Kidney International, Vol. 59 (2001), pp. 1626–1640

PERSPECTIVES IN BASIC SCIENCE

Role of immunocompetent cells in nonimmune renal diseases

BERNARDO RODRIGUEZ-ITURBE, HECTOR PONS, JAIME HERRERA-ACOSTA,and RICHARD J. JOHNSON1

Renal Service Hospital Universitario de Maracaibo, Venezuela; Department of Nephrology, Instituto Nacional de Cardiologıa“Ignacio Chavez,” Mexico City, Mexico; and Renal Division, Department of Medicine, University of Washington MedicalCenter, Seattle, Washington, USA

Role of immunocompetent cells in nonimmune renal diseases. changes that lead to end-stage renal disease indepen-Renal infiltration with macrophages and monocytes is a well- dently of the initial insult, but are also conspicuouslyrecognized feature of not only immune, but also nonimmune present, sometimes in early stages, in a variety of diseaseskidney disease. This review focuses on the investigations that

of the kidney that do not have an immune etiopathogen-have shown accumulation of immunocompetent cells in experi-esis.mental models of acute and chronic ischemia, protein overload,

hypercholesterolemia, renal ablation, obstructive uropathy, We do not discuss the participation of lymphocytespolycystic kidney disease, diabetes, aging, murine hyperten- and macrophages in the development of renal fibrosission, and nephrotoxicity. We examine the mechanisms of infil-

since these aspects have been well covered by authorita-tration of immunocompetent cells and their participation in thetive reviews [3–5]; rather, we examine investigations thatself-perpetuating cycle of activation of the angiotensin system,

generation of reactive oxygen species, and further recruitment have shown accumulation of immunocompetent cells inof monocytes and lymphocytes. We also discuss the possibility nonimmune diseases and the mechanisms for infiltrationof antigen-dependent and antigen-independent mechanisms of and activation of these cells. Finally, we summarize re-immune cell activation in these animal models. Finally, we

cent research that indicates that significant improvementreview the recent studies in which suppression of cellular immu-in histologic and functional damage in nonimmune dis-nity with mycophenolate mofetil has proven beneficial in atten-

uating or preventing the progression of renal functional and eases of the kidney may result from treatment aimed athistologic damage in experimental conditions of nonimmune suppressing cellular immunity.nature.

TUBULOINTERSTITIAL INFILTRATION OFIn 1970, Rocklin, Lewis, and David reported that lym- MACROPHAGES AND LYMPHOCYTES IN

phocytes from some patients with glomerulonephritis NONIMMUNE RENAL DAMAGEshowed in vitro reactivity against glomerular basement Infiltration of macrophages and lymphocytes is a con-membrane [1]. Since the prevailing view at the time stant feature in conditions associated with chronic renalwas that humoral immunity was responsible for immune- damage. Whatever the mechanism for their accumula-mediated renal disease, this finding merited an editorial tion, these cells play a central role in most, if not all,with this title: “What are sensitized cells doing in glomer- pathways leading to progressive scarring of the kidney.ulonephritis?” [2]. Now, three decades later, it may be Immunocompetent cells are particularly conspicuous inworthwhile to ask what immunocompetent cells are do- areas of active tubulointerstitial injury, which since theing in nonimmune renal diseases. This review focuses

landmark observations of Risdon, Sloper, and de Warde-on the presence and role of macrophages and lympho-

ner [6] and Schainuck et al [7], is generally recognizedcytes that not only are associated with the sclerotic

to correlate with the severity of renal failure [8–10].Tubulointerstitial inflammatory injury may result fromantigen-specific stimulation of dendritic cells, infiltratingKey words: macrophages, lymphocytes, cell activation, tubulointersti-

tial injury, proteinuria, progressive renal disease, hypertension. macrophages, and resident endothelial and tubular cells,but cell-mediated injury may also occur in the absence1 Present address is Division of Nephrology, Department of Medicine,

Baylor University, Houston, Texas, USA. of antigen stimulation [11–15]. Table 1 shows a partiallist of experimental conditions that are assumed to have

Received for publication June 20, 2000a pathogenesis unrelated to antigen-specific immune re-and in revised form September 26, 2000

Accepted for publication November 15, 2000 sponses.In the ischemic models of renal damage, there is a 2001 by the International Society of Nephrology

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Rodrıguez-Iturbe et al: Immunocompetent cells 1627

Table 1. Experimental nonimmune renal diseases with this model of renal disease has a nonimmune pathogene-tubulointerstitial infiltration of immunocompetent cells

sis, despite the fact that the induction requires daily intra-Experimental condition References peritoneal injections of bovine serum albumin (BSA)Ischemia into Lewis rats. In fact, humoral immune mechanisms

Acute [16] are unlikely to play a role since proteinuria developsChronic [17]

within 24 to 48 hours of the initiation of the albuminProtein overload [19, 40]Hypercholesterolemia [40] injections, and there are no immune deposits in the kid-Reduction of renal mass [46, 52–54, 56, 57] ney. However, the possibility of participation of immuno-Obstructive uropathy [63, 65]

competent cells in the pathogenesis of this model is notPolycystic kidney disease [67, 68]Diabetic nephropathy [75, 78] ruled out. Studies by Eddy have shown that there is anAging [81, 86] early (,7 days) and prominent macrophage infiltrationPyelonephritis [88, 89]

that remains unabated throughout the duration of theHypertensionDahl sensitive [90, 91] overload proteinuria; furthermore, after two weeks,SHR [92, 93] T-helper and T-cytotoxic cells are also observed in theDOCA-salt sensitive

tubulointerstitial infiltate [19]. While the T-helper infil-Catecholamine infusion [94]Angiotensin II infusion [95] trate tends to decrease after the third week, the T-cyto-Two-kidney one-clip [96, 97] toxic cells remain for at least seven weeks. T-cell de-Nitric oxide synthetase inhibition [98, 103]

pletion with intraperitoneal anti–T-cell monoclonalNephrotoxicityPuromycin aminonucleoside [20, 109, 110, 112, 113] antibody (mAb) administration did not modify the mac-Mercuric chloride [107, 108] rophage infiltration, indicating that the influx of theseCyclosporine A [21, 118, 119]

cells was not dependent on the lymphocytes [19], butTacrolimus [117]more likely resulting from locally expressed osteopontin,References correspond to investigations reporting specific details about the

lymphocyte and macrophage infiltration. monocyte chemoattractant protein-1 (MCP-1), andadhesion molecules vascular cell adhesion molecule(VCAM) and intracellular adhesion molecule (ICAM)[24] and a chemotactic urinary lipid possibly generated

prominent infiltration of macrophages and lymphocytes. by the tubular catabolism of albumin-borne fatty acidsIn the acute ischemia induced in mice by temporal occlu- [25]. Nevertheless, structural changes in the tubules aresion of the renal flow to one kidney, Goes et al found an present in this experimental model [26, 27], and the toxicincreased steady-state mRNA for a number of cytokines damage could result in the expression of autoantigensinvolved in macrophage and T-cell activation, including that could elicit a delayed cellular response. For instance,interferon-g (IFN-g), interleukin (IL)-2, IL-10, and gran- vimentin filaments found in the tubules of rats with over-ulocyte-macrophage colony-stimulating factor (CSF), as load proteinuria [19] are not expressed in normal tubuleswell as overexpression of major histocompatibility com- and neoantigens expressed after activation of the C5b-9plex (MHC) class I and class II molecules [16]. There was attack complex, likely resulting from stimulation of thean intrarenal accumulation of T cells and macrophages complement cascade by proximal tubular cells [28], haveassociated with this cytokine response. been demonstrated in the brush border of tubular cells

In experimental chronic ischemia induced by unilat- [19, 28].eral renal arterial stenosis in the rat, Truong et al found In 1971, Wellman and Volk published one of the earli-that the ischemic kidney showed marked tubulointersti- est investigations linking hypercholesterolemia with re-tial damage, including an abundant inflammatory infil- nal injury [29], but widespread interest in the field wastrate and tubulitis in 42% of the tubular cross sections fueled by Moorhead et al’s article suggesting that in-[17]. The infiltrating cells were mostly macrophages, B creased lipoprotein synthesis associated with proteinuriacells, and T-helper lymphocytes, and there were impor- contributes to the progression to chronic renal failuretant changes in the antigenic constitution of the tubules. [30]. Since then, it has been established that high choles-The authors noted similarities between the phenotypic terol feeding causes experimental renal disease [31, 32]characteristics of the infiltrate in chronic ischemia and and that reduction in lipid levels reduces the renal dam-the infiltrate in autoimmune tubulointerstitial nephritis age of not only hyperlipidemic nephrotic rats [33], but[18], overload proteinuria [19], aminonucleoside nephro- also in a variety of hyperlipidemic renal diseases. Notsis [20], and cyclosporine nephrotoxicity [21]. surprisingly, the initial investigations focused on the

It has been known for more than half a century that pathogenesis of lipid-induced glomerulosclerosis, indi-parenteral administration of proteins induces proteinuria cating that oxidized lipoproteins in the glomeruli would[22, 23], and recent models of overload proteinuria have follow similar pathogenetic pathways, as observed in ath-emphasized the importance of tubulointerstitial infiltra- erosclerosis, including recruitment of macrophages with

scavenger functions, thromboxane-induced glomerulartion with mononuclear cells. It is generally assumed that

Rodrıguez-Iturbe et al: Immunocompetent cells1628

vasoconstriction, and mesangial cell proliferation [31, The histologic changes that follow ureteral obstructionwere initially described almost three decades ago [58].34–40]. Primary tubulointerstitial damage caused by hy-

percholesterolemia has also been documented in the rig- Tubular and interstitial injury is accompanied by cellproliferation and extracellular matrix deposition [59]. Anorous investigation of Eddy, Liu, and McCulloch who

showed that ingestion of a 4% cholesterol diet resulting increased production of angiotensin and thromboxane[60, 61] is responsible for well-defined hemodynamicin a threefold to fourfold increment in plasma cholesterol

with the deposition of neutral lipids and oxidized lipids changes [62]. Careful studies by Schreiner et al detectedan influx of macrophages and lymphocytes in the ob-in both glomerular and tubulointerstitial areas [40]. By 12

weeks, there was a prominent infiltration of macrophages structed kidney as early as 4 hours after obstruction, andthe infiltration of these cells reached maximal intensitythat was preceded by or accompanied with the increment

in mRNA levels for MCP-1, osteopontin, and VCAM. after 24 hours and remained at the same levels until theobstruction was released [63]. Since macrophages are aTransforming growth factor-b1 (TGF-b1) was present

before and during the fibrotic phase of the disease. No known source of angiotensin and thromboxane [64], itis not surprising that the intensity of the mononuclearreference was made to lymphocytes in this work [40], but

T cells are known to be present in the tubulointerstitial cell infiltrate varied in parallel with the levels of thesevasoconstrictors and the fall in glomerular filtration. Ininfiltrate of kidneys with arteriolosclerosis that resem-

bles, at times, that found in pyelonephritis [41], and lym- addition to the participation in the pathogenesis of he-modynamic and renal functional changes, the infiltratingphocytes are a constant finding in atherosclerotic plaques

(Fig. 4A) [42] and in ischemic kidneys [17]. macrophages are also involved in the late fibrogenicchanges resulting from increased synthesis of TGF-b1A reduction of renal mass is a well-defined nonim-

mune model of progressive renal failure studied at length [65]. After release of obstruction, the glomerular macro-phages remain significantly increased, a finding that hasby Hostetter et al after the original description of glomer-

ulosclerosis following 5/6 nephrectomy by Shimamura been postulated to be related to postobstruction loss offunctional glomeruli [63]. Lymphocyte infiltration fol-and Morrison [43, 44]. The development of glomerulo-

sclerosis is related to the hemodynamic disturbances lows the same pattern as the macrophage infiltration.Interestingly, in contrast with most other models of non-present in the remnant nephrons as a result of the reduc-

tion in functioning kidney mass [45]. Mesangial cell acti- immune renal disease, the suppressor-cytotoxic subsetof infiltrating T lymphocytes is five times more promi-vation (a-smooth muscle actin expression) and prolifera-

tion occur within days after renal ablation in association nent than the helper phenotype [63].Polycystic kidney disease is a hereditary disorder thatwith platelet-derived growth factor (PDGF) expression

and precede the mononuclear cell infiltrate and the glo- is the cause of a rapidly fatal form, with uremia shortlyafter birth in the C57BL/6 J-cpk mouse [66], or a moremerular and interstitial sclerosis [46]. Activation of the

renin-angiotensin system by the intraglomerular hemo- slowly progressive form in the DBA/2FG-pcy mouse[67], the latter resembling the autosomic dominant poly-dynamic changes may result in increased TGF-b and

subsequent glomerular sclerosis [47–49], a process that cystic kidney disease in the human. The DBA/2FG-pcymice develop an autosomal recessive form of polycysticis accelerated by a high-protein diet [50, 51]. Macrophage

infiltration in glomeruli and tubulointerstitium is already kidney, manifested at birth by segmental dilation of distaltubules and collecting ducts that progress to cysts, whichfound after 10 days, increases after 4 weeks, and reaches

a maximum after 12 weeks’ postablation [52–54]. The are numerous and dilated by eight weeks of age, andconstitute the dominant feature in the late stages of theinfiltration of macrophages is facilitated by the expres-

sion of MCP-1 [55] and stimulated by angiotensin II [56]. disease [67]. In this model, a prominent tubulointerstitialinfiltrate consisting predominantly of lymphocytes andApproximately one third of the infiltrating macrophages

are proliferating in the remnant kidney [52], and the total macrophages appears between the 18 and 30 weeks ofage. Increased expressions of PDGF, insulin-like growthnumber of macrophages correlate with the functional

parameters of renal failure [56]. T lymphocytes are also factor-1 (IGF-1), and TGF-b have been demonstratedand are thought to play a role in the cyst formationconspicuously present in the tubulointerstitial infiltrate

after seven days [53] and remain in significant numbers [68]. Since macrophages are one of the cells capable ofproducing PDGF [69, 70] and IGF-1 [71], as well asfor the following weeks [53, 54]. The disease is associated

with an overexpression of MHC class II antigens, and TGF-b [72], Nakamura et al have suggested that macro-phages could have a role in the pathogenesis of the dis-the infiltrating T cells are predominantly of the T-helper

phenotype [57]. The pathogenetic importance of immu- ease [68].Diabetic nephropathy is a complex and progressivenocompetent cells in this hemodynamically-induced

chronic renal damage has been dramatically shown by the process that in its early phase is associated with nephronhypertrophy [73] and later with the development of dif-improvement obtained with immunosuppressive treat-

ment [53, 54, 57]; this is discussed later. fuse glomerulosclerosis that sometimes assumes a nodu-

Rodrıguez-Iturbe et al: Immunocompetent cells 1629

lar appearance [74] often associated with widespread rats, there is intense accumulation of macrophages inbrain and kidney. In the brain, they are scattered aroundinterstitial fibrosis [75]. The increase in kidney size is

mostly the result of hypertrophy, even though there is the lesions and appear to act only as scavengers; how-ever, in the kidney, macrophages expressing class II-an early component of hyperplasia. Mesangial expansion

accompanies the global hypertrophic changes and is as- MHC antigens in association with T lymphocytes arelocated in perivascular areas, and their infiltration pre-sociated with an increase TGF-b1 in both glomerular

and the tubulointerstitium. The severity of glomerular cedes the fibrocellular proliferative lesions [92]. The ad-ministration of an angiotensin-converting enzyme inhibi-[76] and tubulointerstitial damage [77] correlates with

functional deterioration. Rarely mentioned is the fact tor or angiotensin II-receptor blocker was associatedwith a significant reduction on macrophage and T-helperthat streptozotocin-treated rats have an important inter-

stitial inflammatory infiltrate [75]. Characteristics of this lymphocyte infiltration and, in parallel, with reduced tu-bulointerstitial proliferation and sclerosis [93]. An infil-infiltrate are undefined but, in humans with diabetic ne-

phropathy, the inflammatory cells are predominantly T tration of macrophages in the interstitium has also beennoted in catecholamine-induced hypertension [94], an-lymphocytes and to a lesser degree macrophages [78].

Clearly, the pathogenesis of the sclerotic transformation giotensin II-induced hypertension [95], and two-kidneyone-clip hypertension [96, 97], and in these models, theof the kidney in diabetes is multifactorial. Hyperglycemia

and nonenzymatically glycated proteins are known to interstitial injury correlates with the blood pressure. Fur-thermore, a reanalysis of the catecholamine infusionstimulate mesangial and proximal tubular cell produc-

tion of TGF-b1 as well as production and gene expression study [94] shows that the macrophage interstitial infiltra-tion present at the end of the catecholamine infusionof fibronectin and type IV collagen [79], but in addition,

immunocompetent cells may participate in the diabetic also correlates with the subsequent blood pressure re-sponse to a high-salt diet (Fig. 2).injury. Macrophage recruitment may be induced by high

serum lipid levels, as discussed earlier, and with advanc- Chronic administration of nitro-l-arginine-methyl es-ther (L-NAME) produces arterial hypertension as a con-ing arteriosclerotic disease, chronic ischemia becomes

an increasingly important mechanism of generation of sequence of suppression of nitric oxide biosynthesis. Thisexperimental model, first described by Oliveira-Ribeiroreactive oxygen species (ROS) and infiltration of mono-

nuclear cells (discussed later in this article). et al [98], induces activation of the renin-angiotensinsystem [99–101] and sympathetic nervous system [102],Aging is associated with a variety of functional and

structural changes [80, 81]. Glomerulosclerosis is the causing intense vasoconstriction. Monocyte/macrophageinfiltration is intense in the intima and media of preglo-classic finding that has attracted most of the research

effort [82–85], but tubulointerstitial injury is also an im- merular arteries and arterioles as well as in tubulointer-stitial areas, where these cells are two to three timesportant characteristic of the senescent kidney. Tubular

dilation and atrophy, widening and fibrosis of intersti- increased in number [103]. Nitric oxide suppresses theendothelial expression of several cytokines and cell ad-tium, phenotypic changes consisting in cellular expres-

sion of a-smooth muscle actin, and imbalance between hesion molecules, particularly VCAM-1 and P-selectin;in addition, L-NAME administration augments the ex-proliferation and apoptosis have all been demonstrated

in the aging rat [86]. TGF-b1 is increased in parallel with pression of VCAM-1. These findings suggest a mecha-nism for the mononuclear cell infiltration associated withthe fibrotic tubulointerstitial changes [87]. Importantly,

a prominent infiltration with macrophages and lympho- inhibition of nitric oxide synthase [104–106].Not surprisingly, experimental models of acute renalcytes in association with increased osteopontin and

ICAM-1 expression has been observed in the intersti- failure are also associated with intense inflammatory in-filtrate in association with acute tubular necrosis. Mercu-tium in aging animals [81].

Experimental pyelonephritis induced by intrarenal ric chloride nephrotoxicity is characterized by proximaltubular necrosis and intense mononuclear cell infiltrationbacterial inoculation is characterized by interstitial

edema, inflammation, and scarring. Contraction and col- that precedes growth factor expression [107]. The macro-phage and lymphocyte infiltration may be stimulatedlapse of the tubulointerstitial parenchyma with fibrosis

are major pathophysiologic mechanisms for new colla- by the generated reactive oxygen species (ROS), sincerecent work from our group found that it decreases withgen production [88]. Mononuclear cell infiltration has

been noted since early descriptions of this model [89]. antioxidant therapy [108].The model of puromycin aminonucleoside nephrosisIn practically every experimental model of hyperten-

sion, there is a prominent tubulointerstitial infiltrate of is characterized by focal glomerulosclerosis and diffuseinterstitial fibrosis [109]. However, several reports haveimmunocompetent cells. In Dahl-sensitive rats, mononu-

clear cell infiltration is prominent in the tubulointersti- emphasized the existence of important interstitial in-flammatory infiltrate [110–112] constituted mainly bytium, especially around sclerosed glomeruli and arteri-

oles [90, 91]. In stroke-prone spontaneously hypertensive macrophages but also by lymphocytes [111]. Macro-

Rodrıguez-Iturbe et al: Immunocompetent cells1630

phages are known to have an important pathogenetic both the functions of a chemokine and the functions ofadhesion molecules.role in the model induced by a single intravenous injec-

tion of puromycin aminonucleoside, since inhibition of Adhesion molecules are responsible for the rolling,adhesion, and eventually penetration of these cells fromthe macrophage infiltration in the acute phase results

in a reduction of the late glomerular injury [113, 114]. circulation into the interstitial spaces [reviewed in 122].Of the various adhesion molecules, ICAM-1 (CD54) andOxidative stress [112, 115] and increased TGF-b1 expres-

sion [111] may result from macrophage activity and pro- VCAM1 (CD106) appear to be particularly importantin experimental models of renal disease [123, 124].mote further macrophage recruitment.

Cyclosporine A and tracolimus induce renal damage Table 2 examines the characteristics of antigen-inde-pendent renal injuries that are capable of inducing thethat has similar histologic features. Increased TGF-b1

production and extracellular matrix deposition [116, 117] production of chemokines and expression of adhesionmolecules.are present in association with intense macrophage infil-

tration and stimulation of the intrarenal renin-angioten- A final pathway of most injuries leading to chronickidney damage includes the participation of proteinuria,sin system [118]. Macrophage accumulation and renal

damage are potentiated by a low-salt diet [119], which oxidized lipids, and chronic ischemia, the cross-talk ofwhich results in a self-perpetuating cycle of activationstimulates angiotensin activity, and injury is reduced by

angiotensin-receptor blockade [118]. Therefore, intrare- of the renin-angiotensin system, generation of ROS, andrecruitment and activation of macrophages and lympho-nal ischemia, angiotensin II generation, and macro-

phage-dependent cytokines are pathogenetically linked cytes (Fig. 1).The role of angiotensin II (Ang II) in the generationin the development of the striped interstitial fibrosis,

tubular atrophy, and hyalinosis of the afferent arteriole, of sclerotic changes is beyond the scope of this articleand has been the subject of excellent reviews [125, 126].which are typical of both cyclosporine and tacrolimus

nephrotoxicity [120]. Pertinent to the present discussion, it should be empha-sized that fibrosis increases chronic ischemia in the rem-nant kidney tissue since the fibrous transformation re-

MECHANISMS OF INFILTRATION ANDduces the interstitial vascular network. Fine, Orphanides,

ACTIVATION OF IMMUNOCOMPETENT CELLS and Norman have emphasized that chronic tubulointer-IN NONIMMUNE RENAL DISEASE stitial hypoxia is capable of promoting progressive renal

The infiltration of immunocompetent cells requires scarring [127]. A variety of growth factors and fibrogenicboth the attraction exerted by the local expression of cytokines is produced by renal cells in vitro in responsechemotactic factors and the expression of adhesion mole- to hypoxia [128].cules. The chemokines are one of the most important Angiotensin II may promote the accumulation of im-chemotactic compounds. They are proteins of 8 to 10 munocompetent cells by its hemodynamic effects, bykD secreted by activated immune cells as well as resident stimulating synthesis of chemokines and adhesion mole-renal cells. Chemokines stimulate only migration but, cules and by direct actions on resident and infiltratingunder certain conditions, may also stimulate cell prolifer- cells. The hemodynamic effects of angiotensin promoteation, angiogenesis, and leukocyte activation. The che- macrophage accumulation by at least two mechanismsmokine superfamily now consists of four subfamilies with contemplated in Figure 1. (1) Generalized vasoconstric-40 members and 17 different receptors [reviewed in 121]. tion resulting from intrarenal angiotensin activity pro-The two more numerous subfamilies are the C-C subfam- motes chronic ischemia and ischemia-derived generationily, which has two cysteines adjacent to each other, and of ROS [129], and (2) angiotensin exerts preferentialthe C-X-C subfamily, which has an additional amino efferent vasoconstriction in the glomerular capillary,acid interposed between the cysteines. Most of C-X-C thereby increasing intraglomerular filtration pressurechemokines are chemoattractant for neutrophils, while and proteinuria [130, 131]. Prevention of these hemody-the C-C chemokines attract monocytes, T cells, and natu- namic effects is largely responsible for the reduction inral killer cells. Two of the cytokines most commonly proteinuria observed with administration of angiotensin-implicated in renal disease, MCP-1 (which is primarily converting enzyme inhibitors [132, 133]. In turn, protein-chemotactic for macrophages) and RANTES (which is uria induces enhanced angiotensinogen mRNA expres-primarily chemotactic for lymphocytes), belong to C-C sion in the proximal tubular cells [134].subfamily. Lymphotactin, a member of the third subfam- In addition to its vasoactive properties, Ang II inducesily (C family), lacks two of the four cysteine residues, the expression of adhesion molecules [135–137], acti-but is homologous to the CC chemokines in the carboxyl vates nuclear factor kappa-B (NF-kB), and stimulatesend. Lymphotactin is a powerful attractor of T lympho- the synthesis of MCP-1 [138], and osteopontin [139],cytes. The final subfamily (CX3C subfamily) is consti- which is assumed to be a macrophage attractor. Further-

more, amino and carboxy-terminal Ang II tetrapeptidestuted by Fractalkine, which has been shown to have

Rodrıguez-Iturbe et al: Immunocompetent cells 1631

Table 2. Expression of chemoattractants and adhesion molecules in pathophysiologic conditions associated withinfiltration of cells of the immune system in the kidney

Chemoattractants Adhesion molecules References

Proteinuria Chemokines, complement (C5a) growth factors, VCAM, ICAM [19, 24, 25, 204, 205]vasoactive mediators, urinary lipid chemoattrac-tant, osteopontin

Ischemia Chemokines, growth factors, osteopontin VCAM, ICAM [16]Oxidized lipids Chemokines, vasoactive mediators, osteopontin VCAM, ICAM [40, 159–161] [206]Obstruction to ICAM-1, VCAM [207–209]

urine flow Chemokines, vasoactive mediators, osteopontinShear stress Chemokines, growth factors/vasoactive mediators ICAM-1, VCAM-1 [210–214]

Chemokines include MCP-1, RANTES and growth factors/vasoactive mediators include PDGF, colony stimulating factors, endothelin-1 and angiotensin II.

are chemotactic for monocytes [140]. In addition to pro- production of ROS with inhibition of the membrane-bound nicotinamide adenine dinucleotide phosphatemoting macrophage recruitment, Ang II is capable of

activating them [141]. (NADPH)-dependent oxidase system, or using ROSscavengers, such as dimethyl- and trimethyl-thio-urea,The role of angiotensin in the accumulation and activa-

tion of immunocompetent cells in vivo is increasingly reduces the expression of these same chemoattractantsand adhesion molecules. ROS may function as secondrecognized by the beneficial effects of angiotensin recep-

tor blockade in several models of immune-mediated dis- messengers [156] in the generation of MCP-1, RANTES,and ICAM-1 by a mechanism that may involve an inter-eases [142–145]. While these findings are largely indirect,

immune modulation by Ang II is strongly suggested by mediate step of activation of the transcription NF-kB[157].the existence of angiotensin II type 1 (AT1) receptor in

macrophages and T cells [146], and more recently by the Oxidized lipids have monocyte chemoattractant activ-finding that proliferation of T cells is induced by Ang II ity [158] and induce endothelial cell expression of adhe-through the AT1 receptor by a calcineurin-dependent sion molecules ICAM-1 and VCAM [159–161]. Highpathway [147]. Finally, Ang II may stimulate indirectly lipid diets induce mRNA of MCP-1, osteopontin, andthe lipid-induced macrophage activation since it has a VCAM in the rat kidney [40]. A reduction of serumstimulatory effect in low-density lipoprotein (LDL) oxi- lipids reduces injury in models of kidney disease thatdation [148]. do not cause increased serum lipids, such as models of

Reactive oxygen species are mediators of tissue injury ureteral obstruction [162, 163]. However, the beneficialthat are pathogenetically involved in a variety of experi- effects of HMG-CoA reductase inhibitors used in manymental models of immune, toxic, and ischemic renal dam- of such studies may result from a direct antiproliferativeage. Resident renal cells and infiltrating leukocytes are effect of these drugs, rather than from its lipid-loweringknown sources of ROS [149]. Macrophages produce su- properties, since they inhibit the mevalonate pathwayperoxide (O2

2), hydrogen peroxide (H2O2) and hydroxyl that generates metabolites that stimulate mesangial pro-radical (·OH) in inflammatory immune-mediated glo- liferation [164] and type IV collagen secretion [165].merulonephritis [149]. ROS have been reported to cause Finally, recruitment of immunocompetent cells by oxi-mesangiolysis and endothelial damage in some [150] but dized lipoproteins may also be indirectly mediated bynot all species [151]. If injected in the renal artery, H2O2 the generation of ROS, which these compounds inducecauses a massive, abrupt, and reversible proteinuria re- in endothelial and mesangial cells (Fig. 1) [166].sulting from a size-selective defect caused by iron-depen-dent metabolites of hydrogen peroxide [151]. Studies by

ARE IMMUNOCOMPETENT CELLSJohnson et al have shown that glomerular interactionACTIVATED BY ANTIGEN-DEPENDENT ORbetween myeloperoxidase, H2O2, and a halide causedANTIGEN-INDEPENDENT MECHANISMS INproteinuria and a damage consisting of necrosis of endo-NONIMMUNE RENAL DISEASES?thelial cells with platelet activation and proliferation of

While the infiltration of neutrophils and macrophagesresident glomerular cells [152, 153].is part of a nonspecific inflammatory reaction, the pres-In addition, ROS are actively involved in the activationence of lymphocytes and dendritic cells within lesionsof chemotactic factor and adhesion molecules (Fig. 1).raises questions about their role in the maintenance andIn a series of elegant experiments, Satriano et al haveamplification of the inflammatory response and whethershown that generation of superoxide anions by the addi-or not their recruitment and activation is mediated bytion of xanthine oxidase and hypoxanthine to mesangialan antigen-specific immune response. These questionscells increase the mRNA levels of MCP-1, RANTES,

and ICAM-1 [154, 155]. Furthermore, suppressing remain largely unanswered at the present time.

Rodrıguez-Iturbe et al: Immunocompetent cells1632

Fig. 1. Interrelation between nonimmune conditions associated with accumulation and activation of immunocompetent cells in the kidney. Theinflux and activation of cells of the immune system results from a complex interrelation of factors that stimulate the production of chemoattractantsand adhesion molecules. Proteinuria, oxidized lipoproteins, obstruction to urine flow, and ischemia are conditions that stimulate the renin-angiotensin system and the production of reactive oxygen species (ROS), both of which induce the production of chemotactic factors and expressionof adhesion molecules (discussed in this article). Macrophages and lymphocytes not only have angiotensin II subtype 1A (AT1A) receptors [147],but are also capable of generating ROS [129, 149] and angiotensin II in response to angiotensinogen or angiotensin I peptides [215, 216], thushaving the potential for retrograde stimulation of the cycle. Chronic hypoxia [127] and angiotensin II (Ang II) [217] are capable of inducing avariety of growth factors and fibrosis.

Inasmuch as the T cells are the effectors of the cellular press class II MHC antigens, which may amplify the cell-mediated injury [14, 15]. Endogenous dendritic cells areimmune responses, their presence, in association with

evidence of cytokine production, raises the possibility also professional antigen-presenting cells that can beidentified in tubulointerstitial lesions [57]. The internal-that they are recognizing and reacting to endogenous

antigens newly expressed in the conditions listed in Table ization of antigen, followed by the degradation by hy-drolytic lysosomal enzymes into peptide fragments, then1. Neilson et al have discussed the possibility of a progres-

sive loss of tolerance to parenchymal self and how tubu- allows the antigen-presenting cells to present the antigenin association with MHC class II molecules to autoreac-lar epithelium, under the influence of cytokines can ex-

Rodrıguez-Iturbe et al: Immunocompetent cells 1633

in the initiation of autoimmunity [172]. T lymphocyteswith ab TCR have a very wide distribution, while lym-phocytes with gd TCR are mostly restricted to specificareas such as epidermis, intestinal epithelium, uterus,and tongue, but they have also been found in the kidneyin IgA nephropathy, where their presence is associatedwith progressive disease [173]. It is therefore conceivablethat T cells with gd TCR could play a role in renalautoimmunity recognizing antigenic stress proteins de-rived from the tubulointerstitial cells injured by varietyof pathogenetic influences.

Antigen-independent pathways may also result inT-lymphocyte activation (Table 1). This possibility hasbeen raised in chronic hepatitis C and in multiple sclero-sis, because in these diseases, there is a discrepancy be-tween the large number of infiltrating T cells and theFig. 2. Relationship of interstitial macrophage infiltration to systolic

blood pressure in catecholamine-induced hypertension [94]. In this small number of them that are specifically reactive forstudy, rats were administered phenylephrine for eight weeks. During hepatitis C virus (HCV) proteins or central nervous sys-this time, blood pressure was episodically elevated. At the end of the

tem antigens, respectively. One explanation for this ob-infusion one kidney was removed and the number of ED-1–positivemacrophages in the interstitium was determined (semiquantitative score servation is the possibility of antigen-independent mech-0 to 5). Rats were subsequently placed on a high (8% NaCl) salt diet anisms that could activate bystander T cells [174]; severalfor four to eight weeks. Shown is the systolic blood pressure at the end

studies have focused on the possibility that T cells couldof the study. (, vehicle-perfused rats; , phenylephrine-infused rats; N 517, r2 5 0.48, P , 0.003). proliferate and display effector functions in response

to cytokines in the absence of TCR occupancy. Infact, Unutmaz et al have found that a combination ofIL-2, tumor necrosis factor (TNF)-a, and IL-6 could in-

tive T cells via specific T-cell receptor (TCR). Peptide duce highly purified naive (CD45RA1) and memoryfragments bound to class II MHC molecules are recog- (CD45RO1) T cells to proliferate and resting memorynized predominantly in T cells expressing CD4 molecules T cells to synthesize cytokines and promote IgG produc-and require a costimulatory signal that is antigen inde- tion by B cells [175, 176]. Bacon et al found thatpendent. RANTES, in addition to its chemotactic properties, in-

Truong et al found that chronic ischemia induces pro- duces antigen-independent cytokine release, IL-2 recep-found changes in the antigens expressed by the renal tor expression, and T-cell proliferation [177], and similartubules [17]. These changes included a loss of cell mem- results were obtained with IL-7 by Fukui et al [178].brane glycoproteins, characterized by a loss of binding Antigen-independent production of mRNA for IL-2properties for the lectins Dolichos biflorus and glycine and expression of IL-2 receptor may also be inducedmax, which are specific markers for D-galactose-N-acetyl by the binding of specific costimulatory molecules, inglucosamine. In addition, there was exposure of cytoskel- particular CD28 [179, 180] and the vitronectin receptor

(VNR), which if engaged by extracellular matrix pro-eton filament antigens that are normally expressed onlyteins, independently of occupancy of the TCR, may in-in embryonic cells, such as vimentin and keratin. Of note,duce secretion of IL-2 in gd TCR T cells [181].these changes are not specific for ischemic injury since

At present, it is not known to what extent, if any,they also occur in other conditions, such as puromycinautoreactive cellular immunity is responsible for the[20] and protein overload [18] nephropathies, raisingmononuclear cell infiltration clearly present in “nonim-the possibility that these alterations in tubular antigenicmune” renal diseases and whether nonspecific activationprofile are common to many, if not all, models of severeof these cells plays a role in their proliferation and ef-tubulointerstitial injury.fector activity.In addition, the early events of injury in the tubuloin-

terstitial cells likely include the release of heat shock(stress) proteins, which are found in all prokaryotic and IS THE PRESENCE OF IMMUNE CELLS

PATHOGENETICALLY RELEVANT INeukaryotic cells and are assumed to be transporters ofNONIMMUNE RENAL DISEASES?target antigens in the initial protective response againstRESULTS OBTAINED WITHmany infectious organisms [167]. These stress proteinsMYCOPHENOLATE MOFETILhave essential roles in the assembly and transport of

other molecules, can be recognized by the gamma delta Several studies have investigated the role of the cellu-lar immune system in some experimental conditionsT cell receptor (gd TCR) [168–171], and may be involved

Rodrıguez-Iturbe et al: Immunocompetent cells1634

Fig. 3. Lymphocyte infiltration in the renal ablation model. Photomi-crographs demonstrating lymphocyte infiltration [staining with fluores-cein-labeled monoclonal antibody (mAb) anti-CD5] in the remnantkidney four weeks after 5/6 nephrectomy in the rat. In this model,proteinuria was prevented and renal function and structure were mark-edly preserved by mycophenolate mofetil (MMF) treatment, which

Fig. 4. Effects of mycophenolate mofetil (MMF) on the infiltration ofreduced infiltration of lymphocytes and macrophages and expressionlymphocytes in atherosclerosis. (A) Lymphocyte infiltration in the aortaof adhesion molecules [54].of a rabbit fed with a high (1%) cholesterol diet for 12 weeks (stainingwith peroxidase-labeled mAb anti-CD5). (B) Treatment with MMF(30 mg daily by gastric gavage) is associated with marked reduction inlymphocyte infiltration. Similar reductions were found in macrophage

listed in Table 1 by using immunomodulatory treatments infiltration, cholesterol content of the aorta and atherosclerotic plaques[188].such as the administration of essential fatty acid-deficient

diets [110, 113], X-irradiation [114], and steroid therapy[182]. In these studies, a reduction in leukocyte infiltra-tion was associated with reduced injury and improved

of cytokines are critically involved in the progressiverenal function.sclerotic renal changes [52, 186]. Furthermore, cytokinesRecently, the role of the cellular immune system hassuch as TNF-a, IL-1 and IL-6 may induce vasodilation,been investigated further by studies using mycopheno-vasospasm, or vessel occlusion by modifying nitric oxidelate mofetil (MMF), an immunosuppressive agent com-vascular pathways [reviewed in 187]. Therefore, threemonly used in transplantation. MMF is a reversible inhib-independent groups, including ourselves, have useditor of inosine 59-monophosphate dehydrogenase, whichMMF alone [53, 54] or in conjunction with angiotensin-is a critical enzyme in de novo synthesis of guanosineconverting enzyme inhibition [57] to suppress the infil-triphosphate [183]. MMF depletes guanosine triphos-tration and proliferation of immunocompetent cells andphate pools in lymphocytes and monocytes and sincereduce inflammatory mediators in the 5/6 nephrectomylymphocyte proliferation depends almost exclusively inmodel.de novo purine synthesis, the drug suppresses the cellular

In the renal ablation model, MMF treatment reducedimmune response. In addition, MMF inhibits the expres-the infiltration of macrophages and lymphocytes [53, 54,sion of adhesion molecules in vascular endothelium57], the expression of MHC antigens [52], and ICAM-1[184], thereby minimizing the extravasation of inflam-and leukocyte function associated antigen-1 (LFA-1) ad-matory cells. Most importantly, in contrast to other im-hesion molecules [54]. In association with these changes,munosuppressive drugs, MMF is not nephrotoxic. Mostthere was a dramatic reduction in the chronic scleroticinterest has centered on the extensively studied renalchanges and in the proteinuria and renal function deteri-ablation model. Progressive renal damage following 5/6oration characteristic of this model [53, 54, 57]. Recently,nephrectomy is triggered by hemodynamic alterationswe have shown that in rabbits with diet-induced hyper-in the remnant nephrons [44], and treatment strategiescholesterolemia [188], MMF treatment reduces aorticdirected to correct glomerular hypertension have beenlymphocyte (Fig. 4), macrophage and foam cell infiltra-successfully used to arrest the progressive nature of renaltion as well as smooth muscle cell proliferation and infil-damage [133, 185]. However, it is well recognized thattration. In association with these findings, there was aninterstitial infiltration of macrophages and lymphocytesapproximately 50% reduction in aortic lipid depositionis a prominent finding (Fig. 3), and cellular proliferation,

accumulation of mononuclear cells, and local production and atherosclerotic plaque formation. While the partici-

Rodrıguez-Iturbe et al: Immunocompetent cells 1635

pation of immune cells in atherosclerosis is well recog- by which MMF prevents salt-sensitive hypertension, thereduction of angiotensin II-producing infiltrate couldnized [42], the treatment with other immunosuppressive

drugs has given conflicting results [189–192]; therefore, certainly play a role. Taken together, the data suggestthat immunocompetent cells play an important role inthe usefulness of MMF in the rabbit model of atheroscle-

rosis is of considerable interest. Clearly, the suppression several mechanisms that are implicated in the pathogen-esis of nonimmune renal damage. Gaining insight intoof the infiltration and proliferation of immunocompetent

cells in response to oxidized lipoproteins is of potential these mechanisms has obvious clinical relevance sincehuman conditions commonly associated with chronic re-benefit in renal conditions in which atherogenic lipopro-

teins play a primary role or participate as a secondary nal failure, such as severe essential hypertension [201],chronic pyelonephritis [202], and diabetes [203] haverisk factor.

More recently, we have used MMF treatment in well- similar infiltration of immunocompetent cells. Immuno-suppressive drugs that lack nephrotoxicity and have spe-established models of salt-sensitive hypertension that,

as discussed earlier, are known to be associated with cific antilymphocytic action as well as a reasonably widetherapeutic window may represent an additional optiontubulointerstitial infiltration of immunocompetent cells.

Preliminary data in the salt-sensitive hypertension that in the treatment of progressive renal damage and shouldbe investigated further.follows short-term angiotensin infusion [95] indicate that

while the hypertension induced by angiotensin infusionis unchanged by MMF, the increase in blood pressure ACKNOWLEDGMENTSobserved when a high salt intake is administered after Research in the authors’ laboratories is supported by Asociacion

de Amigos del Rinon, Maracaibo and Consejo Nacional de Investigaci-angiotensin infusion is prevented by MMF. A pathogenicones Cientıficas (CONICIT), Venezuela; Consejo de Investigacionesrelationship between salt-sensitive hypertension and im-Cientıficas, Mexico; and U.S. Public Health Service Grants DK-43422,

munocompetent cells is suggested by the concomitant DK-52121, and DK-47659.reduction of lymphocyte infiltration and activation, oxi-

Reprint requests to Bernardo Rodrıguez-Iturbe, M.D., Apartadodative stress, and tubulointerstitial damage in the kidney.Postal 1430, Maracaibo 4001-A, Venezuela.

Macrophage infiltration was not significantly reduced E-mail: bri@iamnet.com[218]. Similar studies were done in the model of hyper-tension induced by inhibition of nitric oxide (NO) syn- REFERENCESthesis [98]. In this model, the administration of L-NAME

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