Selectin gene polymorphisms in IgA nephropathy.
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Glomerulonephritis, IGA↗
Biomedical subjects
Kosaku Nitta
Publications and source records attributed to Kosaku Nitta.
Pathogenesis and treatment of autosomal-dominant nephrogenic diabetes insipidus caused by an aquaporin 2 mutation.
Frame-shift mutations within the C terminus of aquaporin 2 (AQP2) cause autosomal-dominant nephrogenic diabetes insipidus (AD-NDI). To identify the molecular mechanism(s) of this disease in vivo and to test possible therapeutic strategies, we generated a mutant AQP2 (763-772 del) knockin mouse. Heterozygous knockin mice showed a severely impaired urine-concentrating ability. However, they were able to slightly increase urine osmolality after dehydration. This milder phenotype, when compared with autosomal-recessive NDI, is a feature of AD-NDI in humans, thus suggesting successful establishment of an AD-NDI mouse model. Immunofluorescence of collecting duct cells in the AD-NDI mouse revealed that the mutant AQP2 was missorted to the basolateral instead of apical plasma membrane. Furthermore, the mutant AQP2 formed a heterooligomer with wild-type AQP2 and showed a dominant-negative effect on the normal apical sorting of wild-type AQP2 even under dehydration. Using this knockin mouse, we tested several drugs for treatment of AD-NDI and found that rolipram, a phosphodiesterase 4 inhibitor, was able to increase urine osmolality. Phosphodiesterase inhibitors may thus be useful drugs for the treatment of AD-NDI. This animal model demonstrates that a mutant monomer gains a dominant-negative effect that reverses the normal polarized sorting of multimers.
3',5'-Cyclic-AMP Phosphodiesterases↗
Reduced capacity of mononuclear cells to synthesize cytokines against an inflammatory stimulus in uremic patients.
BACKGROUND: The local production of cytokines and phagocytosis is pivotal in innate immunity. Uremic patients have a high infectious morbidity, but it remains unclear if this arises from incompetence of these local cellular functions. METHODS: In 30 predialysis uremic patients and 20 controls, we studied the intracellular cytokine synthesis by mononuclear cells in response to stimulation. Moreover, phagocytic activity by leukocytes was tested. Lipopolysaccharide- or mitogen-stimulated peripheral blood cells were labeled with anti-CD14 and -CD4 antibodies, respectively and subjected to intracellular cytokine staining and flow cytometry. Tumor necrosis factor (TNF)-alpha, IL-1beta, IL-6, and IL-8 synthesis was examined in CD14(+) monocytes. IFN-gamma and IL-4 synthesis was examined in CD4(+) helper T cells to determine their Th1 or Th2 phenotype. The flow cytometric analysis of phagocytosis of opsonized bacteria was performed in whole blood. RESULTS: Uremic patients exhibited a significantly reduced monokine response and inhibited development of helper T cells into Th1 or Th2 phenotypes compared with control subjects. Their phagocytic activity was comparable to control subjects. No clinical parameters were linked to in vitro cytokine production and phagocytic activity. CONCLUSIONS: Mononuclear cells in uremic patients are hyporeactive to inflammatory challenge and this may be one reason why uremic patients are vulnerable to infections.
Bacteria↗
Functional impact of IgA nephropathy-associated selectin gene haplotype on leukocyte-endothelial interaction.
Previously, we discovered single-nucleotide polymorphisms (SNPs) associated with Immunoglobulin A (IgA) nephropathy in selectin genes, which were 712C>T(P238S) in L selectin, -642A>G in the promoter region of L selectin, and 1402C>T(H468Y) in E selectin. Interestingly, these SNPs were in nearly complete linkage disequilibrium, thus two haplotypes, disease-associated TGT and wild-type (Wt) CAC, were constructed. To investigate the functional significance of TGT haplotype, a stable CHO transfectant expressing a P238S-L-selectin variant (CHO-varL) and a recombinant adenovirus vector containing an H468Y-E-selectin variant (Ad-varE) were established and compared to their Wt counterparts. Under flow, CHO-varL exhibited significantly less adhesion over IL-1beta-activated HUVEC monolayers compared to CHO-wtL. Furthermore, a luciferase reporter construct, containing a promoter region of the L-selectin variant (luc-varL), exhibited significantly less transcription activity compared to Wt (luc-wtL). These results suggest that the adhesive interactions and expression level of L selectin in disease-associated haplotypes are significantly compromised, indicating a potential role of these SNPs in the pathogenesis of inflammatory diseases, including IgA nephropathy.
Amino Acid Substitution↗
Potential roles of large mafs in cell lineages and developing pancreas.
OBJECTIVES: Maf is a family of transcription factor proteins characterized by a typical bZip structure, and mafA, a member of the large-maf family, is a strong transactivator of insulin in cell lines. The present study investigated the expression profiles of the large-maf family proteins in porcine pancreatic tissue and in primary culture cells. METHODS: Immunohistochemical staining was performed to localize each maf protein. Messenger RNA expression was quantitated by real-time polymerase chain reaction, and protein expression was assessed by Western blotting. RESULTS: Islet formation was not as clear in newborn pancreatic tissue as in adult pancreatic tissue. MafA- and c-maf-positive cells were more diffusely localized in pancreatic tissue with fewer mafB-positive cell clusters scattered throughout. By contrast, islet formation was clearer, and positive staining for mafA and c-maf tended to be more prominent in the islets of adult pancreatic tissue. Messenger RNA and protein expressions were consistent with the immunohistochemical findings. MafA, mafB, and c-maf coexpressed with insulin-positive cells, and c-maf coexpressed with glucagon-positive cells in adult porcine pancreas based on the results of a double-staining study. CONCLUSIONS: Large mafs were identified in normal porcine and human pancreas, and the expression levels and localizations of the large mafs in newborn and adult pancreatic tissues differed. Mafs may play important roles in establishing endocrine function during pancreatic cell differentiation.
Animals↗
[Recent advances in therapy for chronic glomerular diseases].
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Angiotensin II Type 1 Receptor Blockers↗
[Physiopathology, diagnosis and treatment of chronic glomerulonephritis].
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Disease Progression↗
Latent IgA deposition from donor kidney is the major risk factor for recurrent IgA nephropathy in renal transplantation.
BACKGROUND: Previous studies have recognized risk factors for recurrent IgA nephropathy (r-IgAN) in renal transplantation. However the clinical significance of latent IgA deposition from the donor kidney remains to be determined. PATIENTS AND METHODS: Between 1992 and 1999, 0-hour allograft biopsies were performed in 510 renal transplantation recipients at the Kidney Center of Tokyo Women's Medical University. Among these 510 patients, there were 49 whose primary disease was identified as IgAN. Among these 49 patients, 13 patients (26.5%) were diagnosed as having r-IgAN based on renal biopsy. We compared risk factors of r-IgAN, including IgA deposition, between the r-IgAN and non-r-IgAN groups. RESULTS: We assessed factors previously reported to be risk factors for r-IgAN, such as follow-up period after transplantation, sex, ages of donors and recipients, donor type, ABO compatible or incompatible transplantation, number of HLA-A, B, and DR mismatches, number of donors with HLA-A2, B35, B46, and/or DR4, duration to end stage renal disease, duration of dialysis, and latent IgA deposition from donor kidneys. Latent IgA deposition was the only risk factor that differed significantly in frequency between patients with and without recurrence (38.5% in r-IgAN group vs. 9.1% in non-r-IgAN group, p = 0.037). Other factors did not differ significantly between the two groups. Clinical factors, such as urinary protein excretion, urinary red blood cell sediment and serum creatinine, were significantly worse and the number of patients who required hemodialysis 5 yr after transplantation was significantly higher in the r-IgAN group than in the non-r-IgAN group (38.5 vs. 5.6%, p = 0.001). Four of the five patients who required hemodialysis in the r-IgAN group had latent IgA deposition from the donor kidney. CONCLUSION: Our data suggest that 26.5% out of patients with primary IgAN will develop recurrence within 5 yr after transplantation. Latent IgA deposition from the donor kidney was one of the risk factors of r-IgAN and it would lead to the development of r-IgAN. Moreover, r-IgAN will compromise graft survival, especially in cases with latent IgA deposition from the donor kidney.
Adolescent↗
[Pathogenesis and therapy for vascular calcification in patients on chronic hemodialysis].
Vascular calcification is a common complication of end-stage renal disease (ESRD) and is likely related to the high incidence of cardiovascular disease in patients with ESRD. Vascular calcification occurs both in the vascular intima and in the tunica media. Intimal calcification is disseminated and is associated with damaged endothelium and macrophage. On the contrary, medial calcification occurs in patchy distribution and the most frequent cells types found in its vicinity are smooth muscle cells (SMC). The uremic state is associated with numerous metabolic abnormalities and endocrine disturbances primarily involving calcium and phosphorus metabolism. In addition, ESRD is considered state of active inflammatory response. These dysfunctions likely contribute to the development and progression of vascular calcification. Recent reports have shown that this is a highly regulated process governed by factors that closely resemble calcium deposition in bone tissue. Vascular calcification requires changes in the phenotype of SMC and the expression of several bone-associated proteins normally involved in bone metabolism. This review is focused on the role of phosphorus in the pathogenesis of vascular calcification and the therapeutic approaches currently available to slow its progression in patients with ESRD.
Calcinosis↗
[A case of microscopic polyangitis with sepsis due to pyelonephritis].
A 69-year-old woman, who had been diagnosed with interstitial pneumonia at 66 years of age, was admitted to our hospital because of high fever, purpura occurring on her arms and legs, and renal dysfunction. At the time of admission, her renal function had severely deteriorated (sCr 8.2 mg/dl, 24 h Ccr 6 ml/min), she had a severe high fever (BT 39.5 degrees C), back pain, a white blood cell count of 19,540/,microl, and a CRP level of 26.7 mg/dl. Blood and urine cultures yielded identical strains of E. coli. We diagnosed sepsis caused by pyelonephritis, and started intravenous meropenem trihydrate(MEPM) at 0.5 g/day. Her renal dysfunction was severe, so we started hemodialysis therapy. Immunological examination revealed the presence of ANCA-associated glomerulonephritis. Renal biopsy before steroid therapy confirmed the diagnosis of pauci-immune-type crescentic glomerulonephritis. Based on purpura and interstitial pneumonia, along with rapidly MPO-ANCA-positive progressive glomerulonephritis (RPGN) with acute renal failure, we diagnosed microscopic polyangitis (MPA). To treat sepsis and severe pyelonephritis, we started intravenous immunoglobulin 5 g (100 mg/kg)/day for 5 days before starting immunosuppressive steroid therapy (m-PSL 1 g/day, PSL 20 mg/day) for 3 days. These treatments improved her general condition and immediately improved her renal function. It is important to prevent infection during treatment using conventional immunosuppressive therapy. These findings suggest immunoglobulin therapy to be a safe immuno-suppressive treatment that is efficacious against ANCA-associated glomerulonephritis.
Aged↗
Association of a single-nucleotide polymorphism in the immunoglobulin mu-binding protein 2 gene with immunoglobulin A nephropathy.
Immunoglobulin A (IgA) nephropathy is the most common form of primary glomerulonephritis worldwide. The pathogenesis of IgA nephropathy is unknown, but it is certain that some genetic factors are involved in susceptibility to the disease. Employing a large-scale, case-control association study using gene-based single-nucleotide polymorphism (SNP) markers, we previously reported four candidate genes. We report here an additional significant association between IgA nephropathy and an SNP located in the gene encoding immunoglobulin micro-binding protein 2 (IGHMBP2) at chromosome 11q13.2-q13.4. The association (chi2 =17.1, p = 0.00003; odds ratio of 1.85 with 95% confidence interval of 1.39-2.50 in a dominant association model) was found using DNA from 465 affected individuals and 634 controls. The SNP (G34448A) caused an amino acid substitution from glutamine to lysine (E928K). As the gene product is involved in immunoglobulin-class switching and patients with the A allele revealed higher serum levels of IgA (p = 0.048), the amino acid change might influence a class switch to increase serum IgA levels, resulting in a higher risk of IgA nephropathy.
Adult↗
Spironolactone and angiotensin receptor blocker in nondiabetic renal diseases.
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Angiotensin Receptor Antagonists↗
Serum osteoprotegerin levels and the extent of vascular calcification in haemodialysis patients.
BACKGROUND: Osteoprotegerin (OPG) is a glycoprotein that inhibits osteoclast differentiation and activity. OPG-deficient mice develop severe osteoporosis and medial arterial calcification. The expression of OPG is detected in early atherosclerotic lesions in non-uraemic patients. We examined whether serum OPG is associated with aortic calcification in haemodialysis patients. METHODS: Serum OPG was measured in 102 patients who were undergoing haemodialysis. The aortic calcification index (ACI) was assessed by computed tomography scans. RESULTS: Serum OPG level, measured by enzyme-linked immunosorbent assay, was significantly greater in patients with higher ACI than in those with lower ACI. There was a direct relationship between ACI and serum OPG levels and a positive association between OPG and ACI (r = 0.483, P<0.0001). Multiple regression analyses indicated that serum OPG levels were independently associated with the severity of aortic calcification (P<0.0001). CONCLUSIONS: These findings show that serum OPG levels are associated with the extent of vascular calcification, suggesting that OPG may be involved in the development of vascular calcification in haemodialysis patients.
Adult↗
In situ expression of connective tissue growth factor in human crescentic glomerulonephritis.
Connective tissue growth factor (CTGF) has recently been recognized as an important profibrotic factor and is up-regulated in various renal diseases with fibrosis. The present study describes the sequential localization of CTGF mRNA and its association with transforming growth factor (TGF)-beta1 in human crescentic glomerulonephritis (CRGN). Furthermore, we examined the phenotype of CTGF-expressing cells using serial section analysis. Kidney biopsy specimens from 18 CRGN patients were examined using in situ hybridization and immunohistochemistry. CTGF mRNA was expressed in the podocytes and parietal epithelial cells (PECs) in unaffected glomeruli. In addition, it was strongly expressed in the cellular and fibrocellular crescents, particularly in pseudotubule structures. Serial sections revealed that the majority of CTGF mRNA-positive cells in the crescents co-expressed the epithelial marker cytokeratin, but not a marker for macrophages. Moreover, TGF-beta1, its receptor TGF-beta receptor-I, and extracellular matrix molecules (collagen type I and fibronectin) were co-localized with CTGF mRNA-positive crescents. Our results suggest that CTGF is involved in extracellular matrix production in PECs and that it is one of the mediators promoting the scarring process in glomerular crescents.
Activin Receptors, Type I↗
Role of mitogen-activated protein kinase in the regulation of transforming growth factor-beta-induced fibronectin accumulation in cultured renal interstitial fibroblasts.
BACKGROUND: In diabetic nephropathy, tubulointerstitial fibrosis is an important component of renal injury. Transforming growth factor (TGF)-beta is a key cytokine that is involved in the pathogenesis of tubulointerstitial fibrosis. However, signal transduction cascades of TGF-beta under high-glucose conditions remain to be clarified. We undertook this study to elucidate whether mitogen-activated protein (MAP) kinase and Smad proteins were involved in TGF-beta-induced fibronectin (FN) production under high glucose in NRK fibroblasts. METHODS: After serum restriction, NRK cells were exposed to either normal glucose (5.5 mM d-glucose), high glucose (30 mM d-glucose), or 30 mM l-glucose in the presence or absence of TGF-beta for 24 h. MAP kinase inhibitors (SB 203580 and PD 98059) were added to the cultured NRK fibroblasts 2 h before TGF-beta1, and the incubations continued for 8 h. The phosphorylation of p38 MAP kinase, extracellular signal-regulated kinase (ERK)1/ERK2, and c-Jun N-amino terminal kinase (JNK) was assessed by immunoblotting. Reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting were performed to determine FN mRNA and protein expression, respectively. RESULTS: High glucose significantly increased the expression of FN mRNA, by 2.4 +/- 1.4-fold. In the presence of either SB 203580 or PD 98059, the high glucose-induced FN mRNA increase was completely inhibited. Incubation of NRK fibroblasts for 48 h in 30 mM d-glucose did not alter p38 MAP kinase, ERK1/ERK2, or JNK phosphorylation. The addition of exogenous TGF-beta1 (1 ng/ml) for 8 h increased FN mRNA by 2.7 +/- 1.1-fold. Both the TGF-beta1- and high glucose-induced FN mRNA increases were inhibited by SB 203580 and PD 98059. Dominant-negative Smad4 did not affect the FN mRNA increase induced by TGF-beta1 and high glucose. Exogenous TGF-beta1 under both normal and high glucose, enhanced the phosphorylation of both p38 MAP kinase and ERK1/ERK2, but not that of JNK. CONCLUSIONS: NRK fibroblasts exposed to high glucose demonstrated increased TGF-beta1-induced p38 MAP kinase activation. The FN synthesis induced by high glucose and TGF-beta1 was not affected by the Smads pathway and was not due to increased osmolarity. The enhanced activation of p38 MAP kinase may contribute to the altered fibroblast phenotype that leads to progressive diabetic nephropathy.
Cells, Cultured↗
The effectiveness of steroid therapy for patients with advanced IgA nephropathy and impaired renal function.
BACKGROUND: Recent studies have shown that steroid therapy is effective for IgA nephropathy (IgAN) in patients with moderate proteinuria and active histological findings. However, the effectiveness of steroid therapy has not been determined yet in patients with advanced IgAN and impaired renal function. METHODS: Sixty IgAN patients whose creatinine clearance was under 70 ml/min at the time of renal biopsy were studied retrospectively. The patients were divided into two groups according to treatment: a steroid group ( n = 20) and a nonsteroid group ( n = 40). The mean age was 39.6 +/- 14.9 years in the steroid group and 40.6 +/- 10.9 years in the nonsteroid group. The mean follow-up period was 4.5 +/- 2.2 years in the steroid group and 4.6 +/- 2.4 years in the nonsteroid group. Patients with high proteinuria and high histological activity were treated with prednisolone. Clinical and histological findings before treatment and the outcome after treatment were analyzed. RESULTS: In the retrospective analysis, the amount of urinary protein excretion before treatment tended to be higher in the steroid group than in the nonsteroid group, but was not significantly different (2.33 +/- 1.54 vs 1.39 +/- 1.87 g/day). Histologically, the percentage of patients with crescent formation, especially that of cellular or fibrocellular crescents, was significantly higher in the steroid group than in the nonsteroid group (17.2 +/- 15.9% vs 2.3 +/- 4.5%; P < 0.0001). The grades of mesangial cell proliferation (1.65 +/- 0.55 vs 1.21 +/- 0.47; P = 0.002) and mesangial matrix increase (1.88 +/- 0.64 and 1.41 +/- 0.67; P = 0.01) were higher in the steroid group than in the nonsteroid group. In the evaluation of the outcome after treatment, the amount of urinary protein excretion at 1 year after treatment had significantly decreased in the steroid group (before treatment, 2.33 +/- 1.54 g/day; at 1 year, 1.02 +/- 0.98 g/day; P = 0.003), but the amount remained unchanged in the nonsteroid group (before treatment, 1.39 +/- 1.87 g/day; at 1 year, 1.28 +/- 2.19 g/day). The levels of serum creatinine before treatment and at 1 year after treatment were not changed in either of the groups, however, in the nonsteroid group, the level at the final observation was significantly higher than the level before treatment (2.51 +/- 3.43 vs 1.27 +/- 0.33 mg/dl; P = 0.0219). CONCLUSIONS: In the present study, in advanced IgAN patients whose creatinine clearance was under 70 ml/min, steroid therapy effectively reduced the amount of proteinuria and maintained the serum creatinine level, if the treatment was selectively applied to patients with a moderate amount of proteinuria and active glomerular lesions such as cellular and fibrocellular crescents, and mesangial cell proliferation.
Adult↗
Prolonged membranous lupus nephritis with change of anti-ssDNA antibody titer and repeated renal relapse.
We report a case of a 44-year-old woman with nephrotic syndrome who underwent renal biopsy three times. On each occasion, light microscopy showed membranous nephropathy with mild to moderate thickening of the glomerular capillary walls. Immunofluorescence microscopy showed predominant deposition of immunoglobulin (Ig) G, IgG1, IgG2, IgG3, and IgG4; C3; and C1q along the glomerular capillary walls and deposition of IgM and IgA in some parts of the walls. Electron microscopy revealed the accumulation of electron-dense deposits in the mesangium and the subepithelial area of the glomerular basement membrane. Virus-like particles were detected in the subendothelial cells in all three biopsy specimens. A definitive diagnosis of systemic lupus erythematosus (SLE) was made at the time of the second admission, when she was 31 years old. A diagnosis of membranous lupus nephritis was then made on the basis of the pathological and clinical findings. A change in anti-single-stranded (ss)DNA antibody titers was of particular interest in this patient. Occasional small increases in anti-double-stranded (ds)DNA antibody were found, but increased anti-ssDNA antibody titers occurred before there was any elevation of urinary protein during renal relapse, and a sustained increase in the titers was shown subsequently. Hypocomplementemia occurred in parallel with the increase of anti-ssDNA antibody. Immunosuppressive therapy with steroid promptly eliminated anti-dsDNA antibody, but anti-ssDNA antibody remained positive. The patient had normocomplementemia and proteinuria was absent. Later, anti-ssDNA antibody decreased. Renal function has remained in the normal range for 20 years.
Acute Kidney Injury↗
Effects of double blockade of CD28 and inducible-costimulator signaling on anti-glomerular basement membrane glomerulonephritis.
Inducible costimulator (ICOS) is the third member of the CD28 superfamily, expressed on antigen-primed T-cells, enhancing Th2 differentiation. Anti-glomerular basement membrane (anti-GBM) glomerulonephritis results from multiple effects generated by both Th1 and Th2 cells. To evaluate the contribution of these T-cells to the progression of anti-GBM glomerulonephritis, we investigated the effect of double blockade of CD28 and ICOS signaling. Anti-GBM glomerulonephritis was induced in C57BL/6 mice, a Th1-prone strain. CD28 signaling was inhibited with the use of fusion proteins of cytolytic T-lymphocyte-associated antigen-4 (CTLA4 immunoglobulin) and ICOS signaling by the monoclonal antibody (mAb) for ICOS. Blood and urine samples were collected 5 and 14 days after induction of anti-GBM glomerulonephritis. Mice were killed to facilitate histopathologic analyses at the same time. Anti-GBM glomerulonephritis was prevented from functionally deteriorating (eg, proteinuria or increasing serum creatinine) by CTLA4 immunoglobulin or anti-activation-inducible lymphocyte immunomodulatory molecule (AILIM) mAb as an anti-ICOS mAb. Nevertheless, double or single blockade of ICOS signaling showed a weaker inhibitory effect than single blockade of CD28 signaling in terms of the serum immunoglobulin level and histopathologic change. There is no synergistic effect between CTLA4 immunoglobulin and anti-AILIM mAb when simultaneously administered in experimental anti-GBM glomerulonephritis. Double blockade of both CD28 signaling and ICOS signaling is effective for preventing functional deterioration in this model. However, CD28 single blockade is more effective than double blockade both serologically and histopathologically.
Abatacept↗