Angiotensin II mediates the progression of renal disease through the type 1 receptor (AT(1)R). Recent studies have suggested that type 2 receptor (AT(2)R)-mediated signaling inhibits cell proliferation by counteracting the actions of AT(1)R. The aim of the present study was to determine the effect of AT(2)R overexpression on glomerular injury induced by (5/6) nephrectomy ((5/6)Nx). AT(2)R transgenic mice (AT(2)-Tg), overexpressing AT(2)R under the control of alpha-smooth muscle actin (alpha-SMA) promoter, and control wild-type mice (Wild) were subjected to (5/6)Nx. In AT(2)-Tg mice, the glomerular expression of AT(2)R was upregulated after (5/6)Nx. Urinary albumin excretion at 12 wk after (5/6)Nx was decreased by 33.7% in AT(2)-Tg compared with Wild mice. Glomerular size in AT(2)-Tg mice was significantly smaller than in Wild mice after (5/6)Nx (93.1 +/- 3.0 vs. 103.3 +/- 1.8 microm; P < 0.05). Immunohistochemistry revealed significant decreases in glomerular expression of platelet-derived growth factor-BB chain (PDGF-BB) and transforming growth factor-beta(1) (TGF-beta(1)) in AT(2)-Tg with (5/6)Nx compared with Wild mice. Urinary excretion of nitric oxide metabolites was increased 2.5-fold in AT(2)-Tg compared with Wild mice. EMSA showed that activation of early growth response gene-1, which induces the transcription of PDGF-BB and TGF-beta(1), was decreased in AT(2)-Tg mice. These changes in AT(2)-Tg mice at 12 wk after (5/6)Nx were blocked by the AT(2)R antagonist PD-123319. Taken together, our findings suggest that AT(2)R-mediated signaling may protect from glomerular injuries induced by (5/6)Nx and that overexpression of AT(2)R may serve as a potential therapeutic strategy for glomerular disorders.
A 34-year-old Japanese male was admitted to Okayama University Hospital with severe hypertension, rapidly progressive renal failure, blurred vision, dyspnea and hemoptysis. Clinical diagnosis of malignant hypertension was given and antihypertensive therapy and hemodialysis were immediately started. Renal biopsy was performed on the sixth day in hospital to examine the underlying disease, such as microscopic form of polyarteritis, since the complaint of hemoptysis and pulmonary alveolar hemorrhage was noted by computed tomography of the lungs. Typical pathological changes of malignant hypertension, i.e. fibrinoid necrosis of the afferent arterioles and proliferative endoarteritis at the interlobular arteries were observed. There was no evidence of active necrotizing glomerulonephritis and crescent formation. Renal function was gradually recovered and pulmonary hemorrhage completely disappeared by treatment with antihypertensive agents. The authors report a case of malignant hypertension with a rare complication of pulmonary alveolar hemorrhage and speculate that it may be related to vascular injuries at the alveolar capillary level caused by malignant hypertension.
Glucocorticoid has long been used to treat patients with glomerulonephritis because it ameliorates mesangial cell proliferation and proteinuria, in part by suppressing nuclear factor-kappa B (NF-ĸB) activation, which regulates the transcription of various pro-inflammatory genes. Recent evidence shows that NF-ĸB activation increases the resistance to TNF-α-induced apoptosis in mesangial cells. We examined glomerular cell proliferation and apoptosis along with NF-ĸB activation in the Thy-1.1 nephritis model. We also evaluated TNF-α-induced apoptosis in cultured mesangial cells. Methylprednisolone treatment ameliorated mesangial hypercellularity in Thy-1.1 nephritis by decreasing proliferating cells and increasing apoptosis in the glomeruli. These effects were associated with suppressed NF-ĸB activation. This in vitro study revealed that treatment with methylprednisolone and TNF-α induced cultured mesangial cell apoptosis. These results suggest that methylprednisolone may accelerate the resolution phase of Thy-1.1 nephritis in part by sensitizing mesangial cells to apoptosis.
We encountered a hemodialysis patient complicated by idiopathic thrombocytopenic purpura (ITP). A 60-yearold man had been on hemodialysis due to diabetic nephropathy until May 1999. We administered alprostadil from / November 2002 when arteriosclerosis obliterans worsened. Thrombocytes decreased to 0.6×10 4 /mL on February 2003. Although alprostadil and other drugs were discontinued thrombocytopenia did not abate and bone marrow assessment showed ITP. He started oral steroid therapy for ITP but there was no response. Thereafter, developed / a he perianal abscess. Secondly, oral danazol was initiated and three days later, thrombocytes rose to 2.6×10 4
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