Macrophages and the kidney

PURPOSE OF REVIEW: Macrophage infiltration is a hallmark of all forms of inflammatory and non-inflammatory renal injury. However, the classical view of macrophages as cells that cause injury has been superseded with evidence of their heterogeneous role, i.e. with involvement in all stages of the inflammatory process including tissue repair and healing. This review summarizes the major advances in macrophage biology achieved in the last year, highlighting the different activation states, how these are regulated, and their relevance in renal disease. RECENT FINDINGS: New concepts have emerged concerning the factors controlling monocyte recruitment into inflamed tissue and their subsequent differentiation into activated macrophages. There is now compelling evidence for the heterogeneity of macrophages in clinical disease, i.e. they appear to be able to both promote and downregulate inflammation. An increased understanding of the factors regulating the expression of pro-inflammatory or reparative characteristics by macrophages is establishing how their function can be manipulated to attenuate renal inflammation in experimental models. SUMMARY: An understanding of the role of macrophages at different time-points in renal inflammation, and the development of techniques for modulating macrophage activation in vivo, will provide a powerful method for exploiting the reparative attributes of these cells in clinical settings, restoring regulation to the inflammatory process and promoting healing.     

How does proteinuria cause progressive renal damage?

The possibility that proteinuria may accelerate kidney disease progression to end-stage renal failure has received support from the results of increasing numbers of experimental and clinical studies. Evidence indicating that this process occurs through multiple pathways, including induction of tubular chemokine expression and complement activation that lead to inflammatory cell infiltration in the interstitium and sustained fibrogenesis, is reviewed. Macrophages are prominent in the interstitial inflammatory infiltrate. This cell type mediates progression of renal injury to the extent that macrophage numbers in renal biopsy predict renal survival in patients with chronic renal disease. Chemoattractants and adhesive molecules for inflammatory cells are upregulated by excess ultrafiltered protein load of proximal tubular cells via activation of NF-kappaB-dependent and NF-kappaB-independent pathways. This mechanism is a potential target for therapeutic approaches, as shown by beneficial effects of manipulations with inhibitory molecules of NF-kappaB activation or of chemokine receptors in experimental studies. Targeting complement synthesis or activation in proximal tubule might offer novel therapeutic opportunities. Finally, proximal tubular cell receptors for uptake of plasma proteins that are under investigation may provide activation signals on excess tubular protein handling.     

Interactions between angiotensin II and NF-kappaB-dependent pathways in modulating macrophage infiltration in experimental diabetic nephropathy

NF-kappaB-dependent pathways play an important role in macrophage infiltration and kidney injury. NF-kappaB is regulated by angiotensin II (AII). However, the role of this pathway in diabetic nephropathy has not been clearly delineated. First, the activation of NF-kappaB, monocyte chemoattractant protein-1 (MCP-1), and macrophage infiltration in the diabetic kidney were explored, in a temporal manner. The active subunit of NF-kappaB, p65, was elevated in the diabetic animals in association with increased MCP-1 gene expression and macrophage infiltration. Second, the effects of treatment for 4 wk with the AII type 1 receptor antagonist valsartan, the AII type 2 receptor antagonist PD123319, or pyrrolidine dithiocarbamate, an inhibitor of NF-kappaB and on these parameters were assessed. These treatments were associated with a reduction in p65 activation, MCP-1 gene expression, and macrophage infiltration. These findings demonstrate a role for activation of NF-kappaB, in particular the p65 subunit, in the pathogenesis of early renal macrophage infiltration in experimental diabetes. In the context of the known proinflammatory effects of AII, it is postulated that the renoprotection conferred by angiotensin II receptor antagonism is at least partly related to the inhibition of NF-kappaB-dependent pathways.     

Activation of Notch3 in Glomeruli Promotes the Development of Rapidly Progressive Renal Disease

Notch3 expression is found in the glomerular podocytes of patients with lupus nephritis or focal segmental GN but not in normal kidneys. Here, we show that activation of the Notch3 receptor in the glomeruli is a turning point inducing phenotypic changes in podocytes promoting renal inflammation and fibrosis and leading to disease progression. In a model of rapidly progressive GN, Notch3 expression was induced by several-fold in podocytes concurrently with disease progression. By contrast, mice lacking Notch3 expression were protected because they exhibited less proteinuria, uremia, and inflammatory infiltration. Podocyte outgrowth from glomeruli isolated from wild-type mice during the early phase of the disease was higher than outgrowth from glomeruli of mice lacking Notch3. In vitro studies confirmed that podocytes expressing active Notch3 reorganize their cytoskeleton toward a proliferative/migratory and inflammatory phenotype. We then administered antisense oligodeoxynucleotides targeting Notch3 or scramble control oligodeoxynucleotides in wild-type mice concomitant to disease induction. Both groups developed chronic renal disease, but mice injected with Notch3 antisense had lower values of plasma urea and proteinuria and inflammatory infiltration. The improvement of renal function was accompanied by fewer deposits of fibrin within the glomeruli and by decreased peritubular inflammation. Finally, abnormal Notch3 staining was observed in biopsy samples of patients with crescentic GN. These results demonstrate that abnormal activation of Notch3 may be involved in the progression of renal disease by promoting migratory and proinflammatory pathways. Inhibiting Notch3 activation could be a novel, promising approach to treat GN.     

Adenosine A(2A) agonists as therapy for glomerulonephritis

Garcia et al. report the utility of pharmacological activation of the adenosine A(2A) receptor (A(2A)R) in preserving renal function, reversing fibrosis, and reducing macrophage infiltration and inflammatory activation in rat nephrotoxic nephritis. The role of A(2A)R activation in determining outcome in renal inflammation is discussed.     

Macrophages contribute to the development of renal fibrosis following ischaemia/reperfusion-induced acute kidney injury.

BACKGROUND: Ischaemia/reperfusion is a major cause of acute kidney injury and can result in poor long-term graft function. Although most of the patients with acute kidney injury recover their renal function, significant portion of patients suffer from progressive deterioration of renal function. A persistent inflammatory response might be associated with long-term changes following acute ischaemia/reperfusion. Macrophages are known to infiltrate into tubulointersitium in animal models of chronic kidney disease. However, the role of macrophages in long-term changes after ischaemia/reperfusion remains unknown. We aimed to investigate the role of macrophages on the development of tubulointerstitial fibrosis and functional impairment following acute ischaemia/reperfusion injury by depleting macrophages with liposome clodronate. METHODS: Male Sprague-Dawley rats underwent right nephrectomy and clamping of left renal vascular pedicle or sham operation. Liposome clodronate or phosphate buffered saline was administered for 8 weeks. Biochemical and histological renal damage and gene expression of various cytokines were assessed at 4 and 8 weeks after ischaemia/reperfusion. RESULTS: Ischaemic/reperfusion injury resulted in persistent inflammation and tubulointerstital fibrosis with decreased creatinine clearance and increased urinary albumin excretion at 4 and 8 weeks. Macrophage depletion attenuated those changes. This beneficial effect was accompanied with a decrease in gene expression of inflammatory and profibrotic cytokines. CONCLUSIONS: These results suggest that macrophages play an important role in mediating persistent inflammation and fibrosis after ischaemia/reperfusion leading to a development of chronic kidney disease. Strategies targeting macrophage infiltration or activation can be useful in the prevention of development of chronic kidney disease following ischaemic injury.     

Chemokines in renal injury

The main function of chemokines is to guide inflammatory cells in their migration to sites of inflammation. During the last 2 decades, an expanding number of chemokines and their receptors have driven broad inquiry into how inflammatory cells are recruited in a variety of diseases. Although this review focuses on chemokines and their receptors in renal injury, proinflammatory IL-17, TGFβ, and TWEAK signaling pathways also play a critical role in their expression. Recent studies in transgenic mice as well as blockade of chemokine signaling by neutralizing ligands or receptor antagonists now allow direct interrogation of chemokine action. The emerging role of regulatory T cells and Th17 cells during renal injury also forges tight relationships between chemokines and T cell infiltration in the development of kidney disease. As chemokine receptor blockade inches toward clinical use, the field remains an attractive area with potential for unexpected opportunity in the future.     

Toll-like receptor 4 promotes tubular inflammation in diabetic nephropathy

Inflammation contributes to the tubulointerstitial lesions of diabetic nephropathy. Toll-like receptors (TLRs) modulate immune responses and inflammatory diseases, but their role in diabetic nephropathy is not well understood. In this study, we found increased expression of TLR4 but not of TLR2 in the renal tubules of human kidneys with diabetic nephropathy compared with expression of TLR4 and TLR2 in normal kidney and in kidney disease from other causes. The intensity of tubular TLR4 expression correlated directly with interstitial macrophage infiltration and hemoglobin A1c level and inversely with estimated glomerular filtration rate. The tubules also upregulated the endogenous TLR4 ligand high-mobility group box 1 in diabetic nephropathy. In vitro, high glucose induced TLR4 expression via protein kinase C activation in a time- and dose-dependent manner, resulting in upregulation of IL-6 and chemokine (C-C motif) ligand 2 (CCL-2) expression via IκB/NF-κB activation in human proximal tubular epithelial cells. Silencing of TLR4 with small interfering RNA attenuated high glucose-induced IκB/NF-κB activation, inhibited the downstream synthesis of IL-6 and CCL-2, and impaired the ability of conditioned media from high glucose-treated proximal tubule cells to induce transmigration of mononuclear cells. We observed similar effects using a TLR4-neutralizing antibody. Finally, streptozotocin-induced diabetic and uninephrectomized TLR4-deficient mice had significantly less albuminuria, renal dysfunction, renal cortical NF-κB activation, tubular CCL-2 expression, and interstitial macrophage infiltration than wild-type animals. Taken together, these data suggest that a TLR4-mediated pathway may promote tubulointerstitial inflammation in diabetic nephropathy.     

Hypertension induces oxidative stress but not macrophage infiltration in the kidney in the early stage of experimental diabetes mellitus

BACKGROUND: The combination of diabetes and hypertension increases the incidence and severity of kidney disease in an additive manner. Inflammatory and oxidative stress mechanisms contribute to renal damage in both diabetes and hypertension. Therefore, we investigated whether renal macrophage infiltration and oxidative stress events are additive from the beginning in diabetic animals with coexisting hypertension. METHODS: Diabetes was induced in spontaneously hypertensive rats (SHRs) and their genetically normotensive control Wistar Kyoto (WKY) rats by streptozotocin injection at 12 weeks of age for 10 days, and the effects of hyperglycemia on renal macrophage infiltration and oxidative stress were evaluated. RESULTS: Blood pressure was higher in SHR than in WKY groups. Markers of oxidative stress-induced DNA and protein modification, 8-hydroxy- 2'-deoxyguanosine (8-OHdG) and nitrotyrosine, respectively, and the antioxidant glutathione levels were found to be similar in WKY-control and WKY-diabetic groups. However, 8-OHdG was significantly elevated (p = 0.014), the nitrotyrosine level tended to be elevated (p = 0.068) and the glutathione level was significantly reduced (p = 0.034) in the SHR-diabetic group compared to the SHR-control group. On the other hand, glomerular and tubulointerstitial macrophage infiltration was significantly higher in both WKY-diabetic and SHR-diabetic groups than the respective control groups. CONCLUSIONS: A short duration of diabetes mellitus induces renal oxidative stress in the presence of hypertension; however, renal macrophage infiltration becomes evident in early diabetes regardless of the presence or absence of hypertension. We conclude that the combination of diabetes and hypertension adversely affects oxidative stress in the kidney, but the combination has no additive effect on renal macrophage infiltration, at least in early diabetes.     

Methotrexate prevents renal injury in experimental diabetic rats via anti-inflammatory actions

Recent studies suggested the involvement of inflammatory processes in the pathogenesis of diabetic nephropathy. Methotrexate (MTX), a folic acid antagonist, is widely used for the treatment of inflammatory diseases. Recently, it has been shown that treatment with low-dose MTX reduces the cardiovascular mortality in patients with rheumatoid arthritis, suggesting that MTX has anti-atherosclerotic effects via its anti-inflammatory actions. This study was designed to determine the anti-inflammatory effects of this agent on diabetic nephropathy. Diabetes was induced in Sprague-Dawley rats with streptozotocin, and MTX (0.5 or 1.0 mg/kg) was administered once a week for 8 wk. Treatment with MTX reduced urinary albumin excretion, mesangial matrix expansion, macrophage infiltration, expression of TGF-beta and type IV collagen, and intercellular adhesion molecule-1 in glomeruli. MTX also reduced the high glucose-induced NF-kappaB activation in vitro and in vivo. The results indicate that intermittent administration of MTX prevented renal injuries without changes in blood glucose level and BP in experimental diabetic rats. The protective effects of MTX are suggested to be mediated by its anti-inflammatory actions through inhibition of NF-kappaB activation and consequent reduction of intercellular adhesion molecule-1 expression and macrophage infiltration. The results suggest that anti-inflammatory agents might be beneficial for the treatment of diabetic nephropathy.     

Kallikrein/kinin protects against gentamicin-induced nephrotoxicity by inhibition of inflammation and apoptosis.

BACKGROUND: Our previous study showed that kallikrein gene transfer protects against gentamicin-induced nephrotoxicity and enhances renal function. In this study, we investigated the effects and potential mechanisms of kallikrein/kinin on inflammation and apoptosis induced by gentamicin. METHODS: Rats were injected subcutaneously with gentamicin daily for 10 days and received an intravenous injection of adenovirus carrying the human tissue kallikrein gene or control virus on the first day of gentamicin administration. RESULTS: After 10 days of gentamicin treatment, kallikrein gene transfer significantly attenuated gentamicin-induced tubular dilatation and lumenal protein casts. Moreover, kallikrein gene transfer reduced monocyte/macrophage infiltration, monocyte chemoattractant peptide-1 expression and renal cell apoptosis. Kallikrein's protective effects were accompanied by increased nitric oxide formation, and reduced NADH oxidase activity and superoxide production. Suppression of oxidative stress was associated with diminished c-jun N-terminal kinase activation and intercellular adhesion molecule-1 and transforming growth factor-beta protein levels. These biochemical effects were blocked by icatibant, indicating a kinin B2 receptor-mediated signalling event. CONCLUSIONS: This study indicates that kallikrein/kinin protects against gentamicin-induced nephrotoxicity by inhibiting inflammatory cell recruitment and apoptosis through suppression of oxidative stress-mediated signalling pathways. These findings raise the potential of applying kallikrein therapy approaches in treating aminoglycoside-induced renal damage.     

Expression of the chemokines MCP-1/CCL2 and RANTES/CCL5 is differentially regulated by infiltrating inflammatory cells

BACKGROUND: Chemokines are involved in the regulation of the cellular renal infiltrate in glomerulonephritis; however, it is unclear to which degree resident glomerular cells or infiltrating leukocytes contribute to the formation of chemokines in glomerular inflammatory lesions. We therefore examined whether monocytes/macrophages play a role in the expression of the C-C chemokines MCP-1/CCL2 and RANTES/CCL5 in renal tissue in a lipopolysaccharide (LPS)-induced model of inflammation, where previously we have shown increased glomerular RANTES expression and glomerular infiltration of ED-1-positive cells. METHODS: Inflammatory lesions were induced by an intraperitoneal injection of LPS. The infiltration of monocytes into the glomerulus was reduced by two experimental approaches. First, rats were depleted of monocytes by the use of specific monocyte-antisera or by cytotoxic drugs. Second, the infiltration of monocytes into the kidney was reduced by using intercellular adhesion molecule-1 (ICAM-1) knockout mice. RESULTS: Both experimental approaches demonstrated a significant reduction in the number of infiltrating monocytes/macrophages after lipopolysaccharide injection. This reduction in the infiltration of inflammatory cells was associated with significantly reduced RANTES/CCL5 mRNA expression. However, MCP-1/CCL2 mRNA expression was not inhibited after the LPS injection by monocyte/macrophage depletion. Also, the increase in nuclear factor-kappaB (NF-kappaB) binding activity after the LPS injection was not reduced in pretreated animals. The experiments therefore demonstrate that infiltrating monocytes/macrophages contribute to increased RANTES/CCL5 mRNA expression in inflammatory renal lesions, whereas MCP-1/CCL2 mRNA expression and NF-kappaB activation were not reduced by monocyte/macrophage depletion. CONCLUSION: MCP-1/CCL2 released from renal tissue upon stimulation plays a major role in the regulation of monocyte/macrophage infiltration, which contributes significantly to increased renal RANTES/CCL5 expression. This cross-talk between resident renal cells and monocytes/macrophages is therefore likely to boost the number of infiltrating inflammatory cells.     

Five-lipoxygenase products in glomerular immune injury.

Leukocyte infiltration, proliferation, and activation are central pathogenetic components of immune injury in the glomerulus. Initial cellular infiltration by polymorphonuclear leukocytes (PMN) is a consequence of the deposition of immune complexes at discreet sites in the glomerulus. This is often followed by macrophage/monocyte infiltration, as well as proliferation of resident mesangial macrophages. Activated leukocytes constitute a rich source of lipid-derived bioactive autacoids, in particular, oxygenated metabolites of arachidonic acid. Here, we assess the role of the five-lipoxygenase (5-LO) family of eicosanoids, in particular, leukotrienes D4 and B4 (LTD4 and LTB4) in mediating functional and structural deterioration during immune inflammatory reactions in the glomerulus. LTD4 and other peptidyl LT appear to play a central role in the reductions in GFR in the acute phases of injury by virtue of their potent vasoactive properties, in particular, their capacity to reduce the glomerular capillary ultrafiltration coefficient, likely through contraction of smooth muscle elements in glomerular mesangial cells. The latter cells possess specific receptors for LTD4 in both humans and rat and contract in vitro when exposed to LTD4 after receptor-mediated activation of phospholipase C. LTB4, a nonvasoconstrictor LT, is released in the early phases of immune injury, likely from leukocyte sources as well as from transcellular metabolism of its precursor, LTA4, by the enzyme LTA4-hydrolase in glomerular mesangial and endothelial cells. LTB4, a potent promoter of PMN attraction, adhesion, and activation exacerbates glomerular functional impairment and structural damage by amplifying PMN-dependent mechanisms of injury. In their totality, 5-LO products of arachidonic acid contribute to the impairment of the normal glomerular filtration and sieving functions that attend acute inflammatory injury in the renal glomerulus and to the subsequent progression of glomerular destruction. This is high-lighted by the significant degree of protection afforded by the selective inhibition of arachidonate 5-LO in vivo in acute and chronic models of experimental glomerulonephritis.     

HMG-CoA reductase inhibitors and the kidney

During the last two decades, numerous studies have demonstrated that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) diminish the risk of cardiovascular morbidity and mortality. Although these studies have focused primarily on the ability of statins to lower circulating levels of low-density lipoprotein cholesterol, more recent research has shown that statins may protect the vasculature via pleiotropic effects not directly related to lipid lowering. These include adjustments in cell-signaling pathways that play a role in atherogenesis and that affect the expression of inflammatory elements, curtail oxidative stress, and enhance endothelial function. More recently, researchers have begun to explore whether these agents exert similar beneficial effects in renal parenchymal and renovascular disease. This review examines the available evidence that dyslipidemia may augment the inflammatory reaction of cytokines in patients with renal disease and that statins may improve renal dysfunction by altering the response of the kidney to dyslipidemia, even in persons with end-stage renal disease on dialysis or with renal transplantation. In this context, some data suggest that statin-mediated alterations in inflammatory responses and endothelial function may reduce proteinuria and the rate of progression of kidney disease.     

Selective lymphocyte inhibition by FTY720 slows the progressive course of chronic anti-thy 1 glomerulosclerosis

BACKGROUND: Progression is a hallmark of chronic renal disease and histologically characterized by fibrosis and inflammation of the tubulointerstitial compartment. To define the role of lymphocytes in this process, the novel lymphocyte-specific inhibitor FTY720 was administered to rats with anti-thy 1-induced chronic progressive glomerulosclerosis. In this model, the initial and short-term inflammatory glomerular injury progresses self-perpetuatedly toward tubulointerstitial fibrosis by not primarily immune-mediated, intrarenal mechanisms. METHODS: Chronic progressive glomerulosclerosis was induced by murine anti-thy 1 antibody injection into uninephrectomized rats. Treatment with FTY720 (0.3 mg/kg body weight) was started 7 days after disease induction. Proteinuria was measured every 4 weeks. In week 20, the following parameters were determined: blood lymphocyte number, kidney function, both glomerular and tubulointerstitial histologic matrix accumulation, protein expression of transforming growth factor-beta1 (TGF-beta1), fibronectin, and plasminogen activator inhibitor-1 (PAI-1) as well as infiltration with macrophages and lymphocytes. RESULTS: Treatment with FTY720 lowered blood lymphocyte count and renal lymphocyte infiltration highly significantly. In comparison to the untreated chronic progressive glomerulosclerosis animals, the lymphocyte depletion achieved significantly limited the progression of the disease, as shown by lowered proteinuria, tubulointerstitial matrix expansion, and TGF-beta1, fibronectin, and PAI-1 expression, as well as improved renal function. Glomerular matrix protein expression and accumulation was moderately lowered by FTY720. Glomerular macrophage infiltration was not, tubulointerstitial macrophage infiltration was moderately, but not significantly, decreased by FTY720 treatment. CONCLUSION: Lymphocyte depletion by FTY720 limits the progression of anti-thy 1-induced glomerulosclerosis toward chronic tubulointerstitial fibrosis and renal insufficiency. The data suggest that lymphocytes actively participate in the progression of chronic experimental kidney disease, and that FTY720 may be a novel approach to slow the progressive course of human chronic renal diseases.     

Signaling mechanism of TGF-beta1 in prevention of renal inflammation: role of Smad7

TGF-beta has been shown to play a critical role in anti-inflammation; however, the signaling mechanisms of TGF-beta in anti-inflammatory response remains largely unclear. This study reported that mice that overexpress latent TGF-beta1 on skin are protected against renal inflammation in a model of obstructive kidney disease and investigated the signaling mechanism of TGF-beta1 in inhibition of renal inflammation in vivo and in vitro. Seven days after urinary obstruction, wild-type mice developed severe renal inflammation, including massive T cell and macrophage infiltration and marked upregulation of IL-1beta, TNF-alpha, and intercellular adhesion molecule-1 (all P < 0.001). Surprising, renal inflammation was prevented in transgenic mice. This was associated with an increase in latent TGF-beta1 in circulation (a 10-fold increase) and renal tissues (a 2.5-fold increase). Further studies showed that inhibition of renal inflammation in TGF-beta1 transgenic mice was also associated with a marked upregulation of renal Smad7 and IkappaBalpha and a suppression of NF-kappaB activation in the diseased kidney (all P < 0.01). These in vivo findings suggested the importance of TGF-beta-NF-kappaB cross-talk signaling pathway in regulating renal inflammation. This was tested in vitro in a doxycycline-regulated Smad7-expressing renal tubular cell line. Overexpression of Smad7 was able to upregulate IkappaBalpha directly in a time- and dose-dependent manner, thereby inhibiting NF-kappaB activation and NF-kappaB-driven inflammatory response. In conclusion, latent TGF-beta may have protective roles in renal inflammation. Smad7-mediated inhibition of NF-kappaB activation via the induction of IkBalpha may be the central mechanism by which latent TGF-beta prevents renal inflammation.     

Chemokine expression precedes inflammatory cell infiltration and chemokine receptor and cytokine expression during the initiation of murine lupus nephritis.

Lupus nephritis is characterized by immune complex deposition and inflammatory cell infiltration. Therefore, the initiation and progression of lupus nephritis in MRL/MpJ Fas(lpr/lpr) (MRL/lpr) mice were investigated, with a focus on the expression of several chemokines and chemokine receptors. Mice were monitored for proteinuria from 6 to 20 wk of age, and kidneys were examined every 2 wk by light microscopy, electron microscopy, and immunohistologic analyses. Furthermore, the expression of chemokines, chemokine receptors, and proinflammatory cytokines was analyzed in ribonuclease protection assays. MRL/lpr mice demonstrated increased expression of monocyte chemoattractant protein-1, regulated upon activation, normal T cell-expressed and -secreted protein, inducible protein of 10 kD, and macrophage inflammatory protein-1beta at week 8. At that time point, levels of circulating and glomerular immune complexes were increased, and no proteinuria or histopathologic signs of renal damage could be observed. As assessed in immunohistochemical and in situ hybridization analyses, monocyte chemoattractant protein-1 and regulated upon activation, normal T cell-expressed and -secreted protein expression was preferentially located in the glomeruli and interstitium. Mononuclear cell infiltration of the kidney was observed by weeks 10 to 12. At week 12, the renal expression of chemokine receptor 1 (CCR1), CCR2, and CCR5 was increased, mice became proteinuric, and renal damage was histologically evident. Finally, the expression of proinflammatory cytokines was detected (weeks 12 to 14). In summary, (1) chemokines are upregulated before inflammatory cell infiltration, proteinuria, and kidney damage are observed; (2) chemokine generation is restricted to sites of subsequent inflammatory cell infiltration, i.e., glomeruli and interstitium; (3) chemokine receptor expression parallels mononuclear cell infiltration; and (4) proinflammatory cytokines are upregulated later, in parallel with inflammatory cell infiltration and the onset of proteinuria. These results support the hypothesis that chemokines initiate leukocyte infiltration and precede proteinuria and renal damage in MRL/lpr mice.     

Transient Improvement of Hypertension-Induced Chronic Renal Failure with Mycophenolate Mofetil Treatment

A young female with essential hypertension developed progressive azotemia; renal biopsy showed hypertensive nephrosclerosis with considerable tubulointerstitial disease and cellular infiltration. The addition of mycophenolate mofetil (MMF) to her antihypertensive treatment resulted in a dramatic improvement of renal function during the following three months. When the patient discontinued MMF treatment, end-stage renal failure rapidly developed. This patient represents the first report of the beneficial use of MMF in non-immune chronic renal disease and demonstrates that significant functional improvement may be obtained with the addition of MMF to the treatment of hypertensive nephrosclerosis for patients in whom there is significant tubulointerstitial inflammatory infiltration.     

Platelet activating factor (PAF) as a mediator of injury in nephrotoxic nephritis

Release of acetyl glyceryl ether phosphorylcholine, platelet-activating factor (PAF), has been demonstrated to be associated with glomerular inflammatory damage in acute serum sickness. Moreover, PAF can increase glomerular permeability to proteins and induce mesangial contraction. Thus PAF might be a good candidate as a mediator of glomerular damage. However the in vivo evidence that PAF might cause glomerular injury is lacking. To evaluate if PAF has a major role in promoting glomerular inflammatory reaction and fibrin deposition, we studied the effect of a molecule, L-652,731, which blocks the PAF receptor, on the evolution of an experimental model of anti-glomerular basement membrane (anti-GBM) glomerulonephritis (GN). GN was initiated by sheep-anti-rabbit nephrotoxic serum. A proliferative GN regularly occurred in which heavy proteinuria, intra and extracapillary proliferation of resident and inflammatory cells and fibrin deposition in Bowman's capsule were the prominent findings. Our results showed that the PAF receptor antagonist reduces the glomerular damage in anti-GBM GN, supporting the hypothesis that PAF is indeed a mediator of glomerular inflammatory reaction. PAF receptor blocking prevented renal function deterioration in the early phase of the disease, probably preserving glomerular hemodynamics. In the delayed phase of the disease the PAF receptor antagonist reduced proteinuria and prevented renal function deterioration and fibrin deposition. These effects appear to be mediated by an inhibitory action of PAF receptor blocking on macrophage accumulation and activation.