-expressing population is maintained past self-renewal and is multipotent, generating the multiple domains of the whole cortical nephron [34]. Notably, descendants of a Six2+ cell tin exist establish inside molecularly singled-out compartments of a single nephron – podocytes, proximal and distal tubule structures – farther confirming that a single multipotent progenitor is the source of both the glomerular and tubular epithelial cells that plant the adult nephron [34].

Do bone marrow-derived cells contribute to tissue repair?

Some studies accept suggested that cells from os marrow might possess a surprising caste of plasticity and could differentiate into cell types of multiple organs of the trunk [33,35-38]. Accordingly, information technology was claimed that os marrow-derived stem cells (BMSC) could contribute to the generation of new epithelial cells in functionally of import numbers after kidney injury [39,40]. In light of their ease of accessibility, BMSC seem to exist a very strong candidate for the handling of renal diseases. Several subsequent studies have examined this possibility, with contrasting results [40-60].

Sugimoto and colleagues demonstrated that in a mouse model for Alport syndrome, os marrow cells contribute to the emergence of viable podocytes which are associated with the product of new basement membrane [47]. In addition, unfractionated BMSC tin can differentiate into endothelial and mesangial cells in a model of progressive glomerulosclerosis [42,44] and, more surprisingly, they can form new tubular epithelial cells in functionally important numbers after kidney injury [43]. It has recently become articulate that BMSC might fuse with differentiated cells in various developed organs, further complicating the estimation of marrow transplantation studies [61]. Held and co-workers accept shown that cell fusion could exist induced between os marrow-derived cells and renal tubular cells under weather condition of chronic renal damage [60], apparently without impairment of cell partitioning or conferment of genetic instability [44,62]. Additional works by several groups have shown that tubular cell replacement with BMSC is much lower than originally reported, calling into question the concept that BMSC physiologically participate in the repair of kidney injury [47-57]. Importantly, the low charge per unit of functional improvement observed when using unfractionated BMSC suggests that in acute tubular injury, regenerating cells originated from intrarenal cells [6,7]. Accordingly, the absenteeism of label dilution in Six2-GFPCre mice after injury and repair confirms that bone marrow-derived cells exercise non directly contribute to repair of tubular epithelial cells [18]. Taken together, these findings provide strong evidence against a physiological function for BMSC-derived cells in regeneration of mail service-ischaemic tubules by direct replacement of epithelial cells.

However, several studies indicate that mesangial cells might originate from a component of the hematopoietic lineages [62-65], and that BMSC might largely contribute to the regeneration of mesangial cells. Imasawa et al. [44] demonstrated the involvement of os marrow-derived cells in normal mesangial cell turnover. Lethally irradiated mice given transplants of T-cell-depleted bone marrow cells from syngeneic donor transgenic for GFP manifested a fourth dimension-dependent increase in GFP-positive cells in their glomeruli. When isolated and cultured, these cells stained positive for the mesangial jail cell marker desmin and the cells contracted in response to angiotensin Ii (Ang II), confirming that bone marrow-derived cells have the potential to differentiate into glomerular mesangial cells. Similar experiments with mice transplanted with purified clonally expanded hematopoietic progenitor cells were carried out past Masuya et al. [62] to ostend the hematopoietic origin of bone marrow-derived mesangial cells.

Finally, several studies have provided evidence that circulating endothelial progenitor cells (EPC) may contribute to glomerular capillary repair. In rat hematopoietic chimeras, depression levels of bone marrow-derived cells staining for the rat endothelial cell antigen RECA-i [66] were observed and the number of these cells gradually increased over time, suggesting that EPC contribute to normal physiological glomerular endothelial jail cell turnover. Following anti-Thy-1.ane-induced glomerular injury the authors observed a fourfold increase in os marrow-derived endothelial cells in the glomeruli [66]. These data indicate that glomerular repair cannot just be attributed to migration and proliferation of resident endothelial cells just it also involves os marrow-derived cells.

Participation of circulating EPC in renal regeneration has as well been demonstrated in human being adults. Williams and Alvarez [67] were the first to depict the presence of acceptor endothelial cells in kidney allografts. Lagaaij et al. [68] reported that in human being renal transplants the extent of replacement of donor endothelial cells lining the peritubular capillaries past those of the acceptor was related to the severity of vascular injury. They suggested that this endothelial replacement could be explained past the interest of acceptor-derived EPC. Recently, male, donor-derived endothelial cells were observed in the renal macrovasculature of a female person patient who adult thrombotic microangiopathy after gender-mismatched bone marrow transplantation [69]. Taken together, these observations confirm a role for BMSC in maintenance and repair of renal mesangium and endothelium, just non of the epithelial components of renal tissue.

Towards the understanding of renal tissue regeneration

Tissue stem cells can class various lineages in response to physiological stimuli or injuries, a holding that has great potential for regenerative medicine approaches. All the same, in many cases repair of epithelial cells does non depend on cells generated from multipotent stem cells, just directly derives from the migration of epithelial cells from the neighbouring epithelia, as previously reported likewise for the skin [70,71]. Indeed, genetic analyses suggest that the tubular epithelium can be self-renewing later astute kidney injury. Interestingly however, several previous studies take demonstrated that the proximal tubule arises at a diverseness of angles from Bowman's capsule and that at to the lowest degree one office of the tubuloglomerular junction has an area of intermediate appearance, with prominent microvilli on parietal cells in humans, mammals and fish. The finding of intermediate cells, especially in growing animals, suggests that parietal epithelium may exist able to change to tubular and that this might peculiarly occur as the kidney grows, during severe renal disorders [72-75], following unilateral nephrectomy [76] or during ageing [77]. Thus, renal stalk/progenitor cells might contribute to tubular epithelium repair, but this probably occurs merely when a wound cannot spontaneously repair itself through the migration of neighbouring undamaged tubular cells (Figure 2).

Indeed, mice affected past rhabdomyolysis-induced acute tubular necrosis spontaneously recover from acute kidney injury, but mice undergoing early on handling with man renal progenitors prove a complete recovery of renal function and kidney tissue integrity that was non observed in mice treated with saline [15] and, more importantly, a meaning reduction of the severity of ARF, as revealed by the consistently lower blood urea nitrogen levels and extended areas of tubular tissue regenerated by homo renal progenitors that co-expressed markers of proximal and distal tubules. This suggests that CD24⁺CD133⁺progenitors tin regenerate tubular cells of different portions of the nephron, in vitro and in vivo [78,79]. However, the most important goal of regenerative medicine in the kidney is regeneration of glomerular injury, since glomerular diseases together business relationship for 90% of terminate-stage kidney illness (ESKD).

Recent insights accept defined a unified concept of glomerular diseases in which podocyte injury or loss is a common determining factor, which suggests the need for rational clinical efforts to allow podocyte regeneration [80-82]. Mature podocytes are postal service-mitotic cells, which tin undergo Dna synthesis to a express degree but do not proliferate, because they arrest in the G2/Chiliad phase of the prison cell bicycle [80-82]. Notwithstanding, in nigh adult epithelia, replacement of damaged or dead cells is maintained through the presence of stalk/progenitor cells [1]. Unless the epithelial stem/progenitor cells are permanently damaged, near epithelia are able to repair their tissues following injuries [ane]. Although glomerular disorders represent the most prominent cause of ESKD, remission of the affliction and regression of renal lesions have been observed in experimental animals and even in humans [iii]. This shows that remodelling of glomerular compages is possible, which would imply regeneration of the injured podocytes and reconstitution of the glomerular tuft. The inability of the podocyte to proliferate and supervene upon injured cells suggests the existence of potential stem/progenitor cells within the adult glomerulus. Interestingly, CD24⁺CD133⁺renal progenitors are physically located within the Bowman's capsule, the merely place in the kidney which appears to be contiguous with both tubular cells and glomerular podocytes [fifteen]. Previous studies accept suggested the beingness of transitional cells exhibiting a mixed phenotype between the parietal epithelial cells and the podocyte at the vascular pole of the glomerulus [83]. In improver, CD24⁺CD133⁺renal progenitors represent mutual progenitors of tubular cells and podocytes during renal development [29]. Accordingly, recent studies performed in our laboratory propose that CD24⁺CD133⁺renal progenitors tin can also regenerate glomerular podocytes in mice affected by adriamycin nephropathy, and can reduce the severity of proteinuria and of glomerular injury [84]. These results suggest that CD24⁺CD133⁺renal progenitors can too replace and regenerate podocytes through their division and migration forth the Bowman's sheathing towards the glomerular tuft during developed life or in response to podocyte injury (Figure 2).

The response to renal injury: from regeneration to fibrosis

In humans, problems with wound healing can manifest as either delayed wound healing (which occurs with diabetes or radiation exposure) or excessive healing (every bit occurs with hypertrophic and keloid scars). Excessive healing is characterized past the deposition of large amounts of extracellular matrix and by alterations in local vascularization and prison cell proliferation. These excessive fibrotic reactions manifest in humans every bit a 'bad scar'. These commonly occur later on major injuries such every bit burns, in which case they are referred to as hypertrophic scars. They can also appear for unknown reasons after a relatively pocket-size trauma, as is the case for keloid scars, which might accept a genetic ground [85-87]. Chronic infections, toxic and metabolic injuries, and idiopathic inflammatory diseases can promote the development of a scar, leading to tissue fibrosis [85]. In many cases, patients with progressive fibrosis have a poor prognosis and oftentimes require organ transplantation [85-87].

Although fibrosis is a role of the normal pathophysiological response to injury in many tissues, extended exposure to chronic injury results in tissue fibrosis, massive deposition of extracellular matrix, scar formation, and organ failure [87]. Chronic injury causes dysfunction of the tubular epithelial cells, which triggers release of fibrogenic cytokines and recruitment of inflammatory cells to injured kidneys [88-91]. Over the years, the primary focus of tubulointerstitial fibrosis studies has been on interstitial fibroblasts and infiltrated mononuclear cells for obvious reasons [92-94]. However, fibroblast activation after injury is, in essence, a wound-healing response by which the injured kidney attempts to repair and recover from the injury. Therefore, fibroblast activation at most may be necessary, but certainly not sufficient, for development of a full-calibration of renal interstitial fibrosis.

Fibroblasts contribute to 50% of all collagen-expressing cells in the course of renal fibrosis. Renal cortical fibroblasts maintain a quiescent country in normal kidneys, but in response to injury they proliferate and activate into myofibroblasts. Fibroblasts are not especially abundant in normal kidneys as they are in lungs, lymph nodes, and spleen. When renal fibrogenesis sets in, about 36% of new fibroblasts come up from the local epithelial mesenchymal transition (EMT), about 14–xv% from the bone marrow, and the rest from local proliferation [94]. Endothelial cells also contribute to the emergence of fibroblasts during kidney fibrosis via the procedure of EMT, every bit recently demonstrated in mouse models of unilateral ureteral obstructive nephropathy, diabetic nephropathy, and Alport renal illness [95]. Although local activation of the renin-angiotensin system (RAS) and specifically Ang Ii affects all parenchymal organs, its effect is more pronounced in renal fibrosis. RAS stimulates inflammation, including the expression of cytokines, chemokines, growth factors, and reactive oxygen species [94,96]. Ang II induces vascular inflammation, endothelial dysfunction, up-regulation of adhesion molecules, and recruitment of infiltrating cells into the kidney (Figure three) [94,96].

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Hypothetical diagram for kidney fibrosis. Chronic injury causes dysfunction of the tubular epithelial cells, which triggers release of fibrogenic cytokines and recruitment of inflammatory cells to injured kidneys. Myelo-monocytic cells recruited from the bone marrow produce TGF-β1 in injured kidneys. In turn, TGF-β1 induces activation of collagen-producing cells, which more often than not arise from kidney resident cells through epithelial-mesenchymal transition (modified [24]).

In improver, myelo-monocytic cells recruited from the bone marrow produce TGF-β1 in injured kidneys. In plough, TGF-β1 induces activation of collagen-producing cells, which mostly arise from kidney resident cells. The potential part of tubular epithelial cells in renal fibrosis is often concealed, partly because no straight connection seems to be between tubular cells and the production and degradation of extracellular matrix, a hallmark of interstitial fibrosis. Nonetheless, molecular analyses of factor expression have constantly underlined the potential importance of tubular epithelia in the fibrotic process. For instance, while it is well known that TGF-β1 expression is increased in about all of the chronic kidney disease models studied, the expression of TGF-β receptors, which determine the specificity of TGF-β action, is frequently up-regulated predominantly in renal tubular epithelium [97], indicating that tubular epithelial cells are the in vivo natural targets of this pro-fibrotic cytokine. Hence, EMT helps to reconcile the disparity between molecular analysis and pathological findings in fibrotic kidney. Recently, pericytes were too identified as a major source of interstitial myofibroblasts in the fibrotic kidney, suggesting that either vascular injury or vascular factors are the most likely triggers for pericyte migration and differentiation into myofibroblasts (Figure 3) [98].

The aggregating of fibroblasts and an excess of collagen and other matrix components at sites of chronic inflammation pb to scar tissue germination and progressive tissue injury. These fibroblasts derive from the bone marrow, just also ascend from an EMT of cells at injury sites [88,89]. EMT is probable to be involved in the progressive fibrotic diseases of the heart, lung, liver, and kidney, and genetic models provide indisputable evidence for a crucial role for EMT in renal fibrogenesis.

Conclusion

Reversal of renal fibrosis is possible, equally observed in experimental animals and fifty-fifty in humans [4]. However, whether fibrotic kidneys tin can reverse to normal renal compages remains unresolved, and the point of no render in the development of irreversible renal fibrosis still remains to be determined. The rapid interposition of scar tissue probably confers a survival advantage by preventing infectious microorganisms from invading the wound and past inhibiting the continued mechanical deformation of larger tissues (a process that could compound the initial insult), but prevents subsequent tissue regeneration. All the same, the existence of renal epithelial progenitors in the kidney suggests a possible explanation for the regression of renal lesions, and indicates that a manipulation of the wound repair process in society to shift information technology towards regeneration [99] volition probably require the power to slow the rapid fibrotic response so that renal progenitor cells tin can regenerate functional tissue and avoid scar formation.

Abbreviations

Ang II: angiotensin II; ARF: acute renal failure; BMSC: os marrow-derived stem cells; BrdU: bromodeoxyuridine; EMT: epithelial mesenchymal transition; EPC: endothelial progenitor cells; ESKD: end phase kidney disease; GFP: green fluorescent protein; MM: metanephric mesenchyme; RAS: renin-angiotensin system; UB: ureteric bud

Competing interests

The authors declare that they have no competing interests.

Acknowledgements

The inquiry leading to these results has received funding from the European Enquiry Council Starting Grant under the European Customs's Seventh Framework Program (FP7/2007-2013), ERC grant number 205027. This study was besides supported by the Tuscany Ministry of Wellness and the Associazione Italiana per la Ricerca sul Cancro.

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