Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033687 (proteinuria)
 24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During the development of nephrotoxic nephritis (NTN) in the mouse, we find that a variety of chemokines and chemokine receptors are induced: CCR1 (RANTES, MIP-1alpha), CCR2 (MCP-1), CCR5 (RANTES, MIP-1alpha, MIP-1beta), CXCR2 (MIP-2), and CXCR3 (IP-10). Their timing of expression indicated that CXCR2 and CCR1 are probably important in the neutrophil-dependent heterologous phase of the disease, whereas CCR1, CCR2, CCR5, and CXCR3 accompany the subsequent mononuclear cell infiltration characteristic of autologous disease. We therefore assessed the role of CCR1 in NTN using CCR1(-/-) mice. We found that neutrophil accumulation in CCR1(-/-) mice was comparable to that in wild-type animals but that renal recruitment of CD4(+) and CD8(+) T cells and macrophages increased significantly. Moreover, CCR1(-/-) mice developed more severe glomerulonephritis than did controls, with greater proteinuria and blood urea nitrogen, as well as a higher frequency of crescent formation. In addition, CCR1(-/-) mice showed enhanced Th1 immune responses, including titers of antigen-specific IgG2a antibody, delayed-type hypersensitivity responses, and production of IFN-gamma and TNF-alpha. Lastly, using recombinant proteins and transfected cells that overexpressed CCR1, we demonstrated that MIP-1alpha, but not RANTES, bound CCR1 and induced cell chemotaxis. Thus, rather than simply promoting leukocyte recruitment during NTN, CCR1 expression profoundly alters the effector phase of glomerulonephritis. Therapeutic targeting of chemokine receptors may, on occasion, exacerbate underlying disease.
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PMID:Lack of chemokine receptor CCR1 enhances Th1 responses and glomerular injury during nephrotoxic nephritis. 1058 18

Chemokines participate in leukocyte infiltration, which plays a major role in glomerular injury during immune complex glomerulonephritis (IC-GN). Because target cell expression of chemokine receptors (CCR) is thought to mediate leukocyte migration, the expression pattern of chemokines and CCR in a model of IC-GN was examined. The transient course and predominant glomerular pathology of this model allows the examination of both the induction and resolution phases of IC-GN. GN was induced in mice by daily apoferritin injection for 2 wk. Urine samples and kidneys were obtained at 1, 2, and 4 wk. Albuminuria was noted at 2 wk, but resolved after 4 wk. This was associated with glomerular IC deposits and mesangial proliferation. Glomerular macrophage infiltration was prominent at 1 and 2 wk, which resolved at 4 wk. Expression of monocyte chemoattractant protein-1 (MCP-1) and RANTES mRNA was upregulated at week 1 and decreased to control levels at weeks 2 and 4. The expression was localized to glomeruli by in situ hybridization and immunohistochemistry. The mRNA of CCR1, CCR2, and CCR5 but not CCR3 or CCR4 were upregulated at week 1 and decreased at weeks 2 and 4. Expression of CCR5 was located to the glomerulus by in situ hybridization and quantitative reverse transcription-PCR of isolated glomeruli. In summary, in a model of transient IC-GN, MCP-1 and RANTES and their receptors CCR1, CCR2, and CCR5 are expressed early and are already downregulated at the peak of proteinuria and leukocyte infiltration. Resolution of glomerulonephritis is associated with a return to baseline of chemokine and CCR expression. Therefore, it is concluded that glomerular MCP-1 and RANTES production directs circulating leukocytes that express CCR1, CCR2, and CCR5 into the glomerulus. After initiating GN, MCP-1 and RANTES and their receptors are readily downregulated.
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PMID:Chemokine and chemokine receptor expression during initiation and resolution of immune complex glomerulonephritis. 1131 50

Slowly progressive renal injury is the major cause for ESRD. The model of progressive immune complex glomerulonephritis in autoimmune MRL(lpr/lpr) mice was used to evaluate whether chemokine receptor CCR1 blockade late in the disease course can affect progression to renal failure. Mice were treated with subcutaneous injections of either vehicle or BX471, a nonpeptide CCR1 antagonist, three times a day from week 20 to 24 of age [corrected]. BX471 improved blood urea nitrogen levels (BX471, 35.1 +/- 5.3; vehicle, 73.1 +/- 39.6 mg/dl; P < 0.05) and reduced the amount of ERHR-3 macrophages, CD3 lymphocytes, Ki-67 positive proliferating cells, and ssDNA positive apoptotic cells in the interstitium but not in glomeruli. Cell transfer studies with fluorescence-labeled T cells that were pretreated with either vehicle or BX471 showed that BX471 blocks macrophage and T cell recruitment to the renal interstitium of MRL(lpr/lpr) mice. This was associated with reduced renal expression of CC chemokines CCL2, CCL3, CCL4, and CCL5 and the chemokine receptors CCR1, CCR2, and CCR5. Furthermore, BX471 reduced the extent of interstitial fibrosis as evaluated by interstitial smooth muscle actin expression and collagen I deposits, as well as mRNA expression for collagen I and TGF-beta. BX471 did not affect serum DNA autoantibodies, proteinuria, or markers of glomerular injury in MRL(lpr/lpr) mice. This is the first evidence that, in advanced chronic renal injury, blockade of CCR1 can halt disease progression and improve renal function by selective inhibition of interstitial leukocyte recruitment and fibrosis.
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PMID:Late onset of treatment with a chemokine receptor CCR1 antagonist prevents progression of lupus nephritis in MRL-Fas(lpr) mice. 1515 61

Chronic allograft nephropathy (CAN) is the primary cause for late kidney allograft loss. Carbon monoxide (CO), a product of heme metabolism by heme oxygenases, is known to impart protection against various stresses. We hypothesized that CO could minimize the chronic fibroinflammatory process and protect kidney allografts from CAN. Lewis kidney grafts were orthotopically transplanted into binephrectomized Brown-Norway rats under short-course tacrolimus. Recipients were maintained in room air or exposed to CO at 20 parts/million for 30 days after transplant. Efficacy of inhaled CO was studied at day 30 and day 80. Isografts maintained normal kidney function throughout the experiment with creatinine clearance of approximately 1.5 ml/min. Renal allograft function in air controls progressively deteriorated, and creatinine clearance declined to 0.2 +/- 0.1 ml/min by day 80 with substantial proteinuria. CO-treated animals had significantly better creatinine clearance (1.3 +/- 0.2 ml/min) with minimal proteinuria. Histological examination revealed the development of progressive CAN in air-exposed grafts, whereas CO-treated grafts had minimal tubular atrophy and interstitial fibrosis, with negligible collagen IV deposition. In vitro analyses revealed that CO-treated recipients had significantly less T cell proliferation against donor peptides via the indirect allorecognition pathway and less anti-donor IgG antibodies compared with air controls. Intragraft mRNA levels for chemokines (regulated on activation normal T cell expressed and secreted, macrophage inflammatory protein-1alpha, chemokine receptors (CCR1, CXCR3, CXCR5), IL-2, and intercellular adhesion molecule-1 were significantly decreased in CO-treated than in air-treated allografts. Furthermore, reduction of blood flow in air-treated allografts was prevented with CO. In conclusion, inhaled CO at a low concentration efficiently abrogates chronic fibroinflammatory changes associated with CAN and improves long-term renal allograft function.
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PMID:Low-dose carbon monoxide inhalation prevents development of chronic allograft nephropathy. 1613 50

The chemokines, members of a large family of chemotactic cytokines, act as directional cues for sorting inflammatory cell subsets to sites of inflammation or lymphoid microenvironments. In addition to their effects on migration, chemokines can also activate effector function in leukocytes and are involved in cell proliferation and angiogenesis. Therefore, it is not surprising that chemokines play important roles in a wide range of human diseases, including genetic immunodeficiencies, infections, autoimmune diseases, and malignant tumors. In this report, we have reviewed recent developments (since mid 2003) in chemokines in renal diseases. In animal models, chemokines are produced at the site of injury, leading to inflammatory cell recruitment. The therapeutic impact of the blockade of CCR1, CCR2, CCR4, CCR5, or the corresponding ligands has been further studied in various renal disease models. Recent studies on the role of the chemokine receptors in human diseases have demonstrated the expression of CXCR1, CXCR3, CCR2, and CCR5 on different subsets of inflammatory cells. The number of CCR5- and CXCR3-positive interstitial infiltrating cells (mainly T cells) correlates with renal function and proteinuria in glomerular diseases. Polymorphisms of chemokines and chemokine receptors are of impact on renal disease courses and allograft survival. Chemokine receptor blockade has approached clinical applications in nonrenal diseases and awaits the application in patients with kidney diseases.
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PMID:Chemokines in renal diseases. 1620 Mar 31

Chemokines and their receptors have been implicated in the development of diabetic nephropathy. To determine whether the risk of diabetic nephropathy is influenced by two functional polymorphisms in the regulated upon activation normal T-cell expressed and secreted (RANTES) receptor gene (CCR5), we recruited patients with type 1 diabetes, including 496 case subjects with overt proteinuria or end-stage renal disease and 298 control subjects with normoalbuminuria. Male carriers of the 59029G allele, which is associated with diminished expression of CCR5 on the surface of immunocompetent cells, had significantly higher risk of developing diabetic nephropathy than noncarriers (OR [95% CI] 1.9 [1.2-3.0]). Similarly, male carriers of the 32-bp deletion, which causes truncation of the protein, had significantly higher risk of diabetic nephropathy than noncarriers (2.3 [1.3-4.2]). Combining both polymorphisms, three haplotypes were distinguished: one nonrisk haplotype carrying the 59029A allele and the 32-bp insertion and two risk haplotypes carrying the 59029A allele with the 32-bp deletion and carrying the 59029G allele with the 32-bp insertion. The distribution of these haplotypes differed significantly (P < 0.00001) in men with and without diabetic nephropathy but was not associated with diabetic nephropathy in women. In conclusion, two functional polymorphisms in CCR5 that decrease expression of the RANTES receptor on immunocompetent cells are associated with increased risk of diabetic nephropathy in type 1 diabetes, but only in men.
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PMID:Risk of diabetic nephropathy in type 1 diabetes is associated with functional polymorphisms in RANTES receptor gene (CCR5): a sex-specific effect. 1624 62

Diabetic nephropathy is associated with interstitial macrophage infiltrates, but their contribution to disease progression is unclear. We addressed this question by blockade of chemokine receptor (CCR)1 because CCR1 mediates the macrophage recruitment to the renal interstitium. In fact, when CCR1 was blocked with BL5923, a novel orally available CCR1 antagonist, the interstitial recruitment of ex vivo labeled macrophages was markedly decreased in uninephrectomized male db/db mice with advanced diabetic nephropathy. Likewise, BL5923 (60 mg/kg, twice a day) orally administered from months 5 to 6 of life reduced the numbers of interstitial macrophages in uninephrectomized db/db mice. This was associated with reduced numbers of Ki-67 proliferating tubular epithelial and interstitial cells, tubular atrophy, and interstitial fibrosis in uninephrectomized db/db mice. Glomerular pathology and proteinuria were not affected by the CCR1 antagonist. BL5923 reduced renal mRNA expression of Ccl2, Ccr1, Ccr2, Ccr5, transforming growth factor-beta1, and collagen I-alpha1 when compared with untreated uninephrectomized male db/db mice of the same age. Thus, we identified a previously unrecognized role for interstitial macrophages for tubulointerstitial injury, loss of peritubular microvasculature, interstitial inflammation, and fibrosis in type 2 diabetic db/db mice. These data identify oral treatment with the CCR1 antagonist BL5923 as a potential therapy for late-stage diabetic nephropathy.
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PMID:The role of interstitial macrophages in nephropathy of type 2 diabetic db/db mice. 1739 66

The chemokine RANTES (regulated upon activation normal T-cell expressed and secreted) is involved in the formation of an inflammatory infiltrate during glomerulonephritis. However, RANTES receptor inhibition, although reducing glomerular leukocyte infiltration, can also increase damage. We hypothesized that RANTES does not only promote the influx and activation of inflammatory leukocytes but also mediates glomerular microvascular repair by stimulating the homing of bone marrow (BM)-derived endothelial progenitor cells. To investigate the role of RANTES in the participation of BM-derived cells in glomerular vascular repair, we used a rat BM transplantation model in combination with reversible anti-Thy-1.1 glomerulonephritis. Twenty-four hours after the induction of glomerulonephritis, BM-transplanted rats were treated for 7 days with either the RANTES receptor antagonist Met-RANTES or saline. The participation of BM-derived endothelial cells in glomerular repair, glomerular monocyte infiltration, and proteinuria was evaluated at days 7 and 28. Furthermore, we used an in vitro perfusion chamber assay to study the role of RANTES receptors in shear-resistant adhesion of the CD34+ stem cells to activated endothelium under flow. In our reversible glomerulonephritis model, RANTES receptor inhibition specifically reduced the participation of BM-derived cells in glomerular vascular repair by more than 40% at day 7 without impairing monocyte influx. However, no obvious change in recovery from proteinuria or morphological damage was observed. Blockade of RANTES receptors on CD34+ cells in vitro partially inhibited platelet-enhanced, shear-resistant firm adhesion of the CD34+ cells to activated endothelium. In conclusion, our data suggest that RANTES is involved in the homing and participation of BM-derived endothelial cells in glomerular repair.
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PMID:Met-RANTES reduces endothelial progenitor cell homing to activated (glomerular) endothelium in vitro and in vivo. 1756 37

Lupus nephritis is major manifestation of systemic lupus erythematosus and could cause nephrotic syndrome or chronic kidney disease might lead to end-stage renal failure. The pathogenesis of macrophage as well as lymphocyte impairment had been described in lupus nephritis. The interstitial macrophage accumulation and interstitial change or fibrosis is more important than glomerular immunoglobulin deposition or glomerular macrophage accumulation in terms of renal outcome and survival proportion. The expressions of macrophage associated proteins such as CCL2/MCP-1, MIP-1 family and their receptors, CCR2, CCR1 and CCR5 are major target of therapeutic strategy for improving renal illness. The blockade of these chemokines or chemokine receptors ameliorates renal impairment without reducing glomerular immunoglobulin deposition. Deletion of CSF-1 signaling pathway represented more excellent effect in experimental lupus nephritis. The effect of specific antagonist for macrophage associated proteins, specific thyrosine kinase inhibitor for macrophage signaling pathway on glomerulonephritis in lupus prone mice had been reported with evaluation of renal leukocyte infiltration, anti-DNA antibody reduction, the amount of proteinuria, and their survival. The depletion of macrophage could be useful therapeutic tool including M2 macrophage and have synergistic effect with other immunomodulating agents.
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PMID:[The pathogenic role of macrophage in lupus nephritis]. 2621 91