Adrenomedullin inhibits connective tissue growth factor expression, extracellular signal-regulated kinase activation and renal fibrosis.

Systemic administration of the potent vasodilating peptide adrenomedullin reduces cardiac and renal fibrosis in hypertensive animals. Here, we investigated the effects of kidney-specific adrenomedullin gene delivery in normotensive rats after unilateral ureteral obstruction, an established model of renal tubulointerstitial fibrosis. Overexpression of exogenous adrenomedullin in the renal interstitium following ureteral obstruction significantly prevented fibrosis and proliferation of tubular and interstitial cells. In this model, there is upregulation of connective tissue growth factor (CTGF) mRNA expression and extracellular signal-regulated kinase (ERK) phosphorylation, and adrenomedullin overexpression suppressed both of these activities without altering the blood pressure. In NRK-49F renal fibroblasts, adrenomedullin reduced transforming growth factor-beta-induced CTGF and fibronectin mRNA upregulation through the cyclic AMP/protein kinase A signaling pathway, and suppressed ERK phosphorylation and cell proliferation. In the kidneys with an obstructed ureter, adrenomedullin receptor gene expression was upregulated along with cyclic AMP production in kidney slices. The latter effect was partially blocked by a neutralizing antibody to adrenomedullin, indicating that an endogenous peptide-receptor system was activated. Our results show that overexpression of exogenous adrenomedullin in the ureteral-obstructed kidney prevents tubulointerstitial fibrosis and cell proliferation through the cyclic AMP-mediated decrease of CTGF induction and ERK phosphorylation.

Outbreak of Chinese herb nephropathy in Japan: are there any differences from Belgium?

OBJECTIVE: The purpose of this article was to study and clarify the features of Chinese herb nephropathy (CHN) in Japan. PATIENTS AND METHODS: The subjects consisted of patients diagnosed as having CHN in Saiseikai Nakatsu Hospital and of those reported in the literature in Japan. We investigated the clinical and histological features of CHN patients in Japan and compared them with the Belgian cases. RESULTS: The remarkable differences were as follows: (1) high prevalence in males compared with Belgian cases, (2) Fanconi syndrome was found in most cases, (3) no patients had malignant tumors in the urinary tract. In addition, the ascribed Chinese medicines in Japan were divided into three groups: 'Tenshin-toki-shigyaku-ka-gosyuyu-syokyo-to', 'Boui-ougi-to', and others. CONCLUSION: CHN in Japan has some characteristics distinguished from Belgian nephropathy. One hypothesis is a susceptibility to aristolochic acids (AAs), which is considered to be a causative agent, may be different among races. Another is that there could be some other toxic substances affecting the clinical findings although they are not identified at present. Further studies must be undertaken to clarify these differences.

Intraglomerular metastasis from pancreatic cancer.

Few case reports have shown the presence of metastatic tumor cells in renal glomeruli. We report one case with intraglomerular metastasis proved at renal biopsy. A 60-year-old man suffered from weight loss and fever of unknown origin. Urinalysis revealed proteinuria with cellular and granular casts. Because vasculitis was suspected, renal biopsy was performed. Presence of tumor cells occupying the glomerular capillary lumina was shown by means of light microscopy and electron microscopy. Laboratory findings revealed elevated leukocyte count (28.9 x 10(3)/mm(3)), serum granulocyte colony-stimulating factor (G-CSF) (77 pg/mL), and serum CA 19-9 (21,885 U/mL). The patient soon developed disseminated intravascular coagulation and died. Autopsy findings revealed pancreatic cancer showing positive staining for G-CSF and CA 19-9. Tumor cells in the glomerular capillary lumina showed positive staining for CA 19-9 and proliferating cell nuclear antigen (PCNA). These results suggest that the pancreatic tumor cells producing G-CSF were entrapped in the glomerular capillary lumina where they proliferated. This may have been the first step in renal metastasis.

C4d and C4bp deposition along the glomerular capillary walls in a patient with preeclampsia.

Complement (C) 4d and cofactor C4b binding protein (C4bp) are detected in the glomerular capillary walls of a patient with preeclampsia. A 32-year-old nullipara had proteinuria of 1.2 g/d and edema at the 33rd week of pregnancy. Gradually the urinary protein excretion increased, reaching 5.1 g/d at the 37th week. The patient also showed hypertension at this stage. After normal mature delivery, the level of the urinary protein excretion remained at 3 to 4 g/d. Renal biopsy performed by means of light and electron microscopy, 15 days after delivery, showed almost normal glomeruli and modest subendothelial widening. Immunohistochemistry indicated that immunoglobulin (Ig) A, IgG, C1q, C3c, and C4c were not deposited in the glomeruli, whereas weakly positive IgM and fibrin-related antigen (FRA) were observed. Conversely, C4d, C3d, and C4bp were strongly deposited. Protein S (PS) also was observed, with a similar distribution pattern to that of C4bp. Immunoelectron microscopy showed the deposition of C4d along the capillary walls and of C4bp in the subendothelium. These findings suggest that the C4 activation process as well as the regulation process of C system and of the inflammatory coagulation axis by C4bp and PS may play an important role in the pathophysiology of preeclampsia, so-called glomerular capillary endotheliosis (GCE).

Osteoblast maturation suppressed osteoclastogenesis in coculture with bone marrow cells.

The analysis of co-culture system using osteoblast and bone marrow indicated that the mineralized osteoblast decreased osteoclast formation. This finding was an incentive to better investigate the relation of osteoblast development and osteoclastogenesis. The expression of osteoclast differentiation factor (ODF/RANKL) mRNA and protein dramatically decreased. Alternatively, macropharge colony stimulation factor (M-CSF/CSF-1) transcription and protein secreted in media slightly decreased as the development of osteoblast. On the other hands, mRNA expression and the secretion to the culture medium of osteoclastogenesis inhibitory factor (OPG/OCIF) didn't significantly change depending on osteoblast differentiation. We conclude that osteoblast development might suppress osteoclastogenesis especially with the decrease of ODF/RANKL.

[Emergency aortic valve replacement in active infective endocarditis in a chronically hemodialyzed patient].

A 36-year-old housewife, who had been treated with hemodialysis for 15 years is reported. She had suffered from active infective endocarditis of the aortic valve caused by blood access infection for several weeks. She rapidly fell into severe cardiac failure. Five days after the onset of the cardiac failure she was transferred to our hospital. The aortic valve was replaced using #21 Björk-Shiley aortic valve prosthesis shortly after the arrival to the hospital. Postoperatively she was treated with vigorous antibiotics and was anticoagulated. Seven months after the surgery, patient is back to an active life with hemodialysis 3 times a week.