Increased production of adrenomedullin in glomeruli from anti-glomerular basement membrane glomerulonephritis rats treated with methylprednisolone.

BACKGROUND/AIMS: Adrenomedullin (AM) has anti-proliferative and apoptotic effects on mesangial cells (MCs). Both effects play an important role in the progression of glomerulonephritis (GN). Glucocorticoids are widely used for the treatment of GN; however, the relationship between AM regulation in MCs or glomeruli and glucocorticoid treatment has not been clarified. METHODS: Using the cultured rat MCs, AM secretion induced by methylprednisolone (m-PSL), and MC proliferation and apoptosis caused by AM were examined. In addition, the role of AM receptor antagonist, AM(22-52), was also investigated. Then, we made an anti-glomerular basement membrane (GBM) GN rat model and compared the AM expression and production in each glomeruli obtained from the control or m-PSL-treated anti-GBM GN rats. RESULTS: In the cultured rat MCs, AM secretion was increased by m-PSL. MC proliferation was inhibited, while MC apoptosis was increased by AM. MC apoptosis was inhibited by the addition of AM(22-52). M-PSL therapy ameliorated the progression of anti-GBM GN rats. AM expression and production were increased in the glomeruli from m-PSL-treated rats compared to the controls. CONCLUSION: Considering the anti-proliferative and apoptotic effects of AM on MCs, increased AM in the glomeruli might participate in the improvement of glomerular lesions in anti-GBM GN rats treated with m-PSL.

[Two cases of interstitial nephritis with primary Sjögren's syndrome successfully treated by steroid therapy].

We have experienced two cases of interstitial nephritis with Sjögren's syndrome successfully treated by steroid therapy. Case 1. A 50-year-old woman was admitted because of rash and arthralgia of the limb. Although her renal function was normal, serum IgG was extremely high and gallium-67 scintigrams indicated abnormal uptake in both kidneys with swelling on CT scans. Renal biopsy specimens showed a patchy dense interstitial infiltration of lymphocytes, monocytes and partly plasma cells with tubular cell atrophy. To suppress an excessive immune reaction, oral prednisolone was administrated at a dose of 30 mg/day. Six weeks after inception of the therapy, re-biopsy specimens showed a decrease in interstitial infiltration, particularly plasma cells, and interstitial fibrosis did not progress. After 8 weeks, the serum IgG level was normalized. Case 2. A 57-year-old woman was found to have renal involvement(serum creatinine level: 2.2 mg/dl) and anemia. Clinical findings suggested primary Sjögren's syndrome with renal tubular acidosis. Renal biopsy specimens showed a moderate to severe interstitial infiltration of inflammatory cells. After inception of steroid therapy(prednisolone 40 mg/day), renal involvement and renal anemia gradually improved. The renal function has been kept stable(serum creatinine level: 1.5 mg/dl) for 9 years by low-dose steroid therapy. These two cases suggest that steroid therapy plays two important roles: controlling of the acute immune reaction that causes renal fibrosis to progress in case 1, and long-term preservation of the renal function by the continuous use of low-doses in case 2.

Adrenomedullin (AM) and receptor-activity-modifying proteins in glomeruli with Thy.1 glomerulonephritis.

BACKGROUND: Adrenomedullin (AM) has antiproliferative and proapoptotic effects on mesangial cells in culture, but the regulation of AM and its receptors in glomeruli with glomerulonephritis have not been clarified. METHODS: We examined sequential changes in the mRNA expression of AM and its receptors (receptor-activity-modifying proteins; RAMPs), and AM production in the glomeruli of Thy.1 glomerulonephritis, using quantitative reverse transcription-polymerase chain reaction (RT-PCR) and immunoradiometric assay (IRMA). RESULTS: Both the mRNA and the protein levels of AM in glomeruli isolated from rats 7 days after injection with anti-thymocyte serum (ATS), when mesangial cell proliferation peaked, were unchanged compared with those in control rats. However, on day 14, when almost all glomeruli had appeared to return to normal, AM mRNA expression was significantly increased (day 14 vs control: 51.2 +/- 9.1 vs 28.4 +/- 7.1 (mmol/mol glyceraldehyde-3-phosphate dehydrogenase; GAPDH); P < 0.05), as was the AM concentration (12.0 +/- 0.8 vs 8.4 +/- 0.4 fmol/10(4) glomeruli; P < 0.01). Subsequently, by 28 days after ATS injection, both levels decreased to the control ones. The mRNA expression of AM and RAMP2, in the glomeruli of Thy.1 glomerulonephritis changed similarly over time. Immunohistochemical staining revealed that AM production in mesangial cells was increased predominantly on day 14. CONCLUSIONS: AM and RAMP increased during the reso-lution phase of increased mesangial proliferation in Thy.1 glomerulonephritis, but not during the mesangial proliferative phase. Considering the antiproliferative and proapoptotic effects of AM, its action on mesangial cells may be related to the amelioration of glomerulonephritis.