PubMed Health⌕ Search

Biomedical subjects

Hiroshi Kawachi

Publications and source records attributed to Hiroshi Kawachi.

At least 19 recordsLinked to original sources
PubMed2007

Podocyte as the target for aldosterone: roles of oxidative stress and Sgk1.

Accumulating evidence suggests that mineralocorticoid receptor blockade effectively reduces proteinuria in hypertensive patients. However, the mechanism of the antiproteinuric effect remains elusive. In this study, we investigated the effects of aldosterone on podocyte, a key player of the glomerular filtration barrier. Uninephrectomized rats were continuously infused with aldosterone and fed a high-salt diet. Aldosterone induced proteinuria progressively, associated with blood pressure elevation. Notably, gene expressions of podocyte-associated molecules nephrin and podocin were markedly decreased in aldosterone-infused rats at 2 weeks, with a gradual decrease thereafter. Immunohistochemical studies and electron microscopy confirmed the podocyte damage. Podocyte injury was accompanied by renal reduced nicotinamide-adenine dinucleotide phosphate oxidase activation, increased oxidative stress, and enhanced expression of aldosterone effector kinase Sgk1. Treatment with eplerenone, a selective aldosterone receptor blocker, almost completely prevented podocyte damage and proteinuria, with normalization of elevated reduced nicotinamide-adenine dinucleotide phosphate oxidase activity. In addition, proteinuria, podocyte damage, and Sgk1 upregulation were significantly alleviated by tempol, a membrane-permeable superoxide dismutase, suggesting the pathogenic role of oxidative stress. Although hydralazine treatment almost normalized blood pressure, it failed to improve proteinuria and podocyte damage. In cultured podocytes with consistent expression of mineralocorticoid receptor, aldosterone stimulated membrane translocation of reduced nicotinamide-adenine dinucleotide phosphate oxidase cytosolic components and oxidative stress generation in podocytes. Furthermore, aldosterone enhanced the expression of Sgk1, which was inhibited by mineralocorticoid receptor antagonist and tempol. In conclusion, podocytes are injured at the early stage in aldosterone-infused rats, resulting in the occurrence of proteinuria. Aldosterone can directly modulate podocyte function, possibly through the induction of oxidative stress and Sgk1.

Aldosterone↗
PubMed2006

Synaptic vesicle protein 2B is expressed in podocyte, and its expression is altered in proteinuric glomeruli.

Synaptic vesicle protein 2B (SV2B) was identified by the subtraction hybridization technique as a molecule of which mRNA expression was decreased in puromycin aminonucleoside (PAN) nephropathy by glomerular cDNA subtraction assay. The expression of SV2B was detected in glomerular lysate with Western blot analysis. Dual-labeling immunofluorescence studies with glomerular cell markers demonstrated that SV2B is expressed in glomerular visceral epithelial cells (podocytes). The expression of SV2B is detected also in cultured podocyte and in human kidney section as podocytic pattern. The decrease of SV2B mRNA was already detected before the onset of proteinuria in PAN nephropathy. The mRNA expression of SV2B clearly is altered not only in PAN nephropathy but also in another proteinuric state that is caused by an antibody against nephrin, a functional molecule of the slit diaphragm. The decreased intensity in SV2B staining was already detected before the peak of proteinuria in both models with immunofluorescence study. A reduced amount of SV2B was detected in both models also with Western blot analysis. CD2AP, another functional molecule of the slit diaphragm, was observed in cytoplasm, including the processes area of the cultured podocyte, and when the podocyte was treated with small interfering RNA for SV2B, CD2AP staining at the process area was not detected. These results suggest that SV2B is a functional molecule of podocyte, and SV2B may play a role in the expression and proper localization of CD2AP.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Histological differences in new-onset IgA nephropathy between children and adults.

BACKGROUND: It is suggested that IgA nephropathy (IgAN) manifests differently in children vs adults on the basis of biopsy findings. However, this has been difficult to establish owing to the uncertainty of the timing of disease onset in adult IgAN. We addressed this question by comparing both histology and leucocyte accumulation in biopsies of recently diagnosed childhood and adult IgAN. METHODS: Biopsies taken within 2 years from the onset of renal abnormalities in 33 childhood (10 +/- 3 years of age) and 38 adult (35 +/- 6 years) cases of IgAN were examined for histological changes (cellularity in mesangial, endocapillary and extracapillary areas, matrix expansion, adhesions/crescents and interstitial damage), glomerular deposition of immunoglobulin and complement, and the presence of macrophages, activated macrophages and T cells by immunohistochemistry. RESULTS: Glomerular hypercellularity owing to increased cells in mesangial area was prominent in paediatric IgAN and significantly greater than in adult IgAN. In contrast, glomerular matrix expansion, crescent formation and interstitial damage were more severe in adults compared to paediatric IgAN. Indeed, glomerular hypercellularity correlated with proteinuria in paediatric but not in adult IgAN, whereas glomerular matrix correlated with proteinuria and renal function in adult but not in paediatric IgAN. The degree of C3c deposition was significantly greater in paediatric IgAN, while deposition of fibrinogen was greater in adult IgAN. Glomerular and interstitial CD68+ macrophages and a subset of sialoadhesin (Sn)+ activated macrophages were identified in both paediatric and adult IgAN, being significantly greater in number in adult IgAN. Glomerular leucocyte infiltration correlated with proteinuria while interstitial leucocyte infiltration correlated with interstitial damage in both groups. However, only the subset of Sn+ macrophages gave a significant correlation with renal function, glomerular hypercellularity and glomerular matrix. CONCLUSIONS: This study has demonstrated significant differences in the early glomerular lesions of IgAN in children vs adults. Furthermore, Sn+ activated macrophages are implicated in the pathogenesis of IgAN in both patient groups. The prognostic significance of these findings warrants further study.

Adolescent↗
PubMed2006

Rat nephrin modulates cell morphology via the adaptor protein Nck.

Nephrin is a transmembrane molecule essential for morphology and function of kidney podocytes. We and others reported previously that the cytoplasmic domain of human and mouse nephrin interacts with the adaptor protein, Nck, in a tyrosine phosphorylation-dependent manner. In the current study, we characterized the interaction of rat nephrin with Nck and further addressed its impact on cell morphology. Rat nephrin expressed in Cos-1 cells co-immunoprecipitated with Nck in a manner dependent on the phosphorylation of Y1204 and Y1228. Nephrin from normal rat glomeruli was also tyrosine phosphorylated and associated with Nck. Overexpression of rat nephrin in HEK293T cells induced morphological changes resembling process formation, which became more distinct when the extracellular domain of nephrin was cross-linked by antibodies. The morphological changes were attenuated by expression of dominant negative constructs of Nck. In the rat model of podocyte injury and proteinuria, nephrin tyrosine phosphorylation and nephrin-Nck interaction were both reduced significantly. Taken together, we propose that Nck couples nephrin to the actin cytoskeleton in glomerular podocytes and contributes to the maintenance of normal morphology and function of podocytes.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Contribution of nonproteolytically activated prorenin in glomeruli to hypertensive renal damage.

Prorenin is activated without proteolysis by binding of prorenin receptor to the pentameric "handle region" (HR) of prorenin prosegment. It was hypothesized that such activation occurs in the kidneys of hypertensive rats and causes tissue renin-angiotensin system (RAS) activation and end-organ damage. Because the HR's binding to its binding protein made the adjacent tetrameric "gate region" (GR) accessible to its specific antibody, immunohistochemistry of the GR was performed to test the hypothesis. Methods also were devised specifically to inhibit the nonproteolytic activation by the decapeptide corresponding to the HR as a decoy. Immunohistochemistry of the GR demonstrated that the majority of nonproteolytically activated prorenin is present in podocytes of the kidneys from stroke-prone spontaneously hypertensive rats, in which activation of renal tissue RAS, proteinuria, and glomerulosclerosis occurred. Continuous subcutaneous administration of the HR decoy peptide completely inhibited both nonproteolytic activation of tissue prorenin and activation of tissue RAS without affecting circulating RAS or arterial pressure and significantly attenuated the development and progression of proteinuria and glomerulosclerosis. These studies clearly demonstrated that nonproteolytic activation of prorenin in glomeruli is critically involved in renal tissue RAS activation, leading to renal damage in hypertensive animals.

Animals↗
PubMed2006

Antagonism of PDGF-D by human antibody CR002 prevents renal scarring in experimental glomerulonephritis.

Glomerular mesangial cell proliferation and/or matrix accumulation characterizes many progressive renal diseases. PDGF-D was identified recently as a novel mediator of mesangial cell proliferation in vitro and in vivo. This study investigated the long-term consequences of PDGF-D inhibition in vivo. Rats with progressive mesangioproliferative glomerulonephritis (uninephrectomy plus anti-Thy-1.1 antibody) received the PDGF-D-neutralizing, fully human mAb CR002 on days 3, 10, and 17 after disease induction. Glomerular mesangioproliferative changes on day 10 were significantly reduced by anti-PDGF-D treatment as compared with control antibody. Eight weeks after disease induction, anti-PDGF-D therapy significantly ameliorated focal segmental glomerulosclerosis, podocyte damage (de novo desmin expression), tubulointerstitial damage, and fibrosis as well as the accumulation of renal interstitial matrix including type III collagen and fibronectin. Treatment with anti-PDGF-D also reduced the cortical infiltration of monocytes/macrophages on day 56, possibly related to lower renal cortical complement activation (C5b-9 deposition) and/or reduced epithelial-to-mesenchymal transition (preserved cortical expression of E-cadherin and reduced expression of vimentin and alpha-smooth muscle actin). In conclusion, these data provide evidence for a causal role of PDGF-D in the pathogenesis of renal scarring and point to a new therapeutic approach to progressive mesangioproliferative renal disease.

Animals↗
PubMed2006

Addition of the antioxidant probucol to angiotensin II type I receptor antagonist arrests progressive mesangioproliferative glomerulonephritis in the rat.

Angiotensin II (Ang II) and reactive oxidative species (ROS) that are produced by NADPH oxidase have been implicated in the progression of glomerulonephritis (GN). This study examined the effect of simultaneously interrupting Ang II and ROS with an Ang II receptor blocker (ARB), candesartan, and a free radical scavenger, probucol, in a model of progressive mesangioproliferative GN induced by the injection of anti-Thy-1 antibody into uninephrectomized rats. Nephritic rats were divided into four groups and given daily oral doses of the following: Vehicle, 1% probucol diet, 70 mg/L candesartan in drinking water, and probucol plus candesartan. These treatments lasted until day 56. Vehicle-treated nephritic rats developed progressively elevated proteinuria and glomerulosclerosis. Candesartan kept proteinuria significantly lower than vehicle or probucol. The addition of probucol to candesartan normalized urinary protein excretion. Increases in BP in nephritic rats were lowered by these treatments, except with probucol. It is interesting that both glomerular cell number and glomerulosclerosis were significantly decreased by candesartan and normalized by the addition of probucol. Immunohistochemical studies for TGF-beta1, collagen type I, and fibronectin revealed that the combined treatment abolished glomerular fibrotic findings compared with candesartan. In addition, glomerular expression of NADPH oxidase components and superoxide production suggested that the combined treatment completely eliminated NADPH oxidase-associated ROS production. In conclusion, our study provides the first evidence that the antioxidant probucol, when added to an Ang II receptor blockade, fully arrests proteinuria and disease progression in GN. Furthermore, the data suggest that NADPH oxidase-associated ROS production may play a pivotal role in the progression of GN. The combination of probucol and candesartan may represent a novel route of therapy for patients with progressive GN.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2006

Attenuation of mouse acute colitis by naked hepatocyte growth factor gene transfer into the liver.

BACKGROUND: Hepatocyte growth factor (HGF) has multiple biological effects on a wide variety of cells. It modulates intestinal epithelial proliferation and migration, and critically regulates intestinal wound healing. AIMS: To investigate the therapeutic effect of HGF gene transfer, we introduced the HGF gene into the liver of mice with acute colitis. METHODS: The rat HGF expression plasmid vector, pCAGGS-HGF, was injected via the tail vein into C57BL/6 mice, followed by dosing with dextran sulfate sodium in distilled water. Firstly, the HGF gene was injected once on day 0. Secondly, the HGF gene was injected on day 0 and again on day 2. RESULTS: Injection of the HGF gene ameliorated colitis with inhibition of both loss of body weight and shortening of colon length. It protected the colon from epithelial erosions and cellular infiltration. Expression of mRNAs for IFN-gamma, IL18, and TNF-alpha was reduced in the colon. In contrast, expression of mRNA for IL-10 was increased. The numbers of BrdU-positive intestinal epithelial cells were increased, and the numbers of TUNEL-positive apoptotic cells were decreased. Furthermore, a second injection prolonged the elevation of serum HGF levels, and ameliorated the symptoms better than a single injection. The empty pCAGGS plasmid did not ameliorate acute colitis. CONCLUSIONS: HGF gene transfer attenuated acute colitis by facilitating intestinal wound repair as well as inhibiting inflammation, suggesting a new strategy for treatment of IBD.

Acute Disease↗
PubMed2006

Real-time in vivo virtual histology of colorectal lesions when using the endocytoscopy system.

BACKGROUND: The histological findings of GI lesions are based on light-microscopic examination of H&E-stained thin-slice specimens. Recently, a concept of optical biopsy has been advocated. A study of the observation of colorectal lesions using endocytoscopy to obtain real-time histological images in vivo during endoscopy was performed. DESIGN: Prospective study. AIM: To evaluate the usefulness of optical biopsy of colorectal lesions with the endocytoscopy (E-C) system. PATIENTS: The subjects were 113 consecutive patients who underwent a complete colonic examination, from April 2003 to March 2004, performed by a single colonoscopist. SETTING: Digestive Disease Center of Showa University Northern Yokohama Hospital. RESULTS: With E-C, it was possible to observe lesions at the cellular level and evaluate cellular atypia in addition to structural atypia in vivo. The correlation was statistically significant between the endocytoscopic diagnosis and the histological diagnosis. LIMITATIONS: The endocytoscope had to be touched to the target colonic glands. CONCLUSIONS: It was possible to distinguish neoplastic from non-neoplastic lesions, and also possible to distinguish invasive cancer from adenoma. "Ultra-high" magnifying endoscopy, the E-C system, provides real-time histological images in vivo, which correspond well with those of H&E-stained microscopic images.

Adenoma↗
PubMed2006

Role of podocyte slit diaphragm as a filtration barrier.

Although the role of glomerular basement membrane has been emphasised as the barrier for retaining plasma proteins in the past three decades, some recent studies have demonstrated that the slit diaphragm of the glomerular epithelial cell (podocyte) is the structure likely to be the barrier in the glomerular capillary wall. Nephrin and podocin were identified as gene products mutated in Finnish-type congenital nephrotic syndrome and autosomal recessive steroid-resistant nephrotic syndrome, respectively. Nephrin s located at the outer leaflet of plasma membranes of the slit diaphragm. Podocin is reported to have an interaction with nephrin. The anti-nephrin antibody is capable of inducing massive proteinuria, which indicates that nephrin is a key functional molecule in the slit diaphragm. The expression of nephrin and podocin was reduced in glomeruli of minimal change nephrotic syndrome, which suggested that the altered expression of these molecules contributes to the development of proteinuria also in acquired diseases. Some recent studies demonstrated that CD2-associated protein (CD2AP) is also a functional molecule in the slit diaphragm, and its expression is altered in membranous nephropathy. These observations suggested that alteration of the molecular arrangement in the slit diaphragm is involved in the development of proteinuria in several kinds of glomerular diseases.

Animals↗
PubMed2006

Role of IP-10/CXCL10 in the progression of pancreatitis-like injury in mice after murine retroviral infection.

Exocrinopathy and pancreatitis-like injury were developed in C57BL/6 (B6) mice infected with LP-BM5 murine leukemia virus, which is known to induce murine acquired immunodeficiency syndrome (MAIDS). The role of chemokines, especially CXCL10/interferon (IFN)-gamma-inducible protein 10 (IP-10), a chemokine to attract CXCR3+ T helper 1-type CD4+ T cells, has not been investigated thoroughly in the pathogenesis of pancreatitis. B6 mice were inoculated intraperitoneally with LP-BM5 and then injected every week with either an antibody against IP-10 or a control antibody. Eight weeks after infection, we analyzed the effect of IP-10 neutralization. Anti-IP-10 antibody treatment did not change the generalized lymphadenopathy and hepatosplenomegaly of mice with MAIDS. The treatment significantly reduced the number of IP-10- and CXCR3-positive cells in the mesenteric lymph nodes (mLNs) but not the phenotypes and gross numbers of cells. In contrast, IP-10 neutralization reduced the number of mononuclear cells infiltrating into the pancreas. Anti-IP-10 antibody treatment did not change the numbers of IFN-gamma+ and IL10+ cells in the mLN but significantly reduced their numbers, especially IFN-gamma+ and IL-10+ CD4+ T cells and IFN-gamma+ Mac-1+ cells, in the pancreas. IP-10 neutralization ameliorated the pancreatic lesions of mice with MAIDS probably by blocking the cellular infiltration of CD4+ T cells and IFN-gamma+ Mac-1+ cells into the pancreas at least at 8 wk after infection, suggesting that IP-10 and these cells might play a key role in the development of chronic autoimmune pancreatitis.

Animals↗
PubMed2006

Pathophysiologic implications of reduced podocyte number in a rat model of progressive glomerular injury.

Changes in podocyte number or density have been suggested to play an important role in renal disease progression. Here, we investigated the temporal relationship between glomerular podocyte number and development of proteinuria and glomerulosclerosis in the male Munich Wistar Fromter (MWF) rat. We also assessed whether changes in podocyte number affect podocyte function and focused specifically on the slit diaphragm-associated protein nephrin. Age-matched Wistar rats were used as controls. Estimation of podocyte number per glomerulus was determined by digital morphometry of WT1-positive cells. MWF rats developed moderate hypertension, massive proteinuria, and glomerulosclerosis with age. Glomerular hypertrophy was already observed at 10 weeks of age and progressively increased thereafter. By contrast, mean podocyte number per glomerulus was lower than normal in young animals and further decreased with time. As a consequence, the capillary tuft volume per podocyte was more than threefold increased in older rats. Electron microscopy showed important changes in podocyte structure of MWF rats, with expansion of podocyte bodies surrounding glomerular filtration membrane. Glomerular nephrin expression was markedly altered in MWF rats and inversely correlated with both podocyte loss and proteinuria. Our findings suggest that reduction in podocyte number is an important determinant of podocyte dysfunction and progressive impairment of the glomerular permselectivity that lead to the development of massive proteinuria and ultimately to renal scarring.

Animals↗
PubMed2005

IFN-inducible protein-10 plays a pivotal role in maintaining slit-diaphragm function by regulating podocyte cell-cycle balance.

IFN-inducible protein-10 (IP-10/CXCL10) is a potent chemoattractant for activated T lymphocytes and was reported recently to have several additional biologic activities. In this study, the pathophysiologic role of IP-10 in the glomerular visceral epithelial cell (podocyte) was investigated. In cultured podocytes subjected to recombinant IP-10 treatment, the expression of slit-diaphragm (SD) components nephrin and podocin clearly was heightened. Rats that had puromycin aminonucleoside nephropathy and anti-nephrin antibody-induced nephropathy and were subjected to anti-IP-10 function-blocking antibody (anti-IP-10 mAb) treatment displayed a decrease in the protein level of SD components, as well as exacerbated proteinuria. For exploration of the mechanisms of this process, the interaction between IP-10 and the cell-cycle regulatory proteins was investigated. Cultured podocytes subjected to recombinant IP-10 treatment displayed an increase in the protein level of p27(Kip1), whereas the levels of cyclins E and A decreased. The expression of IP-10 and SD components was heightened by the treatment of siRNA of cyclin A, whereas these expressions were lowered by the treatment of siRNA of p27(Kip1). Proteinuric rats subjected to anti-IP-10 mAb treatment displayed a heightened expression of cyclin A from the early phase of the disease, which indicates that the anti-IP-10 mAb treatment exacerbates podocyte injury by disturbing the cell-cycle balance. These results raise the possibility that IP-10 could become a novel therapeutic target in nephrotic syndrome and several diseases with altered cell-cycle balance.

Animals↗
PubMed2005

Up-regulation of integrin-linked kinase activity in rat mesangioproliferative glomerulonephritis.

This study investigated whether integrin-linked kinase (ILK) is involved in the pathogenesis of chronic glomerulonephritis (GN) by analyzing the expression and activity of glomerular ILK in a chronic rat model of mesangioproliferative GN. Double immunostaining of kidneys obtained at different time points with glomerular cell-specific markers revealed that ILK was primarily expressed by glomerular epithelial cells, and weakly by mesangial cells (MCs) and endothelial cells in control rats, but dramatically increased in a typical mesangial pattern at days 21 and 28 of GN. Semiquantitative assessment indicated that the level of glomerular ILK expression closely parallels the level of accumulation of glomerular extracellular matrix (ECM) as well as fibronectin (FN). Immunoprecipitation and kinase activity assays using isolated nephritic glomeruli indicated a striking increase of ILK activity on days 21 and 28 of GN. Further, cultured rat MCs overexpressing kinase-deficient ILK diminished FN assembly and collagen matrix remodeling as compared with control transfectants. The results showed that glomerular ILK expression and activity are markedly increased in an experimental model of chronic GN. Increased activity of ILK in MCs may contribute to the development of chronic mesangial alterations leading to glomerular scarring.

Animals↗
PubMed2005

Exogenous 5'-nucleotidase improves glomerular autoregulation in Thy-1 nephritic rats.

Experiments were performed to characterize renal hemodynamics in Thy-1 nephritic rats. A monoclonal antibody against Thy-1 was intravenously injected to induce mesangiolysis in rats, and 2 days later renal hemodynamic responses to variations in blood pressure were determined. In the first series of experiments, autoregulation of renal plasma flow (RPF) or glomerular filtration rate (GFR) was impaired in nephritic rats. In response to a reduction in blood pressure (98 +/- 2 to 80 +/- 1 mmHg), both RPF (4.17 +/- 0.63 to 3.20 +/- 0.45 ml x min(-1) x g kidney wt(-1), P < 0.05, n = 6) and GFR (0.88 +/- 0.05 to 0.75 +/- 0.06 ml x min(-1).g kidney wt(-1), P < 0.05) were decreased in nephritic rats. Intravenous administration of furosemide and 30% albumin, both of which inhibit tubuloglomerular feedback, diminished renal autoregulation in control but not nephritic rats. In the second studies, the infusion of 5'-nucleotidase, an enzyme expressed on mesangial cells, into a renal artery ameliorated the magnitude of autoregulatory decrements in GFR in nephritic rats (-16 +/- 5 to -6 +/- 2%, P < 0.05, n = 6), but this enzyme failed to alter renal autoregulation in control rats. In the third studies, the effects of indomethacin were examined in nephritic rats. Inhibition of prostaglandin synthesis reduced RPF (4.07 +/- 0.30 to 1.54 +/- 0.22 ml x min(-1) x g kidney wt(-1), P < 0.05, n = 5) and GFR (1.03 +/- 0.18 to 0.69 +/- 0.13 ml x min(-1) x g kidney wt(-1), P < 0.05) in nephritic rats. However, cyclooxygenase inhibition failed to restore renal autoregulation in nephritic rats. Our results indicate that renal autoregulation is impaired in Thy-1 nephritis. Furthermore, the present data provide evidence that prostanoids contribute to maintain renal circulation in nephritic rats. Finally, our findings suggest that mesangial cells and/or 5'-nucleotidase plays an important role in mediating renal autoregulation.

5'-Nucleotidase↗
PubMed2005

The sialoadhesin (CD169) expressing a macrophage subset in human proliferative glomerulonephritis.

BACKGROUND: Sialoadhesin (Sn; CD169) is a lectin-like receptor whose expression is restricted to subsets of tissue and inflammatory macrophages. We have previously identified accumulation of Sn+ macrophages as an important marker of disease progression versus remission in rat mesangial proliferative nephritis. The current study examined the significance of Sn+ macrophages in human proliferative glomerulonephritis. METHODS: Frozen kidney sections from normal adult human kidney (n = 4) and pediatric nephropathy (n = 40) were stained for total macrophages (CD68+ cells), Sn+ macrophages, CD3+ T-cells and collagen type I by immunofluorescence. Leukocyte infiltration and the severity of glomerular lesions and interstitial damage were scored. A second protocol biopsy was performed in 27 cases and clinical and biopsy-based data obtained. RESULTS: Sn+ macrophages were absent from glomeruli in normal adult human kidney and in thin basement membrane disease (n = 4), but were detected in 4 of 9 cases of purpura nephritis; 7 of 17 IgA nephropathy; 5 of 5 membranoproliferative glomerulonephritis, and 5 of 5 lupus nephritis. Sn+ macrophages were localized in areas of focal glomerular and interstitial damage. Two-colour immunostaining confirmed that Sn+ cells are a subset of total CD68+ macrophages. The number of glomerular Sn+ macrophages correlated with the degree of proteinuria and glomerular lesions (r = 0.44, P = 0.0045 and r = 0.82, P<0.0001; respectively), while interstitial Sn+ macrophages correlated with the degree of proteinuria and interstitial damage (r = 0.59, P<0.0001 and r = 0.75, P<0.0001; respectively). Combined immunostaining revealed that interstitial Sn+ macrophages and CD3+ T-cells co-localized in areas of tubulointerstitial damage with increased type I collagen deposition. There was significant correlation between the number of interstitial Sn+ macrophages and CD3+ T-cells (r = 0.74, P<0.0001). Most patients responded to a 2 year period of glucocorticoid therapy with a reduction in proteinuria and glomerular lesions and this correlated with the reduction in the number of glomerular Sn+ macrophages. CONCLUSION: This study has identified Sn+ cells as a macrophage subset whose accumulation in the kidney correlates with proteinuria and histologic damage. These results, together with recent findings from animal studies, suggest that Sn+ macrophages may play an important role in progressive renal disease.

Adolescent↗
PubMed2005

Altered expression of junctional adhesion molecule 4 in injured podocytes.

Recent investigations have revealed the importance of glomerular podocytes with its diaphragm as the major filtration barrier. Junctional adhesion molecule 4 (JAM4) has been identified as a protein that interacts with membrane-associated guanyl kinase inverted (MAGI)-1 and is reported to be expressed on podocytes. To elucidate the role of JAM4 on podocytes, we examined the expression of JAM4 and MAGI-1 in normal and two different proteinuric rat models: puromycin aminonucleoside (PAN) nephropathy and anti-nephrin antibody-induced (ANA) nephropathy, one model with and one without effacement of podocyte foot processes. JAM4 was detected by immunomicroscopy at the apical membrane of normal podocytes. JAM4 immunostaining was focally increased in the podocytes in PAN nephropathy but not in ANA nephropathy. In proteinuric podocytes, the expression of JAM4 was distinct from that of MAGI-1 or other slit diaphragm molecules such as nephrin and ZO-1. Close colocalization of JAM4 and ezrin was maintained in PAN nephropathy. By immunoelectron microscopy, the signals for JAM4 were detected at the free apical membrane of the podocytes with effaced foot processes. Studies with selective detergent extract revealed that the subcellular localization of JAM4 was altered in PAN nephropathy. Thus the altered expression of JAM4 appears to be associated with morphological changes in podocytes and can be a useful marker of injured podocytes. JAM4 may have a different role at the apical membrane besides the role as a junctional molecule and is likely associated with the unique structure of this epithelium.

Amino Acid Sequence↗