Biomedical subjects

Yuji Sato

Publications and source records attributed to Yuji Sato.

At least 37 records · Page 2Linked to original sources

PubMed2005

A Novel alphavbeta3 integrin antagonist suppresses neointima formation for more than 4 weeks after balloon injury in rats.

OBJECTIVES: We performed a detailed kinetic analysis in a rat balloon injury model to clarify the essential roles of alphavbeta3 integrin and endothelial cell (EC) regeneration in neointima formation. Using this model, we evaluated the antistenotic effect of Dainippon compound BS-1417, a novel alphavbeta3 integrin antagonist. METHODS AND RESULTS: Kinetic analysis using RT-PCR showed that alphavbeta3 integrin-related genes are upregulated before neointima formation. Morphological and functional analyses revealed that EC regeneration requires >4 weeks after injury, and that recovery of EC normal function coincides with the arrest of neointima formation. Subcutaneous infusion of BS-1417 for 2, 4, 7, or 12 weeks after injury potently inhibited neointima formation without affecting EC regeneration. Although withdrawal of treatment with BS-1417 after short-term administration after injury resulted in catch-up growth of neointima, a long-term study suggested that this catch-up growth can be prevented by continuous administration of BS-1417 until EC regeneration. CONCLUSIONS: We clarified that alphavbeta3 integrin and EC regeneration play an essential role in neointima formation, and that continuous administration of BS-1417 potently and stably inhibits neointima formation without affecting EC regeneration. These findings suggest that BS-1417 might be useful as a novel systemic drug for the treatment of restenosis.

Angioplasty, Balloon↗

PubMed2005

Cross-linking of CD45 on suppressive/regulatory T cells leads to the abrogation of their suppressive activity in vitro.

CD4(+)CD25(+) T cells have immunoregulatory and suppressive functions and are responsible for suppressing self-reactive cells and maintaining self-tolerance. In addition to CD4(+)CD25(+) T cells, there is some evidence that a fraction of CD4(+)CD25(-) T cells exhibit suppressive activity in vitro or in vivo. We have shown, using aged mice, that aging not only leads to a decline in the ability to mount CD4(+)CD25(-) T cell responses, but, at the same time, renders aged CD4(+)CD25(-) T cells suppressive. In this study we report two newly established mAbs that could abrogate the suppressive function of aged CD4(+)CD25(-) T cells. These mAbs recognized the same protein, the transmembrane phosphatase CD45. Cross-linking of CD45 on aged CD4(+)CD25(-) T cells was required for the disruption of their suppressive activity. Surprisingly, these mAbs also abrogated the suppressive action of CD4(+)CD25(+) T cells in vitro. Our results demonstrate an unexpected function of CD45 as a negative regulator neutralizing the suppressive activity of aged CD4(+)CD25(-) and young CD4(+)CD25(+) T cells.

Age Factors↗

PubMed2005

Comparison of hippocampal synaptosome proteins in young-adult and aged rats.

The hippocampus is important in learning and memory functions but its ability to aid in these functions declines during aging. In this study, we examined hippocampal proteins whose expressions changed in the aging process. A comparison of synaptosome proteins of hippocampus prepared from young-adult (9-week-old) rats with those from aged (30-month-old) rats by two-dimensional fluorescence difference gel electrophoresis revealed 24 spots that were expressed differently among about 1000 spots detected in both young-adult and aged rat samples. Nineteen of these 24 spots were identified by peptide mass fingerprinting. These proteins included chaperone proteins and proteins related to the cytoskeleton, neurotransmission, signal transduction and energy supply. The cytoskeleton-related proteins included actin and T-complex 1, which is thought to play a role in actin folding. Actin was up-regulated but T-complex 1 was down-regulated in aged rat synapses. These results suggest that age-dependent changes of actin filament formation are related to neuronal dysfunction associated with aging.

Actins↗

PubMed2005

Macrophage migration inhibitory factor promotes tumor invasion and metastasis via the Rho-dependent pathway.

PURPOSE: Macrophage migration inhibitory factor (MIF) plays an important role not only in the immune system but also in tumorigenesis. In this study, we investigated the potential role of MIF in association with tumor invasion and metastasis. METHODS: To assess the function of MIF, we knocked down the MIF mRNA using small interfering RNA (siRNA). Twenty-one base siRNA specific for the mRNA sequence of mouse MIF was introduced to a murine colon cancer cell line, colon 26. Tumor cell invasion was evaluated using a transwell method (8-microm pores) coated with Matrigel on the upperside membrane and with fibronectin on the underside membrane. Moreover, we investigated the signal transduction of lysophosphatidic acid (LPA) relevant to the Rho-dependent pathway and further examined the effect of MIF siRNA on this signal transduction system. In vivo, the tumor cells were pretreated with MIF siRNA and injected into the portal vein, and the effects on metastasis to the liver were evaluated. RESULTS: We found that MIF siRNA markedly reduced the invasion of the cells from the upperside to lowerside membranes. We revealed that the Rho-dependent pathway activated by LPA was suppressed by MIF siRNA. Next, we found that the tyrosine-phosphorylation of focal adhesion kinase and LPA-induced expressions of integrin beta1 were significantly suppressed by MIF siRNA. In vivo, metastasis to the liver was significantly inhibited by pretreatment of the cells with MIF siRNA. CONCLUSION: Taken together, these results suggest that MIF promotes tumor invasion and metastasis via the Rho-dependent pathway.

Animals↗

PubMed2005

Aggressive Lennert's lymphoma: report of three cases in comparison to non-aggressive Lennert's lymphoma.

The present article describes three cases of Lennert's lymphoma exhibiting aggressive clinical courses. These cases were accompanied by disseminated intravascular coagulation (DIC) or hemophagocytic syndrome (HPS). These cases were compared to non-aggressive type of Lennert's lymphoma. Of the three cases, two demonstrated involvement of the liver and the other possessed bone marrow involvement. In one patient, while a lymph node biopsy revealed Lennert's lymphoma histologically, a liver biopsy obtained 2 months later revealed a high-grade large cell cytotoxic T-cell lymphoma. Two of these cases showed HPS and the other exhibited DIC. All patients died within 1 year of diagnosis, with the shortest survival period being 1.5 months. Immunohistochemically, lymphoma cells were CD8+, CD4-, granzyme B+, and T-cell intracellular antigen-1 (TIA-1)+, showing a cytotoxic T-cell phenotype. Two cases demonstrated positive reactivity for Epstein-Barr virus in lymphoma cells by in situ hybridization. These cases were compared with eight cases of non-aggressive Lennert's lymphoma. In comparison to non-aggressive disease, these three cases displayed a higher percentage of Ki-67-positive cells. In conclusion it was found that a subset of Lennert's lymphoma cases share common features with high-grade cytotoxic T-cell lymphoma, indicating that Lennert's lymphoma may be part of the spectrum of cytotoxic T-cell lymphoma.

Aged↗

PubMed2005

The hyperresponsiveness of W/W(v) mice to oral sensitization is associated with a decrease in TCRgammadelta-T cells.

We have already reported that WBB6F1-W/W(v) (W/W(v)) mice, which have mutations in the c-kit gene, are highly susceptible to oral sensitization, and that the proportion of TCRgammadelta-T cells among the intraepithelial lymphocytes (IELs) (gammadelta-IELs) of W/W(v) is much lower than in congenic wild-type (+/+) mice. In this study we examined an inhibitory role of gammadelta-IELs in oral sensitization using two different methods. First, wild-type (+/+) mice were sensitized by oral administration of 1.0 mg ovalbumin (OVA) by gavage every day for 9 weeks after anti-TCRgammadelta antibody treatment 4 times. The treatment resulted in an enhanced OVA-specific IgG1 antibody production, active systemic anaphylaxis (ASA), and Th2-dominant cytokine production. Next, W/W(v) mice whose bone marrow cells were reconstituted from C57BL/6J mice for 5 months were sensitized by oral administration of OVA. The OVA-specific IgG1 antibody titer in the bone marrow-reconstituted W/W(v) mice was neither significantly enhanced, nor ASA was induced. The proportion of gammadelta-IELs in the reconstituted mice was much higher than that in the untreated W/W(v) mice. The above findings suggest that the decrease or increase in number of gammadelta-IELs enhances or decreases oral sensitization respectively. These results show that gammadelta-IELs have an important role in the oral tolerance to food antigens.

Administration, Oral↗

PubMed2005

Blood pressure-lowering effects of lifestyle modification: possible involvement of nitric oxide bioavailability.

Lifestyle modification is recommended as a non-pharmacological approach to treatment of hypertension. Many investigators have reported that exercise has antihypertensive effects, and various mechanisms have been proposed to explain this phenomenon. For example, nitric oxide (NO), which may be increased by exercise, has been reported to play a crucial role in preserving vessel homeostasis both by regulating vascular tone and by exerting anti-atherosclerotic effects. NO is known to be exquisitely sensitive to inactivation by superoxide radicals. However, the relationship between the blood pressure-lowering effect of lifestyle modification and NO bioavailability remains unknown. We investigated the effects of a 12-week lifestyle modification program consisting of mild exercise and diet on changes in blood pressure, plasma nitrate/nitrite (NOx), plasma nitrotyrosine, which is the footprint of NO interaction with reactive oxygen species, and plasma extracellular-superoxide dismutase (EC-SOD). The 12-week lifestyle modification program lowered blood pressure and increased plasma NOx. When the subjects were divided into two groups according to the change of plasma nitrotyrosine as an indicator of NO bioavailability, the subjects whose plasma nitrotyrosine decreased exhibited a significant relationship between the blood pressure-lowering effect of the lifestyle modification and the increase in EC-SOD, whereas those without a decrease in plasma nitrotyrosine exhibited a significant relationship between the blood pressure-lowering effect and the increase in maximum oxygen consumption. These results indicate that the level of NO bioavailability influences the mechanism of the blood pressure-lowering effect of aerobic exercise and diet.

Adult↗

PubMed2005

Multivariate analysis of prognostic factors and effect of treatment in patients with IgA nephropathy.

BACKGROUND: Although the clinical and histological prognostic factors of IgA nephropathy have been investigated in detail, the value of treatment in terms of renal outcome is not well understood. METHODS: The authors examined data from 237 patients with IgA nephropathy (age 31.4+/-13.5 years, mean+/-SD) who had been followed-up for at least six months (follow-up periods, 62.3+/-45.5 months). The authors initially tested the significance of prognostic factors (age, sex, systolic blood pressure, proteinuria, serum creatinine, and histological severity) and treatment strategies (steroid therapy, renin-angiotensin system inhibitors and tonsillectomy) on renal outcome with univariate analysis, then evaluated the findings using the Cox proportional hazards model. RESULTS: Univariate and multivariate analyses showed that among the prognostic variables, a high level of serum creatinine at renal biopsy, large amounts of proteinuria, and extensive histological injury were significant risk factors for end-stage renal failure. Kaplan-Meier analysis showed that the renal survival rates associated with these factors were significantly poorer depending on their severity. Univariate analysis revealed that tonsillectomy was the only significant treatment that contributes to the maintenance of renal survival. Moreover, urinary abnormalities disappeared at a significantly higher frequency when patients were treated by tonsillectomy. The Cox proportional hazards model showed that steroid therapy independently contributed to improve renal prognosis in addition to tonsillectomy, and the hazard ratios were 0.26 (95% CI, 0.07 to 0.93) and 0.37 (95% CI, 0.14 to 0.99), respectively. CONCLUSION: Steroid therapy and tonsillectomy can independently improve renal outcome in patients with IgA nephropathy.

Adolescent↗

PubMed2005

[Evaluation of low-dose FP therapy as adjuvant therapy for gastric cancer].

In the present study, we demonstrate the result of low-dose FP treatment as an adjuvant therapy for 30 patients of stage II or more progressive gastric cancer. 5-FU and CDDP were injected intravenously for 10 days from day 1 through day 5, and day 8 through 12 for 2 weeks at a dose of 250 mg/body and 10 mg/body, or for 14 days at a dose of 250 mg/m2/day and 5 mg/m2/day, respectively. Patients were excluded if they received less than 80% of the respective doses in a course of treatment by the protocol. This constituted a course of chemotherapy, which was repeated every 4 weeks. Grade 3 neutropenia was observed in one case. Other toxicities were anorexia, nausea, weight loss, diarrhea, general fatigue and elevation of serum creatinine, but they were not so severe. The two-year survival rate was 100% in cur A cases, 85% in cur B, and 0% in cur C. The median survival time of the cur C patients was 10 months. These results indicate that low-dose FP therapy is safe and recommendable for cur A and cur B patients. However, other treatment methods such as sequential chemotherapy are needed for cur C gastric cancer patients.

Adult↗

PubMed2005

Evidence of dual function of macrophage migration inhibitory factor relevant to tumor progression and regression.

Macrophage migration inhibitory factor (MIF) is known to play an important role in broad-spectrum inflammation and immune responses. To evaluate the role of MIF in tumor growth, we established transgenic (Tg) mice (ICR strain) driven by cytomegalovirus (CMV) enhancer and beta-actin promoter. We inoculated Tg mice in the back with murine sarcoma cell line S-180 cells. The tumor growth rate was more enhanced in Tg mice than in littermate non-Tg mice up to day 9 after tumor inoculation. Surprisingly, most tumors embedded on the back of Tg mice regressed at day 10 after inoculation and eventually disappeared. Tumor volumes of non-Tg mice incessantly increased until death. We reinoculated the Tg mice with S-180 cells, which had been recovered from the first challenge, and found that the tumor cells were completely rejected in all cases. To identify the effector cells that eradicated the tumor cells, we prepared spleen cells from tumor-bearing Tg mice and carried out cell lysis assay. The magnitude of cytolytic activity of spleen cells obtained from Tg mice was significantly higher against S-180 cells, as well as natural killer cell-sensitive YAC-1 cells, than was the activity of cells from non-Tg mice. Furthermore, we observed that CTL activity of Tg mice against S-180 cells was significantly decreased by the deletion of CD8+ T cells or NK cells. On the other hand, the deletion of CD4+ cells minimally affected the cytolytic activity. Taken together, these results suggest that MIF has the potential to promote tumor growth and angiogenesis in the early phase and, by contrast, this protein could activate CD8+ cytotoxic T cells and NK cells, leading to tumor regression.

Animals↗

PubMed2005

Effect of sevelamer on dyslipidemia and chronic inflammation in maintenance hemodialysis patients.

BACKGROUND: Hemodialysis (HD) patients often experience cardiovascular events, that might be related to altered calcium-phosphate metabolism, dyslipidemia, and chronic inflammation in addition to hypertension. Sevelamer, a non-calcium-containing phosphate binder, may improve the lipid profile of HD patients. However, the influence of sevelamer on chronic inflammation has not been clarified. METHODS: We enrolled 36 maintenance HD patients with a serum calcium (Ca) or phosphate (P) level constantly greater than 9.5 mg/dL and 5.5 mg/dL, respectively. The dose of sevelamer was titrated to achieve a serum Ca and P in the target ranges. The study period was 24 weeks. Patients underwent the following measurements: bone mineral markers, lipids, and a high-sensitivity C-reactive protein (hs-CRP). RESULTS: In the 28 patients who completed the study, sevelamer significantly reduced the mean non-high-density lipoprotein cholesterol (non-HDL-C) level by 15% and 20% (p < 0.0001) after 12 and 24 weeks, respectively, in addition to reducing the serum P level and Ca x P product. Similarly, there was a significant reduction of the serum hs-CRP level after 12 and 24 weeks [median at baseline: 1.03 mg/dL (interquartile range 0.26-3.98 mg/dL) versus 0.57 (0.17-1.47) and 0.38 (0.16-1.03), respectively, p = 0.0259]. The reduction rate of hs-CRP was significantly correlated with those of non-HDL-C (r = 0.451, p < 0.0401) and P (r = 0.453, p < 0.0008) CONCLUSION: Hs-CRP levels were reduced by sevelamer administration, as well as non-HDL-C, P, and the Ca x P product. Sevelamer may have an anti-inflammatory effect, in addition to lowering phosphate and lipid levels in HD patients.

Aged↗

PubMed2005

[Three patients with nephrotic syndrome due to membranous nephropathy complicated by Sjögren's syndrome].

We describe three females patients (age 40, 62 and 63 y) with nephrotic syndrome due to membranous nephropathy complicated by Sjögren's syndrome(SS). The patients satisfied the criteria for SS, but not those for systemic lupus erythematosus(SLE). All of them developed nephrotic syndrome, and light immunofluorescence as well as electron microscopy of renal biopsy specimens revealed membranous nephropathy. Two were positive for the SS-A antibody, and the other was positive for the SS-B antibody. Two were complicated with primary biliary cirrhosis (PBC) and autoimmune thyroiditis, whereas the other was complicated with interstitial pneumonia, but not with either PBC or autoimmune thyroiditis. Prednisolone (PSL) with or without cyclophosphamide improved the nephrotic syndrome in two of the patients. In conclusion, some patients with SS might become complicated with nephrotic syndrome due to membranous nephropathy if another systemic autoimmune disease exists.

Adult↗

PubMed2004

The diphtheria and pertussis components of diphtheria-tetanus toxoids-pertussis vaccine should be genetically inactivated mutant toxins.

Replacement of cellular with acellular pertussis (aP) vaccines has considerably reduced the systemic reactions observed with diphtheria-tetanus toxoids-pertussis vaccine but has not eliminated the extensive swelling (sometimes involving an entire limb) observed after the fifth injection of diphtheria-tetanus toxoids-aP (DTaP) vaccine. This local reaction, which is likely an Arthus hypersensitivity reaction caused by high levels of antibodies reacting with DTaP vaccine, could discourage its use in adults, who serve as the major reservoir of pertussis for infants. That a critical level of antibodies to pertussis toxin is both essential and sufficient to prevent infection with Bordetella pertussis is derived from data from animal and clinical studies, including data showing the similarities between the immunity induced by diphtheria and pertussis toxoids. The genetically inactivated diphtheria and pertussis mutant toxins are more immunogenic and, therefore, induce comparable levels of antitoxin at lower protein levels than do the formalin-treated native toxins. Replacement of the diphtheria and aP components with these improved antigens will reduce the amount of protein in DTaP vaccine and, most likely, the incidence and severity of local reactions in teenagers and adults.

Adult↗

PubMed2004

Synthesis and structure-activity relationships of 3-substituted 1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridines as novel antitumor agents.

In order to obtain clinically useful antitumor agent, we have designed and synthesized various 3-substituted 1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridines, and evaluated their cytotoxic activity. The series of novel 3-substituted derivatives synthesized in this study showed good antitumor activity against murine P388 leukemia. Particularly, the 3-formyl 1,8-naphthyridine displayed an antitumor activity equal to that of the 3-carboxy 1,8-naphthyridine against murine and human tumor cell lines as well as in vivo test for mouse leukemia. These results demonstrate that the carboxy group at the C-3 position of 1,8-naphthyridine ring is not essential for antitumor activity. In addition, the trend of cytotoxic activity for the 3-substituted 1,8-naphthyridines was different from that of antibacterial activity.

Animals↗

PubMed2004

Discovery of a potent and selective alpha v beta 3 integrin antagonist with strong inhibitory activity against neointima formation in rat balloon injury model.

A new series of phenylpiperazine-based derivatives with strong antagonistic activity for alpha v beta 3 integrin were synthesized. Of these derivatives, the fluorine-substituted compound 8 showed strong inhibitory activity and high selectivity for alpha v beta 3 integrin receptor (IC(50) = 0.055 nM). In vivo evaluation of the antistenotic effects of 8 indicated that this compound significantly inhibits neointima formation in rat balloon injury model.

Angioplasty, Balloon↗

PubMed2004

Synthesis and structure-activity relationships of novel 7-substituted 1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acids as antitumor agents. Part 2.

We have previously reported that a series of 7-substituted 6-fluoro-1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acids possess moderate cytotoxic activity. In a further attempt to find clinically useful antitumor agents, we investigated the structure-activity relationships (SARs) of a new series of compounds obtained by changing the C-6 position of the fluorine atom in addition to the C-5 and C-7 positions and evaluating their cytotoxic activity against several murine and human tumor cell lines. Our results showed that the 6-unsubstituted 1,8-naphthyridine structure had the most potent cytotoxic activity against murine P388 leukemia twice that of the 6-fluoro analogue. In addition, introduction of an amino group at the C-5 position did not have any substantial effect on the cytotoxic activity, while both the 5-chloro and 5-trifluoromethyl groups decreased the cytotoxic activity by 5- to 10-fold. Moreover, aminopyrrolidine derivatives at the C-7 position showed more potent cytotoxic activity than other amines or carbon derivatives. Among the 7-(3-aminopyrrolidinyl) derivatives, the trans-3-methoxy-4-methylaminopyrrolidinyl derivative (27l) was determined to have potent cytotoxic activity in both in vitro and in vivo assays and high water solubility. Finally, the (S,S)-isomer (AG-7352, 3) of 27l, with a cytotoxic activity against human tumor cell lines more potent than that of etoposide, was selected for further development.

Animals↗

PubMed2004

Humoral responses to peptides correlate with overall survival in advanced cancer patients vaccinated with peptides based on pre-existing, peptide-specific cellular responses.

PURPOSE: The aim of this study is to find a laboratory marker for overall survival in advanced cancer patients who were vaccinated with peptides based on pre-existing, peptide-specific CTL precursors in the circulation. EXPERIMENTAL DESIGN: A group of 113 patients with advanced cancer (28 colorectal, 22 prostate, 15 lung, 14 gastric, and 34 other cancers) was enrolled in a Phase I clinical study of peptide vaccination in which peptide-specific CTL precursors of prevaccination peripheral blood mononuclear cells were measured, followed by vaccination with these peptides (maximum of four). For cellular responses, pre and postvaccination (sixth) peripheral blood mononuclear cells were provided for measurement of both peptide-specific CTL precursors by IFN-gamma release assay and tumor reactivity by (51)Cr release assay. Delayed type hypersensitivity was also measured. For humoral response, pre and postvaccination (sixth) sera were provided for measurement of peptide-reactive IgG by an ELISA. RESULTS: The median survival time and 1-year survival rate of the total cases were 346 +/- 64.9 days and 44.6%, respectively, and those of patients vaccinated more than six times (n = 91) were 409 +/- 15 days and 54.4%, respectively. In these 91 patients, the overall survival of patients whose sera showed increased levels of peptide-reactive IgG (n = 60) was significantly more prolonged (P = 0.0003) than that of patients whose sera did not (n = 31), whereas none of cellular responses correlated with overall survival. CONCLUSIONS: Peptide-specific IgG in postvaccination sera could be a suitable laboratory maker for the prediction of prolonged survival in advanced cancer patients vaccinated with peptides based on pre-existing CTL precursors.

Adult↗

PubMed2004

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.

Adrenomedullin↗