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Saudi Journal of Kidney Diseases and Transplantation
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EDITORIAL Table of Contents   
Year : 2008  |  Volume : 19  |  Issue : 1  |  Page : 1-19
Modulation of Renal Inflammation: Therapeutic Strategies


Kanoo Kidney Center, Dammam Central Hospital, Dammam, Saudi Arabia

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   Abstract 

Inflammation is a complex process that reflects the local and systemic responses to different immunological and non-immunological stimuli, enable resistance to disease, repair of tissue damage, and restoration of normal function with the least possible tissue damage. This is achieved by intact regulatory immune system, which includes pro- and anti-inflammatory cytokines, chemokines, growth factors, complement cascade system, renin-angiotensin system, and different sets of adhesion molecules expressed on leukocytes and vascular endothelium, in addition to neutrophils, monocytes/macrophages, and different subsets of T-lymphocytes. Once imbalance occurs in the different factors of the inflammatory response to injurious stimuli, inflammation will proceed and exacerbate tissue damage. Inflammation can be initiated by different stimuli such as deposition or formation of antibody-antigen immune complexes, sensitized T-cells, trauma, tissue necrosis, or infection. It is characterized by activation of acute phase response and release of reactants/markers such as C-reactive protein. Renal inflammation can occur either as an isolated local acute inflammatory reaction or as part of a systemic inflammatory disorder. Recently, there have been tremendous advancements in the fields of immunology and molecular biology that helped in exploring the mechanisms of renal inflammation. This has been accompanied by extensive in vitro and in vivo studies that led to a better understanding of phenotypic changes and multifunctional potentials of local and infiltrating cells, role and control of different inflammatory mediators, adhesion molecules, and the rennin-angiotensin system within the site of inflammation. These achievements helped in researching into ways to modulate renal inflammation, control the severity of renal injury, promote regeneration and tissue repair, and induce tolerance.

Keywords: Inflammation, Macrophages, T-cells, Stem cells, Cytokines, Angiotensin

How to cite this article:
Karkar A. Modulation of Renal Inflammation: Therapeutic Strategies. Saudi J Kidney Dis Transpl 2008;19:1-19

How to cite this URL:
Karkar A. Modulation of Renal Inflammation: Therapeutic Strategies. Saudi J Kidney Dis Transpl [serial online] 2008 [cited 2020 Sep 26];19:1-19. Available from: http://www.sjkdt.org/text.asp?2008/19/1/1/37427

   Introduction Top


Inflammation is a major risk factor for mortality and cardiovascular complications in patients with renal disease. It is now established that inflammation plays a primary role in kidney tissue and arterial damage leading to glomerulosclerosis, interstitial fibrosis, and atherosclerosis. Inflammation is a complex process that reflects the local and systemic responses to different immunological and non-immunological stimuli, and enable resistance to disease, repair of tissue damage and restoration of normal function with the least possible tissue damage. Inflammation can be initiated by different stimuli such as deposition or formation of antibody-antigen immune complexes, sensitized T-cells, trauma, tissue necrosis, or infection. It is characterized by activation of acute phase response and release of reactants/ markers such as C-reactive protein. [1]

Renal inflammation (glomerulonephritis and tubulo-interstitial nephritis) can occur either as an isolated local acute inflammatory reaction, or as part of a systemic inflamma­tory disorder, which usually results in inters­titial fibrosis, tubular atrophy, and glomerular sclerosis if not treated or spontaneously repaired. However, specific treatment for many causes of renal inflammation are still lacking such as most autoimmune diseases. This may be explained by the complexity and variable inter-relationship of several factors as in [Table - 1].

However, the tremendous development and advancement in the fields of immunology and molecular biology in recent years helped in exploring the mechanisms of inflammation and in particular, renal inflammation. This has been accompanied by extensive in vitro and in vivo studies that resulted in a better understanding of the phenotypic changes and multifunctional potentials of local and infiltrating cells within the site of inflamma­tion. These include activation, transition and plasticity of residential cells, adhesion, tra­fficking and activation of local and infiltrating inflammatory cells (neutrophils, monocytes/ macrophages and lymphocytes) with the release of a wide variety of inflammatory mediators, which include different sets of adhesion molecules, proteases and degrading enzymes, oxygen free radicals, complements, nitric oxide, chemokines, growth factors and different types of pro-and anti-inflammatory cytokines. [1],[2],[3]

The advancement in molecular biology has resulted in isolation and reproduction of different inflammatory mediators and their antagonists that have a pivotal role in modulation of inflammation. In addition, advancement in characterization of specific epitopes and markers on monocytes/macro­phages, bone marrow cells and different subsets of T-cells has facilitated the isolation and induction of specific regulatory cells and evaluation of their role in the modulation of renal inflammation and tissue repair.

A large body of evidence from different in vivo experimental and clinical studies reveals that renal inflammation can be modulated by cytokines and other inflammatory mediators. These include blocking different sets of adhesion molecules, blocking one or more of pro-inflammatory cytokines or administration of anti-inflammatory cytokines, systemic neutralization of inflammatory cytokines by their natural soluble inhi­bitors, [2] or by local delivery of these regulators to the site of inflammation. [3] In addition, renal inflammation in different settings has been illustrated to be modulated by alteration of the status of infiltrating cells; for example by inducing depletion, blocking adhesion, inhibiting proliferation, changing the status of activation, or stimu­lating regulatory cells. [5] This is particularly the case in stem cell therapy due to its potential in the regeneration of renal tissues. [6] Another example is the infusion of regu­latory CD4 + /CD25 + T-cells for the manage­ment of autoimmune diseases and induction of tolerance. [7] Furthermore, significant reduc­tion in the intensity of renal inflammation, in autoimmune diseases, kidney transplan­tation and malignancy, has been achieved experimentally and clinically by depleting or inhibiting T- and B-cells using blockers of interleukin-2 receptor, interferons and monoclonal antibodies to CD20 on B-cells. [8]

This review explores renal inflammation in different settings of kidney disease, and the different therapeutic strategies in pre­venting and/or modulating renal damage together with their potential in controlling disease activity, inducing tolerance, and achieving physiological repair.


   Inflammation in Acute Renal Failure Top


Acute renal failure (ARF) occurs in 5-7% of hospitalized patients and results in a mortality rate in excess of 50%. [9],[10] ARF often occurs in a setting of infection and a systemic inflammatory response syndrome. Despite the multi-contributing factors (e.g. hypotension, renal ischemia and antibiotic toxicity) that results in the loss of renal function, inflammatory mechanisms contribute to ischemia/reperfusion injury, and nephro­toxic drug-induced ARF.

The transient exposure of renal tubular epithelial cells and vascular endothelial cells to mild ischemia and/or nephrotoxic agents results usually in reversible impairment of functional activity of these cells, but can also lead to apoptosis; as the magnitude of these insults are below those required to induce rapid metabolic collapse and necrosis. By contrast, continuous exposure to these insults results in severe injury represented usually by acute tubular necrosis. [11] The resultant apop­tosis and necrotic tissue initiate an inflamma­tory cascade, which causes further necrosis. This effect is mediated by different sets of enzymes and liberation of free radical­mediated tubular damage from infiltrating inflammatory cells, in addition to some pro­inflammatory cytokines released from local and/or infiltrating cells. The natural prolifera­tive repair process is dependent upon the delivery of appropriate concentrations of growth factors, chemokines and anti infla­mmatory cytokines. This is demonstrated in some experiments on transgenic mice expressing hepatocyte growth factor and exposed to acute ischemic renal injury. These mice had rapid recovery of renal function following a fourfold increase in tubular cell proliferation and a threefold decrease in apoptotic tubular cell death. [12] This prolife­rative repair process requires the activation of the resident cells and recruitment of different inflammatory cells to the site of injury. [13]

Early studies in ischemic renal injury have demonstrated that prominent peritubular neutrophil accumulation in both cortex and medulla. [14] This has been associated with increased expression of selectins, integrins and endothelial adhesion molecules. [15] Inhi­bition of intercellular adhesion molecule-1 (ICAM-1), [15] or depletion of neutrophils or lymphocytes ameliorates ischemic renal injury. [16] In fact, T-cell receptor (TCR) may play an important role, as TCR-deficient mice have been shown to have structural protection from ischemia-reperfusion injury. [17] Further­more, a reduction of cellular infiltrate of monocytes in a model of ischemia reper­fusion injury to kidneys in mice, by gene therapy expressing an amino-terminal dele­tion mutant of monocyte chemoattractant protein-1 (MCP-1) called 7ND to inhibit MCP-1/CCR2 signaling in vivo, has been associated with a marked reduction in the intensity of acute tubular necrosis. [18] Expe­rimental studies have shown that LPS-primed neutrophils, which are a known source of oxidants, proteases, and cytokines, causes ARF in mildly ischemic kidneys. [14] Further­more, elevation of blood levels in both pro­inflammatory tumor necrosis factor (TNF-α), and interleukin-1beta (IL-1β), in addition to anti-inflammatory (IL-10) cytokines have been demonstrated in humans with ARF. [19] Administration of IL-10 has been demons­trated to inhibit ischemia/ reperfusion injury to the kidney. [20] Moreover, the levels of certain cytokines and gene polymorphism for other cytokines may have predictive values in clinical ARF. [19],[21]

Recent experimental post-ischemic ARF studies have demonstrated that activation of adenosine receptor, by its agonist, significantly improved renal function, reduced expression of inflammatory markers, tissue necrosis, and apoptosis. [22] Other experimental studies repor­ted that blocking endothelin-1, a potent renal vasoconstrictor, by its dual receptor anta­gonist (bosentan) resulted in remarkable functional and histological improvement of affected kidneys. [23]

More recently, other studies on hypoxic or ischemic acute renal injury have found that erythropoietin inhibits apoptotic cell death, enhances tubular epithelial regeneration, and promotes renal functional recovery inde­pendent of its hemopoietic actions. [24]

In fact, the repair of tubules after ischemia-reperfusion injury seems to be mediated by the surviving tubular cells that border the region of injury. [25] These cells express thrombospondin 1, a protein that inhibits angiogenesis and causes apoptosis, [26] and rapidly lose their brush border and dedifferentiate into a more mesenchymal phenotype, where they proliferate and eventually redifferentiate into an epithelial phenotype and complete the repair process. This process, which requires the local release of growth factors such as hepatocyte growth factor (HGF) and insulin-like growth factor-1 (IGF-1), has been demonstrated by the examination of kidney specimens from humans who died following ARF, as well as of kidneys from animal models of acute renal failure induced ischemia and reperfusion. [27]

In contrast to ischemia-reperfusion injury, the role of inflammation in nephrotoxic drugs-induced ARF is not well investigated. However, studies on cisplatin-induced ARF, [28] a highly effective chemotherapeutic agent for solid tumors, have shown that the nephrotoxic effect of cisplatin is mediated, at least in part, by caspases which are intracellular cysteine proteases essential for stimulation of pro-inflammatory cytokines and for induction of apoptosis. [29] Caspase-1 has the capability of converting IL-1β and IL-8 to their active forms, and the production of caspase-3, which is responsible for induc­tion of apoptosis. [29] In addition, cisplatin induces the expression of TNF-α and TNF receptor type II within the kidney. [30]

Salicylates, which reduce cisplatin nephro­toxicity, inhibits the up-regulation of TNF-α.[31] Furthermore, IL-10 has also been revealed to reduce the renal injury following cisplatin administration. This effect was associated with a reduction in mRNA expression of TNF-α, ICAM-1 and inducible nitric oxide synthase; IL-10 also inhibited staining for markers of apoptosis and cell cycle activity. [20]

More recently, the nephrotoxic effects of certain drugs such as flucloxacillin, penicillin G, and disulfiram have been found to be mediated through specific T-cells that are activated locally (within the kidney) and orchestrate a local inflammation via secretion of various cytokines. [32]

Finally, markers of acute kidney injury have recently emerged to help in early diagnosis of ARF before the rise of serum creatinine. This is the case in urinary IL-18, where levels of more than 100 pg/ml were found to be predictive of acute kidney injury within 2 days and correlated with mortality rate. [33]

Overall, these data show that inflammation is a major factor in ARF. Careful regulation of cytokine cascade and immune regulatory cells by different effectors may predict and modulate the degree of renal injury and promote regeneration.


   Inflammation in Acute Glomerulonephritis Top


More evidence implicate cytokines in the pathogenesis of glomerulonephritis: (1) TNF-α and IL-1 are expressed in glomeruli of rodents with experimental models of nephritis, in addition to the biopsies, sera, and urine of patients with different types of glomerulonephritis [34],[35] (2) in vitro and in vivo studies document that TNF-α and IL-1, and other cytokines are produced locally within inflamed glomeruli by mesangial and epithelial cells, as well as by infiltrating monocytes/macrophages[36] (3) systemic admi­nistration of TNF-α and IL-1β results in glomerular damage in rabbits 37 (4) TNF-α and IL-1β stimulate the acute phase response and hepatic synthesis of acute phase reactants, [38] and IL-6 is the major stimulant [39] (5) an established acute phase response can influence and enhance the severity of experimental nephritis [40] (6) TNF-α and/or IL-1 exacerbate the degree of glomerular injury in nephrotoxic nephritis in rats [41] (7) blocking endogenous TNF-α and IL-1β secretion by polyclonal [42] and monoclonal antibodies [43] or by their natural inhibitors such as soluble TNF receptor (sTNFr), soluble IL-1 type 1 receptor (sIL-1Rt1), and IL-1ra [44] in experimental nephritis ameliorates proteinuria, glomerular capillary thrombosis, and inflammatory cell infiltrate. These effects were associated with down regulation of glomerular gene expression of the neutrophil chemoattractant protein (MIP-2) and mono­cyte chemoattractant protein-1 (MCP-1). [45] Blocking these cytokines also downregulates glomerular IL-1β mRNA expression and circulating TNF-α concentrations. [44],[46]

Furthermore, similar effects were repro­duced by pretreatment with type IV phosphodiesterase inhibitor,[47] IL-6, [39] and by continuous infusion of IL-6 in nephrotoxic nephritis. [48] Likewise, interleukin-4 amelio­rates experimental glomerulonephritis and up-regulates glomerular gene expression of IL-l decoy receptor. [49] These findings docu­ment the pivotal role of cytokines in acute glomerular inflammation, and how renal injury can be modulated by them or their antagonists.


   Inflammation in Autoimmune and Chronic Glomerulonephritis Top


The persistence of inflammation and progressive nature of autoimmune chronic glomerulonephritis are likely to be modu­lated by different sets of cytokines and growth factors. Bone morphogenic proteins (BMP), members of the TGF-β super-family, play a pivotal role in chronic glomerular inflammation independent of the original disease. BMPs regulate migration, prolife­ration and differentiation of pluripotent pro­genitor cells involved in the organogenesis. [50] The kidney has been identified as a major site of BMP-7 synthesis. [51] It is expressed with its receptors mainly in collecting ducts, proximal tubules, and podocytes. Recent studies of BMP-7 knock out transgenic mice failed to develop kidneys and died of uremia on the first postnatal day. [50] Furthermore, experimental administration of BMP-7 in mice with diabetic nephropathy results in reduction of proteinuria and restoration of GFR, with significant reduction of growth factor-beta (TGF-β) production. This effect was associa­ted with reversal of tubulo-interstitial fibrosis and normalization of glomerular histology. [52],[53]

Experimental studies have documented the involvement of cytokines, particularly TNF-α, in the pathogenesis of different models of autoimmune disease. [54] These include collagen induced arthritis, experi­mental autoimmune encephalitis, experi­mental autoimmune uveitis, type-I insulin dependent diabetes mellitus, and autoimmune glomerulonephritis. [55],[56] Clinical studies have confirmed the existence of elevated plasma concentration and different pro- and anti­inflammatory cytokines in the urine of patients with different types of autoimmune diseases. [34],[35],[36] Furthermore, blocking TNF-α is effective in controlling resistant sarcoidosis and allows reduction of corticosteroids doses without the need for additional immuno­suppressive agents. [56] Clinical trials in rheumatoid arthritis [58] and chronic infla­mmatory bowel disease [59] have shown that neutralization of endogenous TNF controls progression of the disease, and reduce production of other cytokines.

Furthermore, previous studies on an expe­rimental model of crescentic glomerulo­nephritis [60] have shown that short treatment with sTNFr p55 or monoclonal antibody to TNF-α caused a marked reduction of albu­minuria and fibrinoid necrosis; it also reduced glomerular cell infiltration, activation, and proliferation. [61] Furthermore, prolonged treat­ment with sTNFr p55 caused sustained reduc­tion of albuminuria and all histological and cellular parameters of glomerular inflamma­tion; particularly, it completely prevented the development of crescents. These findings were associated with less glomerular expre­ssion of IL-1β and lower serum concentrations of IL-1β in the sTNFr p55 treated rats. [61] Furthermore, TNF-α has been shown to play an important role in the pathogenesis of experimental autoimmune vasculitis. [43]

More recently, the 'ACTIVE' trial open label multi-center study that was conducted in patients with acute and persistent ANCA associated systemic vasculitis have shown that blockade of TNF- α, by a monoclonal antibody (infliximab), reduced remission and permitted reduction of steroid dose. [62] Furthermore, the urinary level of the mono­cyte chemoattractant protein-1 (MCP-1) is a useful marker for its relationship with albuminuria and interstitial macrophages in chronic kidney disease, [63] renal inflammation in ANCA associated vasculitis, [64] and in monitoring activity of lupus nephritis. [65] These findings clearly document the important role of TNF- α, and possibly other cytokines, in chronic and autoimmune glomerulonephritis.


   Inflammation in Chronic Kidney Disease Top


Different studies have documented the existence of chronic inflammatory process in patients with chronic kidney disease (CKD) with or without ongoing dialysis treatment. This is reflected by elevated plasma concentrations of CRP with preva­lence of 30-50% of such patients, and of pro-inflammatory (TNF-α and IL-1β) and anti-inflammatory (IL-4, IL-10, sTNFr and IL-1ra) cytokines. [66] The cause(s) of this ongoing micro-inflammatory process is not well understood, but it is accepted that continuous exposure to an inflammatory stimulus (e.g. uremia, oxidative stress and endotoxin exposure) results in local and systemic cell activation. Eventually, this produces different sets of inflammatory mediators that include cytokines, chemokines, and growth factors, CRP, vasodilators and vasoconstrictors, reactive oxygen species, and many degrading enzymes, in addition to activation of the complement system and expression of different sets of adhesion molecules. [67]

The original cause of renal disease is an initiator of the process of inflammation, but may also contribute to its persistence. However, CKD is associated with a reduced rate of clearance of many metabolic products. The accumulation of advanced glycation end­products [68] and advanced oxidation protein products, [69] where the kidney is the major site for elimination, may contribute largely to the activation and persistence of inflamma­tion. In addition, heavy proteinuria act as signal for fibrosis, interstitial inflammation, and oxidative stress by direct toxic effect on tubular epithelial cells, and by induction of tubular chemokines expression, complement activation and stimulation of renin­angiotensin system, and the release of angiotensin II with its multipotent proinflammatory effects. [70],[71] Furthermore, metabolic acidosis may augment the production of pro-inflammatory cytokines, as treatment of acidosis reduces plasma concentrations of TNF-α. [72] Fluid overload in CKD may also contribute to inflammation, as it has been associated with elevated plasma concen­trations of several cytokines, which have been reduced by treatment with diuretics. [73]

The causative factors of chronic infla­mmation in patients with end-stage renal failure and on hemodialysis (HD) are better defined. In addition to all the above men­tioned pro-inflammatory conditions, patients on HD are exposed to different external artificial stimuli. These include high/low flux dialysis, bio-incompatible membranes, dialysate contamination, intravenous iron therapy and access site infection. [66]

Therefore, it is clear that the process of inflammation in chronic renal failure is multi­factorial, and its management requires early detection and tackling of the deleterious consequences of renal insufficiency, such as correction of acidosis and fluid overload. Furthermore, control of dialysis parameters such as the use of erythropoietin as an anti­inflammatory agent, [74] high flux dialysis, adequate dialysis, biocompatible membranes, proper treatment of dialysis water and adequate treatment of access site infection are specific measures to modulate the state of inflammation in patients on hemodialysis. [75]


   Therapeutic Implications in Modulating Renal Inflammation Top


Genetically Modified Macrophages

Macrophages are one of the main sources of pro- and anti-inflammatory cytokines. They infiltrate the renal parenchyma in all types of renal injury, and their quantity correlates with the intensity of inflammation and renal injury. This was confirmed by depletion studies, [76] and more recently by repletion with intravenously injected bone marrow-derived macrophages. [77] There is marked macrophage heterogeneity and diversity of responses and functions depen­ding on the nature of the stimulus/injury (immune or non-immune) and location within the kidney (glomerular or interstitial). For example, glomerular macrophages in patients with ANCA positive vasculitis express different activation markers from those in cryoglobulinemic glomerulonephritis. [78] Glo­merular macrophages also express different chemokine receptors from interstitial macro­phages in severe proliferative glomerulo­nephritis and renal transplant rejection. [4] Furthermore, macrophages stimulated by INF-γ are capable of secreting pro­inflammatory cytokines and respond by killing microorganisms, whereas macrophages stimulated by IL-4 and IL-13 produce anti­inflammatory cytokines such as IL-1ra and IL-10 and develop regulatory functions. On the other hand, macrophages stimulated by immune complexes secrete TNF, IL-6, and IL-10 that can mediate immunosuppressive effects and tissue repair. [79]

Different experimental studies have shown that macrophage function is determined by the initial cytokine contact, which induces 'programmed' unresponsiveness to subsequent cytokines. Furthermore, there is a hierarchy when macrophages are exposed to two cytokines simultaneously, e.g. INF-γ dominates over TNF-α and TGF-β. [79]

The studies of genetically modified macro­phages transduced by recombinant adenovirus to express different cytokines including IL-4, IL-10, [5] and interleukin-1 receptor antagonist (IL-1ra). [80] These cytokines, injected systemi­cally into rats with NTN, were localized to inflamed glomeruli, produced the cytokines in vivo, and reduced albuminuria and histo­logical markers of glomerular inflammation. This was associated with a decrease in macrophage infiltration and expression of their activation markers, MHC class II and ED3. [81] More recent experiments have shown that injection of IL-4 and IL-10-expressing macrophages into the renal artery of rats with NTN resulted in highly effective locali­zation to the glomeruli of the injected kidney and very small infiltrates in the contra­lateral kidney. [79] This was associated with an attenuation of inflammation in the contra­lateral kidney. [6] Thus, local manipulation of macrophages to release certain cytokines(s) provides a powerful tool to control glome­rular inflammation and systemic immune response.


   CD20 molecule Top


The CD20 antigen, which is a trans­membrane protein, is found on immature and mature B-cells (but not plasma cells), as well as on malignant B-cells. CD20 mediates B-cell proliferation and differentiation. The CD20 antigen is not internalized upon antibody binding, and is not shed or found in soluble forms. CD20 has been found in more than 85% of non-Hodgkin's lymphoma. In late 1990s a monoclonal antibody, rituximab, was introduced for the treatment of non-Hodgkin's lymphoma. [82] Recently, this antibody has been used with some success, alone and in combination with other conven­tional immunosuppressive drugs, in renal transplantation and in different settings of renal inflammation where CD20+ cells have been found in renal biopsies. These include idiopathic membranous glomerulonephritis, focal segmental glomerulosclerosis, mixed essential cryoglobulinemia, SLE and systemic vasculitis. [8] Following treatment with ritu­ximab, B-cells are prevented from prolifera­ting, and undergo apoptosis and lysis through complement-dependent and complement­independent mechanisms. However, despite the promising effects of rituximab, rando­mized controlled trials and studies on longterm effects in autoimmune diseases and possible development of antibodies to the chimeric molecule are required before this drug is accepted as a standard treatment in autoimmunity and renal transplantation.


   Regulatory CD4 + /CD25 + T-Cells Top


There are different subsets of CD4 + T-cells, but the ones that express the α-subunit of the IL-2 receptor (CD25) and the transcription/ functional factor forkhead box P3 (Foxp3 + ) can diminish responsiveness of the antigen­specific effecter T-cells and act as potent suppressor of the immune responses. The CD4 + /CD25 + Foxp3 + T-cell is the most well­characterized CD4 + cell with regulatory properties, and is thought to play a pivotal role in the maintenance of tolerance and autoimmune diseases and transplantation, in rodents and humans. [83],[84],[85] Depletion of these cells (CD4 + /CD25 + Foxp3 + ) or lack of the activation markers (e.g. CD25 and Foxp3) precipitates severe systemic autoimmunity in mice and humans. [86] In experimental models, regulatory CD4 + /CD25 + Foxp3 + T-cells can prevent autoimmunity, prevent graft-versus-host disease and play an impor­tant role in both the induction and maintenance of allograft tolerance. [83],[87] Despite their vital role in controlling immunity, only 5­10% of CD4 + cells emerging from the thymus constitutively express CD25 (IL­2R α-chain), Foxp3 and other activation markers. This explains the extensive in vitro and in vivo research in identifying agents that can boost their endogenous cell mass. Polyclonal rabbit antithymocyte globulin (ATG), which has long been thought to cause immunosuppression by depletion of peripheral lymphocytes, has been found recently to induce five-fold increase in CD4 + cells expressing CD25 and Foxp3 after 24 h in vitro. [7] This effect was not due to the depletion of the CD4 + CD25 - cells per se, but rather to the rapid and sustained phenotypic conversion of CD4 + CD25 - to the regulatory CD4 + /CD25 + Foxp3 + T-cells and to a lesser degree to proliferation of natural CD4 + /CD25 + T-cells. The potential of regulatory T-cells in controlling inflamma­tion in glomerulonephritis, autoimmune diseases and inducing long lasting tolerance in kidney, and other organ, transplantation currently depends on the ability of ATG in optimal doses, and possibly other stimulating agents (e.g. rapamycin, IL-10 or TGF-β), to expand (without T-cell proliferation) the ex vivo and/or in vivo conversion of CD4 + CD25 - to the regulatory CD4 + /CD25 + Foxp3 + T-cells. [88]


   Hematopoietic Stem Cells Top


Hematopoietic stem cells have recently emerged as a new exciting therapeutic option for a variety of diseases, with a possibility of regenerating injured or diseased organ(s), thereby, simulating a physiological healing process. [89] In fact, these smart cells have been used for clinical bone marrow transplan­tation for many years. Clinical studies of intracoronary infusion of stem cells in patients after myocardial infarction showed to enhance infarct area perfusion, improve stroke volume, end-systolic volume and regional contractility. [90] The hematopoietic stem cells have the capacity of self-renewal and the potential to generate several different types of differentiated progeny. [89] They are characterized by the marker protein CD34 or the more immature marker protein CD133. [91] These cells can be obtained from different sources including cord blood (embryonic stem cells), fatty tissue and peripheral blood, but the best established source of stem cells is the bone marrow. [90] More recently, multi­potent progenitor cells have been isolated from renal tubules. [92]

It is believed that in response of the mesan­gium to injury hematopoietic progenitor stem cells, such as endothelial progenitor cells, migrate into injured glomeruli and get involved in the normal turnover of mesangial cells. [93] The migration and proliferation of these cells are controlled by certain growth factors such as platelet derived growth factor (PDGF) and basic-fibroblast growth factor (b-FGF). The PDGF plays an impor­tant role in the migration of the progenitor cells into the glomerulus, whereas bFGF has been linked to the proliferation of repopu­lating mesangial cells. [94] Studies of experi­mental bone marrow transplantation from normal mice into those producing high circulating IgA levels, and are prone to IgA nephropathy led to resolution of the glomerular sclerotic changes. [95] Infusion of bone marrow-derived cells, that can diffe­rentiate into endothelial and mesangial cells, in a model of progressive glomerulo­sclerosis in rats improved renal function and glomerular hemodynamics, and reduced glomerular infiltration of macrophages. These bone marrow-derived cells also con­tributed to repair and regeneration of endo­thelial and mesangial cells, and dramatically reduced mortality rate. [96] In addition, intra­renal injection of mesenchymal stem cells, even in low quantity, in anti-thy1.1 nephritis model illustrated glomerular localization in injured mesangium and caused marked acceleration of recovery of glomerular histo­logy. [6] In a model of ischemia/reperfusion injury in rats, a significant infiltration of regenerating tubules with CD34+ hemato­poietic cells has been observed. [97] Moreover, hematopoietic stem cells contribute to the regeneration of renal tubules after renal ischemia-reperfusion injury in mice, [97] though this depends on the adequate quantity of transferred mesenchymal stem cells and their purity from inflammatory cells. [25] Thus, it appears that there are certain cytokines/ growth factors that are responsible for attraction, or inhibition, of hematopoietic progenitor stem cells to repopulate injured glomeruli and tubules. Furthermore, charac­terization of the different types of these cytokines/growth factors, new techniques of isolation, growth of the relevant stem cells, isolation of their contents of potential effector mediation and development of an appropriate delivery system to the site of inflammation portend an important and specific therapeutic potential in regenerating glomerular and in­terstitial tissue following renal inflammation.


   Renin-Angiotensin System Top


It has always been considered that renin­angiotensin system (RAS) is an endocrine system, where the glycoprotein angiotensi­nogen (produced by the liver) is cleaved by renin (released from renal juxtaglomerular cells) to release angiotensin I, which in turn is converted by angiotensin converting enzyme (from lungs) into the active angiotensin II. [98] However, recent experimental and clinical studies have demonstrated that the RAS system is also exists and activated locally in proximal tubular cells within the kidney. [99] Renal injury/inflammation activates local RAS directly and indirectly; for example, proteinuria is a potent stimulator [100] whereas 1,25 dihydroxyvitamin D3 is a negative regulator. [101] Furthermore, other angiotensin II-generating enzymes, such as serine protease chymase, are expressed and pro­duced by cardiovascular tissues and kidneys, where angiotensin converting enzyme (ACE) inhibitors do not inhibit chymase activity. [102] This results in two pathways for angiotensin II (AngII) synthesis: the chymase-dependent and the ACE-dependent AngII formation. In fact, the majority (60-80%) of systemic Ang II production is chymase-dependent, which can be blocked by specific chymase inhi­bitors. [103] Furthermore, another ACE (ACE2) has been found expressed on visceral epi­thelial cells (podocytes) and to a lesser degree on mesangial cells, unlike ACE that is mainly expressed on glomerular endothelial cells. [104] ACE2 cleaves Ang I and Ang II into inactive Ang1-9 and the vasodilator and anti-proliferative Ang 1-7, thus preventing Ang II accumulation in the glomerulus and leading to an increase in glomerular permea­bility. [105] However, there are no current available therapies to enhance ACE2 expression and production; which may help controlling Ang II and its pro-inflammatory effects.

Angiotensin II (Ang II) is the major com­ponent in the renin-angiotensin system. It binds to two types of receptors: angiotensin type 1 receptor (AT1) and angiotensin type 2 receptor (AT2). Both receptors are differentially expressed within the kidney and share about 30% homology on the protein level. AT1 receptor expression is induced by different stimuli including hypercholesteremia and changes in osmo­larity, but down-regulated by high concen­tration of AngII. In contrast, AT2 are induced by tissue injury but are not downregulated by AngII. [106] Earlier reports showed that AT2 receptors act in a similar fashion to AT1, but more recent studies demonstrated that the function of AT2 is to counteract the effects mediated by AT1 including vasoconstriction and pro-inflammatory effects, [107],[108] though the role of AT2 receptors in renal pathophysiological processes is not fully elucidated. [109] AT1 receptors are coupled to heterotrimeric G proteins, which allow Ang II to engage in various signal transduction pathways including activation of phospho­lipases, inhibition of adenylate cyclase and stimulation of tyrosine phosphorylation. [110]

Most of the known physiological and patho­logical effects of angiotensin II are mediated through stimulation of the AT1 receptor. Binding of Ang II to AT1 receptors mediates vasoconstriction (systemic and afferent arterioles), releases aldosterone and stimulates the tubular transport system. [98] Furthermore, Ang II regulates the expression of profibrotic factors such as connective tissue growth factor and the Smad (Smad2 and Smad4) signaling pathways, which causes an increase in TGF-β[111] and vascular smooth muscle cells (VSMC) expression leading to mesangial cell proliferation, extracellular matrix deposition and fibrosis, angiogenesis and proteinuria. [98],[112],[113] . In addition, Ang II stimulates the expression of plasminogen activator inhi­bitor-1 (PAI-1), a multifunctional glycol­protein with powerful fibrosis-promoting effects in the kidney, an effect that can be blocked by AT1 receptor antagonists. [114] Ang II, through AT1, also activates the Rho kinase pathway and upregulates Toll-like 4 receptors on mesangial cells resulting in enhanced nuclear factor kappaB (NFidB) and the whole inflammatory cascade activation. [98] This results in expression and production of different sets of pro-inflammatory cytokines and chemokines and adhesion molecules. [98],[113],[115] More recently, aldosterone, independent of its sodium and water retention effects, has been found to cause proteinuria. [116] Therefore, blocking RAS by inhibiting the release of Ang II, blocking its receptor and the receptor of aldosterone has great potential in modu­lating renal inflammation and tissue injury, and improving renal function. [117] In fact, several laboratory and clinical studies have demonstrated that blocking the RAS by ACE­inhibitors and/or AT1 receptor blockers, [112] and possibly together with aldosterone recaptor antagonist (spironolactone or eplerenone), caused marked modulation of renal inflamma­tion, independent of their blood pressure lowering effect, or sodium and water retention effects. [118],[119] This includes reduction in local and systemic expression and production of different sets of inflammatory mediators and profibrotic growth factors (e.g. NFicB, TNF-α, MCP-1, TGF-β, PDGF, Smad signaling pathway), amelioration of renal histological damage (tubulointerstitial fibrosis and glomerulosclerosis), significant abrogation of proteinuria, and improvement of renal function. [103],[116],[119],[120],[121] These effects have been achieved even in the late stages of chronic renal failure, [122],[123] with evidence of regene­ration of glomerular tissue. [123]


   Statins Top


Patients with different types and stages of renal diseases, including glomerulonephritis and nephrotic syndrome and in those on dialysis, suffer usually from alterations in lipid metabolism. These include elevation in serum levels of low density lipoprotein (LDL) cholesterol and triglycerides, and reduction in high density lipoprotein (HDL) cholesterol. [124] These abnormalities are associated with cardiovascular complications and may accelerate the progression of renal disease. [125]

Statins (3-hydroxy-3-nethylglutaryl coenzyme A reductase-inhibiting drugs) are efficient agents in blocking the synthesis of choles­terol, and inhibiting the mevalonate pathway and consequently the synthesis of iso­prenoids, which are essential for the post translational modification of several proteins that are involved in signaling pathways and numerous additional effects of statins. [126] This effect on mevalonate enables statins, inde­pendent of their ability to lower serum cholesterol, to exert pleiotropic effects. These include anti-oxidant (e.g. reduction of super-oxide formation and increase in oxygen free radical scavenging), anti-thrombotic (e.g. reduction in endothelin-1 expression and increase in endothelial nitric oxide synthase expression), immunoregulatory effects (e.g. limitation of T-cell maturation and activation), and anti-inflammatory effects (e.g. inhibition of proinflammatory cytokines and chemokines, nuclear factor-~B activation, leukocyte-endothelial cell adhesion and reduction in CRP). [127] Several in vitro and in vivo experimental studies have elucidated the capability of statins to suppress mesangial cell proliferation and mesangial matrix expansion and synthesis of type IV collagen, reduce­tion of glomerular expression of adhesion molecules, inhibition of TGF-β and PDGF and vascular endothelial growth factor expression, abrogation of monocyte/macrophage infil­tration, reduction of protein excretion, and inhibition of global sclerosis. [128]

The beneficial effects of statins in these experimental studies were independent of their cholesterol lowering effects, and have been attained with dosages that exceeded those of therapeutic use in humans. A recent systematic review and the meta-analysis conducted by Sandhu et al, [129] indicates that statins seems to result in a modest reduction of proteinuria, especially in patients with cardiovascular disease, and a small (1.22 ml/min per year) but significant reduction in the decline of renal function. Despite their mild clinical anti­inflammatory and anti-proteinuric effect, statins should be at least prescribed, alone and/or in combination with angiotensin converting (ACE) inhibitors or angiotensin receptor blockers (ARB), in renal patients with cardiovascular disease; blocking AT1 receptor reduces oxidative stress, and amelio­rates adipocytokine dysregulation. [130] How­ever, there are two ongoing trials, AURORA (rosuvastatin) and SHARP (combined simvastatin and ezetimibe therapy), which will address the impact of statins on outcomes in predialysis and dialysis patients.

In conclusion, there are therapeutic benefits of administration of one or more of anti­inflammatory cytokines or their antagonists. However, their effects are currently limited by the lack of appropriate way of delivering them directly to the site of inflammation, and by their possible side effects. Statins and blockers of the rennin-angiotensin system have great potential in blocking the infla­mmatory cascade and inhibiting the pro­fibrotic growth factors. Other therapeutic interventions that simulate the natural bio­logical healing process, such as activation or administration of regulating cells, pure mesenchymal stem cells, or endothelial pro­genitor cells into the site of inflammation may control the inflammatory mediators in renal inflammation. Depletion of inflamma­tory or antigen presenting cells, by anti-CD20 monoclonal antibody, alone or in combina­tion with other immunosuppressive drugs, and/or stimulation or infusion of ex-vivo expanded regulatory CD4 + /CD25 + Foxp3 + T­cells, are other promising therapeutic options in modulating renal inflammation and indu­cing tolerance in a variety of autoimmune diseases and renal transplantation.

 
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Correspondence Address:
Ayman Karkar
Department of Nephrology, Kanoo Kidney Center, P.O. Box 11825, Dammam 31463
Saudi Arabia
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