Aya Abe

Significance of mesangial expression of α-smooth muscle actin in the progression of IgA nephropathy

To determine whether phenotypic modulation of mesangial and interstitial cells correlated with the long-term prognosis of IgA nephropathy (IgAN), we analyzed retrospectively 27 patients with IgAN whose creatinine clearance at the time of renal biopsy was normal. The patients were subdivided into two groups according to the course of renal function during follow-up. Thirteen patients maintained normal renal function for more than 15 years (stable group), and 14 progressed to end-stage renal disease (ESRD group). The score of mesangial cell cellularity in the ESRD group was significantly higher than in the stable group. Immunohistochemistry localized alpha-smooth muscle actin (alpha-SMA) in renal mesangial cells of approximately half these patients. Macrophages localized predominantly in the mesangial area in patients with mesangial expression of alpha-SMA, which was associated with the expression of macrophage-colony-stimulating factor. Noteworthily, the score of mesangial alpha-SMA expression and the incidence of patients with mesangial expression of alpha-SMA at the time of renal biopsy were markedly higher in the ESRD group than in the stable group. However, there was no significant difference in both the score of interstitial alpha-SMA expression and the incidence of patients with interstitial expression of alpha-SMA between these two groups. These results suggest that macrophages recruited into the mesangium may induce phenotypic modulation of mesangial cells and that mesangial alpha-SMA expression predicts a progressive decline in renal function in patients with IgAN.

Macrophage‐colony stimulating factor (M‐CSF) enhances proteinuria and recruitment of macrophages into the glomerulus in experimental murine nephritis

In this study, we examined the effects of macrophage‐colony stimulating factor (M‐CSF) on glomerular macrophages in lipopolysaccharide (LPS)‐induced murine nephritis. Mice injected intraperitoneally with either M‐CSF plus LPS, LPS alone, M‐CSF alone or saline every day for 8 days were examined for the degree of urine albumin excretion and lymphocyte‐function associated antigen‐1‐positive (LFA‐1+) cells in peripheral blood as well as renal pathology. From our results, LPS or M‐CSF combined with LPS emphasized the degree of proteinuria, glomerular deposition of immunoglobulins and mesangial proliferation, associated with accumulation of macrophages in the glomeruli. However, in immunohistological examination of kidneys from these nephritic mice, neither intercellular adhesion molecule‐1 (ICAM‐1), which may play an important role in the recruitment of macrophages into glomeruli, M‐CSF receptor nor the number of LFA‐1+ cells in peripheral blood was enhanced by M‐CSF. On the other hand, M‐CSF alone induced neither proteinuria nor any pathological changes and did not increase the number of glomerular Mac‐1+ cells above that in saline‐treated controls. These results indicate that M‐CSF does not directly cause glomerulonephritis but might participate in accelerating the glomerular inflammatory process by stimulating a potent chemoattractant to recruit monocytes‐macrophages into the glomeruli.

Development of nephrotic syndrome in a patient with acute myeloblastic leukemia after treatment with macrophage—Colony-stimulating factor

We describe a patient with acute myeloblastic leukemia (AML) who developed nephrotic syndrome after receiving several courses of chemotherapy, including macrophage-colony-stimulating factor (M-CSF). At the onset of nephrotic syndrome, the patient remained in a hematological remission. A renal biopsy showed diffuse mesangial proliferation with marked glomerular infiltration of macrophages and massive subendothelial and mesangial deposits. After the institution of the combined therapy with corticosteroid, anticoagulant, and dipyridamole, urinary protein excretion was attenuated to less than 1.0 g/day. It should be emphasized that the recurrence of nephrotic syndrome was observed after the following chemotherapy, including M-CSF, whereas the bone marrow still remained completely remitted. In contrast, after the last course of chemotherapy, which did not include M-CSF, urinary protein excretion was not enhanced. Of note is that the renal histology at autopsy showed a remarkable improvement of mesangial hypercellularity with concomitant reduction in the number of glomerular macrophages. These evolutional changes in both proteinuria and glomerular histology suggest a close linkage between the M-CSF treatment and macrophage-related glomerular injury. The possibility can be raised that M-CSF accelerated the underlying renal disease in this case through enhancing macrophage accumulation into the glomerulus, leading to the development of nephrotic syndrome.

Bacterial Superantigen Enhances Cytokine Production by T-Helper Lymphocyte Subset-2 Cells and Modifies Glomerular Lesions in Experimental Immunoglobulin A Nephropathy

BackgroundThe purpose of this study was to examine the effects of bacterial suporantigens, which can derange the immune response and contribute to the renal lesions of immunoglobulin A (lgA) nephropathy.MethodsTwenty-five micrograms of a bacterial superantigen, staphylococcal enterotoxin B (SEB), was injected into IgA nephropathy-prone ddY mice intrathymically when they reached 6 weeks of age. Evaluation included measurement of albumin excretion in urine, immunoglobulin concentration, and lymphokine production in vitro, as well as analysis of T-cell receptor expression in splenic T-cell subsets and examination of renal histology by light and fluorescence microscopy.ResultsAt 40 weeks of age, the serum level of IgA in these mice was substantially increased and the number of Vβ8+ CD4+splenic T-cells was significantly decreased compared with measurements in untreated controls. Both control and SEB-treated mice excreted less than 30 μg/mL of urinary albumin. In mice given SEB, the amount of interleukin 2 (IL-2) and tumor necrosis factor-α (T helper 1 [Th1]-type cytokines) produced by the in vitro-stimulated lymphocytes significantly decreased. whereas that of interleukin 4 (IL-4) and interleukin 6 (IL-6) (Th2-type cytokines) markedly increased compared with measurements in control mice. At 40 weeks of age, mice given SEB showed marked glomerular hypercellularity and enhanced glomerular C3 deposition by renal histology, compared with control mice.ConclusionThese results suggest that bacterial superantigen SEB may modify glomerular lesions through activating Th2 cells, while inducing deletion of Th1 cells in this experimental model.