Protective effect of astaxanthin on ANCA-associated vasculitis.

OBJECTIVE: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic autoimmune disease characterized by inflammation and fibrinoid necrosis of medium and small vessels, and its pathogenesis is closely related to inflammation and oxidative stress. Astaxanthin (ATX) is a carotenoid with anti-inflammatory, antioxidant, and immunomodulatory effects. We hypothesized that ATX could play a role in AAV treatment. This study aimed to investigate whether ATX has a protective effect against AAV and to elucidate its regulatory mechanism. METHODS: In vitro experiments, neutrophils isolated from healthy people were treated with ATX or not and cultured with serum from myeloperoxidase (MPO) -ANCA-positive patients and healthy persons. The levels of IL-6 and TNF-α in neutrophil culture supernatant before and after stimulation were measured. Neutrophil extracellular traps (NETs) and intracellular reactive oxygen species (ROS) in neutrophils were detected after stimulation. In vivo study, experimental autoimmune vasculitis (EAV) rat models were established and then treated with ATX via intragastric administration for 6 consecutive weeks. Urinary erythrocytes, urinary proteins, and serum creatinine were detected and HE staining was performed to assess renal injury in rats. Lung hemorrhage was observed by gross dissection and microscopic Prussian blue staining. The level of serum MPO-ANCA was detected. Serum IL-6, TNF-α, superoxide dismutase (SOD), and glutathione peroxidase (GSH-px) in rats were measured to explore the effects of ATX on oxidative stress and inflammation in EAV rats. The deposition of MPO in kidney and lung of rats was detected by immunohistochemistry. RESULTS: ATX significantly inhibited neutrophil secretion of inflammatory factors IL-6 and TNF-α. ATX reduced the elevated levels of ROS in neutrophils stimulated by serum from AAV patients and alleviated the release of NETs. ATX administration was observed to reduce the degree of hematuria, proteinuria, and glomerular crescent formation in EAV rats. The degree of pulmonary hemorrhage was significantly reduced. Besides, the serum levels of IL-6 and TNF-α were attenuated, and antioxidant SOD and GSH-px increased in serum. Pathological results showed that MPO deposition was decreased in lung and kidney tissues after ATX treatment. CONCLUSION: ATX could ameliorate the organ damages in EAV rats. It could serve as a hopeful therapy for AAV by its anti-inflammatory and anti-oxidative feature as a unique nature carotenoid.

Using Machine Learning to Identify Risk Factors and Establishing a Clinical Prediction Model to Predict Atherosclerosis Complications in Idiopathic Membranous Nephropathy.

BACKGROUND: Clinically, it has been observed that patients with idiopathic membranous nephropathy (IMN) have a higher probability of coronary heart disease. We aim to investigate the risk factors associated with coronary heart disease in IMN patients using a mechanomics approach and establish a clinical diagnosis model. METHODS: We collected sixty-nine clinical data points from patients undergoing phospholipase A2 receptor (anti-PLA2R) tests at the Affiliated Hospital of Qingdao University between July 9, 2019 and March 15, 2021. We excluded patients with cancer, hepatitis B, recent injuries or surgeries, and those under 18. Finally, 162 patients were considered for our study, which included 73 patients with coronary heart disease. The patients were split into test and validation groups at a 7:3 ratio. We utilized the Mann-Whitney U test for initial factor screening and the least absolute shrinkage and selection operator (LASSO) regression for further index screening. Eventually, the effectiveness of the clinical model was evaluated through visual statistical methods. RESULTS: Age, lymphocyte count, the sum of high-density lipoprotein (HDL) and low-density lipoprotein (LDL), serum creatinine, and antithrombin III were risk factors for coronary heart disease in patients with idiopathic membranous nephropathy in a multivariate regression (p < 0.1). In the training group, 14 clinical features were finally screened by the LASSO regression, and the area under the curve (AUC) of the training group was 0.90 (95% CI 0.877-0.959), accuracy (ACC) was 0.85, sensitivity was 0.76, specificity was 0.91, and precision was 0.85. F1 scored 0.80. In the verification group, AUC was 0.84 (0.743-0.927), ACC was 0.80, sensitivity was 0.67, specificity was 0.87, precision was 0.75, and F1 scored 0.71. We then visualized them using a nomogram based on multivariate regression. The C index and clinical decision curve evaluated them. The C index was 83.8%, and the clinical decision curve was also excellent. CONCLUSIONS: We've established an effective clinical prediction model for patients with IMN who also have coronary heart disease. This model holds significant potential for enhancing clinical decision-making.

Randomized Phase 2 Trial of Telitacicept in Patients With IgA Nephropathy With Persistent Proteinuria.

Introduction: To date, no specific therapies have been approved for immunoglobulin A nephropathy (IgAN) treatment. Telitacicept is a fusion protein composed of transmembrane activator and calcium-modulating cyclophilin ligand interactor and fragment crystallizable portion of immunoglobulin G (IgG), which neutralizes the B lymphocyte stimulator and a proliferation-inducing ligand. Methods: This phase 2 randomized placebo-controlled trial aimed to evaluate the efficacy and safety of telitacicept in patients with IgAN. Participants with an estimated glomerular filtration rate (eGFR) >35 ml/min per 1.73 m2 and proteinuria ≥0.75 g/d despite optimal supportive therapy, were randomized 1:1:1 to receive subcutaneous telitacicept 160 mg, telitacicept 240 mg, or placebo weekly for 24 weeks. The primary end point was the change in 24-hour proteinuria at week 24 from baseline. Results: Forty-four participants were randomized into placebo (n = 14), telitacicept 160 mg (n = 16), and telitacicept 240 mg (n = 14) groups. Continuous reductions in serum IgA, IgG, and IgM levels were observed in the telitacicept group. Telitacicept 240 mg therapy reduced mean proteinuria by 49% from baseline (change in proteinuria vs. placebo, 0.88; 95% confidence interval, -1.57 to -0.20; P = 0.013), whereas telitacicept 160 mg reduced it by 25% (-0.29; 95% confidence interval, -0.95 to 0.37; P = 0.389). The eGFR remained stable over time. Adverse events (AEs) were similar in all groups. Treatment-emergent AEs were mild or moderate, and no severe AEs were reported. Conclusion: Telitacicept treatment led to a clinically meaningful reduction in proteinuria in patients with IgAN in the present phase 2 clinical trial. This effect is indicative of a reduced risk for future kidney disease progression.

Glycated albumin level is significantly decreased in patients suffering nephrotic syndrome.

Serum glycated albumin (GA) level is used along with that of glucose and glycated hemoglobin (HbA1c) as indicators of glycemic control for diabetic patients. Although serum GA levels are affected by blood glucose level, they are also influenced by serum albumin metabolism and other pathological conditions. However, a systematic comparison of the serum GA levels in different types of human diseases has not been reported. In current study, 86,319 clinical lab test results of GA levels from healthy individuals and patients with 57 different types of diseases during the past 5 years in our hospital were retrieved and analyzed. Based on the mean (SD), median, and p (-Log10p) values, we found 29/57 diseases including type 2 diabetes, diabetic nephropathy, uremia, pancreatic cancer, liver cancer, hepatic encephalopathy, and azotemia had significantly (p<0.05, -Log10p>1.30) increased GA levels whereas 18/57 diseases including nephrotic syndrome, preeclampsia, Wilms' tumor, lupus erythematosus, and sepsis had significantly decreased GA levels compared to that of healthy controls. Moreover, the highest -Log10p values (>100) were observed in nephrotic syndrome, type 2 diabetes, preeclampsia, coronary heart disease, uremia, acute cerebral infarction, leukemia, and cerebrovascular disease in a descending order. These data indicated that the serum GA levels could be increased or decreased significantly in a disease-specific manner. Revealing the molecular mechanisms underlying these observations might make the increased or decreased serum GA levels indicators for different types of diseases, especially as an indicator that distinguishes nephrotic syndrome from other types of kidney diseases.

RETRACTED: MicroRNA-30b promotes lipopolysaccharide-induced inflammatory injury and alleviates autophagy through JNK and NF-κB pathways in HK-2 cells.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief as there are concerns about the reliability of the results included in the article. The journal was initially contacted by the first author to request the retraction as they reported that results were not reproducible post publication. Also, the author acknowledged that the corresponding authors were not aware of the submission of this article. Given the comments of Dr Elisabeth Bik https://scienceintegritydigest.com/2020/02/21/the-tadpole-paper-mill/ regarding this article, the journal requested the author to provide the raw data. However, the author was not able to fulfil this request.

Cytoprotective Effect of Heat Shock Protein 27 Against Lipopolysaccharide-Induced Apoptosis of Renal Epithelial HK-2 Cells.

BACKGROUND: In response to various stimuli, heat shock protein 27 (Hsp27) functions as an anti-apoptotic or/and anti-inflammatory factor which confers a survival advantage to cells. This study was aimed to explore whether Hsp27 also has a cytoprotective role in human renal tubular epithelial cells, and to evaluate its potential in treating septic acute kidney injury (septic AKI). METHODS: HK-2 cells were subjected to different concentrations (0-10 µg/mL) of lipopolysaccharide (LPS) for various times (0-24 h) to establish a septic AKI model in vitro. Before LPS administration, HK-2 cells were transfected either with vectors or siRNA against Hsp27, and the changes in cell viability and apoptotic cells rate were assessed using CCK-8 and flow cytometry. The expression changes in apoptosis-related proteins, proinflammatory cytokines and chemokine, as well as main factors in NF-κB and JNK pathways were mainly determined by Western blotting. Besides, the relationship between Hsp27 and Bcl-2 was detected by co-immunoprecipitation. RESULTS: LPS remarkably damaged HK-2 cells by reduction of cell viability, induction of apoptosis, and stimulation of proinflammatory cytokines and chemokine release. Hsp27 overexpression significantly impaired LPS-induced damage in HK-2 cells. Hsp27 overexpression couldn't alter the mRNA level of Bcl-2, but could interact with Bcl-2 at an endogenous level. Both NF-κB and JNK pathways were activated by LPS, while were blocked in Hsp27-overexpressing cells. CONCLUSION: Hsp27 overexpression conferred a survival advantage to LPS-injured HK-2 cells by controlling cell viability, apoptosis and inflammation, possibly via interaction with Bcl-2 and modulation of NF-κB and JNK pathways.

[ARTICLE WITHDRAWN] Satb1 promotes osteoclastogenesis by recruiting CBP to upregulate miR-223 expression in chronic kidney disease-mineral and bone disorder.

THIS ARTICLE WAS WITHDRAWN BY THE PUBLISHER IN OCT 2021

Pathogenesis of antimicrobial peptides LL-37 and CpG-ODN in ANCA associated vasculitis.

OBJECTIVES: Anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV) are a group of systemic autoimmune disorders characterized by necrotizing inflammation of small- to medium-sized blood vessels. The pathogenesis of patients with AAV are still in investigation. In this study, we explored the involvement of LL-37 and nucleic acids in AAV. METHODS: 15 patients with AAV diagnosed according to the Chapel Hill definition between October 2014 and July 2015 in the department of Nephrology of Huangdao, affiliated Hospital of Qingdao University were enrolled. 16 patients with chronic bronchitis (CB) were selected  as disease control group. 15 cases of healthy people from Medical Healthy Center were as healthy control group. Peripheral blood mononuclear cells (PBMCs) were collected from these groups and stimulated by LL-37and (or) two types of CpG-ODN for 7 days. The IFN-α and ANCA in vitro were measured by ELISA. The serum IFN-α, LL-37 and ANCA were measured also. RESULTS: The serum level of IFN-α in AAV group was much higher than that in CB group (692.13 ± 407.28 vs 397.07 ± 211.62 pg/ml, p = 0.019), and that in healthy control group (692.13 ± 407.28 vs 251.54 ± 190.46 pg/ml, p < 0.001). The serum level of LL-37 in AAV group was much higher than that in CB group (101.18 ± 66.59 vs 40.23 ± 13.51 ng/ml, p < 0.001, and that in healthy control group (101.18 ± 66.59 vs 27.80 ± 16.86 ng/ml, p < 0.001). Also the level of IFN-α showed a significant positive relationship with ANCA in AAV group both in serum and in supernatant of cultured PBMCs stimulated by LL-37 and (or) CpG-ODN (r = 0.783, p = 0.001; r = 0.575, p = 0.064; r = 0.649, p = 0.031; r = 0.806, p = 0.003). In patients with AAV, the supernatant levels of IFN-α in cultured PBMCs stimulated by LL-37 and (or) CpG-ODN were higher than that without stimulating factor (p < 0.05). The supernatant level of IFN-α in cultured PBMC stimulated by LL-37 alone was lower than that stimulated by CpGA alone (699.57 ± 476.26 vs 2342.63 ± 2025.11 pg/ml, p = 0.001). But the supernatant level of IFN-α in cultured PBMCs stimulated by LL-37 alone was higher than in that stimulated by CpGB alone (699.57 ± 476.26 vs 153.35 ± 78.08 pg/ml, p < 0.001). The supernatant level of IFN-α in cultured PBMCs stimulated by both LL-37 and CpG-ODN was higher than that stimulated by LL-37 or CpG-ODN alone (2550.57 ± 2217.41 vs 699.57 ± 476.26 pg/ml, p = 0.003; 2550.57 ± 2217.41 vs 153.35 ± 78.08 pg/ml, p = 0.001; 2660.95 ± 391.31 vs 699.57 ± 476.26 pg/ml, p < 0.001; 2660.95 ± 391.31 vs 153.35 ± 78.08 pg/ml, p < 0.001). Either it is stimulated by LL-37 or CpG-ODN or both, the supernatant level of IFN-α in cultured PBMCs in AAV patients was the highest, that in healthy controls was the lowest. Either stimulated by LL-37 or CPG-ODN, or both, the levels of ANCA production in vitro in AAV groups were statistically significantly higher than those in CB group and healthy control group. CONCLUSIONS: There were higher serum levels of LL-37 and IFN-α in patients with AAV. IFN-α could reach a higher level stimulated by LL-37 and nucleic acids both of which are related to infection. Patients with AAV have ANCA-producing B lymphocytes in the circulation even in remission stage. Infections could induce the relapse of AAV.

Significance of serum peptidylarginine deiminase type 4 in ANCA-associated vasculitis.

OBJECTIVE: To investigate the clinical significance of peptidylarginine deiminase type 4 (PAD4) in the pathogenesis of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). To make a primary observation on the relationship of chronic bronchitis and bronchiectasis (CB) with the pathogenesis of AAV by PAD4. METHODS: The sera from 13 patients with AAV, 13 patients with CB, 11 patients with rheumatoid arthritis (RA), 11 patients with primary chronic kidney disease (CKD) and 12 normal controls were collected. Serum PAD4 was detected using commercial ELISA kits. The serum levels of PAD4 were compared not only among the different groups but also between the activity and remission stage of the same disease. The associations between serum PAD4 and the Birmingham Vasculitis Activity Score (BVAS) of AAV were further investigated. RESULTS: (1) The serum levels of PAD4 in patients with AAV, RA and CB at activity stage were all higher than that in the normal controls (P<0.001, respectively, α'=0.007). The serum level of PAD4 in patients with CB at remission stage and that in CKD group were not found elevated compared with the normal controls (P=0.02, P=0.085, respectively, α'=0.007). (2) At activity stage, among the groups of simple AAV, AAV with a long history of CB and CB without AAV, no significant difference was detected. While at remission stage among the 3 groups, the serum level of PAD4 was at the lowest level in CB group without AAV. (3) The serum level of PAD4 in some patients with CB without AAV were found still higher at remission stage. (4) The serum level of PAD4 in AAV with renal damage at activity stage was positively correlated with BVAS (the activity score of AAV, r=0.71, P=0.02). CONCLUSION: PAD4 is involved in the pathogenesis of AAV. Whether some patients with CB might progress to AAV by the link with PAD4 still need further investigation.

Modified C-reactive protein might be a target autoantigen of TINU syndrome.

BACKGROUND AND OBJECTIVES: The cross-reactive antigen(s) of tubulointerstitial nephritis and uveitis (TINU) syndrome from renal tubulointerstitia and ocular tissue remain unidentified. The authors' recent study demonstrated that the presence of serum IgG autoantibodies against modified C-reactive protein (mCRP) was closely associated with the intensity of tubulointerstitial lesions in lupus nephritis. The study presented here investigates the possible role of IgG autoantibodies against mCRP in patients with TINU syndrome. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: mCRP autoantibodies were screened by ELISA with purified human C-reactive protein in 9 patients with TINU syndrome, 11 with drug-associated acute interstitial nephritis, 20 with IgA nephropathy, 19 with minimal change disease, 20 with ANCA-associated vasculitis, 6 with Sjogren's syndrome, and 12 with amyloidosis. mCRP expression was analyzed by immunohistochemistry in renal biopsy specimens from the 9 patients with TINU syndrome and 40 from disease controls. Frozen normal human kidney and iris were used to demonstrate co-localization of human IgG and mCRP from patients with TINU syndrome with laser scanning confocal microscopy. RESULTS: The mCRP autoantibodies were detected in all nine patients with TINU syndrome, significantly higher than that of those with disease controls (P < 0.05). The renal histologic score of mCRP in TINU syndrome was significantly higher than that in disease controls (P < 0.05). The staining of mCRP and human IgG were co-localized in renal and ocular tissues. CONCLUSIONS: It is concluded that mCRP might be a target autoantigen in TINU syndrome.

Renal neutrophils infiltration in antineutrophil cytoplasmic antibodies-negative pauci-immune crescentic glomerulonephritis.

INTRODUCTION: This study aims to investigate the evidence of neutrophil infiltration in renal tissue from patients with antineutrophil cytoplasmic antibodies (ANCA)-negative pauci-immune crescentic glomerulonephritis (CrGN), and a comparison with their ANCA-positive counterparts was performed. METHODS: Renal biopsy specimens from 31 patients with pauci-immune CrGN were collected. Twelve patients were ANCA negative, and 19 patients were ANCA positive. Neutrophil infiltration was investigated by staining of 2 markers, CD15 and myeloperoxidase (MPO), using immunohistochemistry. RESULTS: Positive-stained cells of CD15 (CD15) and MPO (MPO+) were mainly located in glomeruli with cellular crescents and segmental fibrinoid necrotic lesions and in periglomerular area of cellular crescents, especially at the area of ruptured Bowman capsule. Scanty positive staining was found in normal renal tissue. The number of CD15 cells in the glomeruli and periglomerular area was significantly higher in ANCA-negative group than in ANCA-positive group (in glomeruli: 2.70 ± 1.61 versus 1.38 ± 0.85, P = 0.019; in periglomerular area: 4.35 ± 4.36 versus 1.48 ± 1.67, P = 0.047). The number of MPO+ cells in the periglomerular area was also significantly higher in ANCA-negative group than that in ANCA-positive group. CONCLUSIONS: Renal neutrophil infiltration might play a pathogenic role in ANCA-negative pauci-immune CrGN, and the neutrophil infiltration might be more severe in ANCA-negative pauci-immune-CrGN than in ANCA-positive one.

Common apolipoprotein E gene mutations contribute to lipoprotein glomerulopathy in China.

BACKGROUND: Lipoprotein glomerulopathy (LPG) is a unique disease characterized by thrombus-like lipoprotein deposition in glomeruli and an increased serum apolipoprotein E level (ApoE protein or APOE gene). Several APOE mutations contribute to the occurring of LPG. METHODS: We confirmed LPG in 7 individuals by renal biopsy, and investigated families of 2 patients with urinalysis, serum creatinine and serum lipid examination. Exons of APOE of all individuals as well as their relatives were amplified and sequenced directly. RESULTS: Two types of APOE mutations were identified in the 7 patients and their relatives. APOE Maebashi (Arg142-Leu144-->0) heterozygotes were found in 5 individuals who were from 4 different families. APOE Kyoto (Arg25-Cys) was confirmed heterogeneous in another 2 individuals. Both mutations present incomplete penetrance. CONCLUSION: Our research indicates that APOE Maebashi (Arg142-Leu144-->0) is a common mutation in Chinese LPG. However, not all carriers of the 2 mutations have LPG, although hyperlipidemia and high serum ApoE level are tested. There are likely other reasons, such as a local mechanism in the glomeruli, which participated in the renal injury.

Differential deposition of C4d and MBL in glomeruli of patients with ANCA-negative pauci-immune crescentic glomerulonephritis.

OBJECTIVE: Our previous study suggested involvement of alternative pathway activation of complement in ANCA-positive pauci-immune crescentic glomerulonephritis (CrGN). This study was to investigate the evidence of complement activation in renal biopsy specimens of patients with ANCA-negative pauci-immune CrGN. METHODS: Renal biopsy specimens from 12 patients with ANCA-negative pauci-immune CrGN were used to detect the staining of membrane attack complex (MAC), C3d, C4d, mannose-binding lectin (MBL), factor B by immunohistochemistry, and/or immunofluorescence. Renal tissue from eight patients with minimal change disease (MCD) and renal tissue obtained from a normal kidney and the normal parts of a nephrectomized kidney due to renal carcinoma was used as disease and normal controls, respectively. RESULTS: MAC and C3d could be detected in the active renal lesions of cellular crescents in each of the 12 ANCA-negative CrGN patients but not or scarcely detected in patients with MCD and in normal renal tissue. The deposition of other complement components in the 12 patients was heterogeneous. Although none of them had C1q staining, eight of the 12 were C4d positive and six out of the eight were MBL positive. The remaining four only had evidence of the alternative pathway activation by positive staining of C3d, factor B, and MAC. The staining intensity of C4d and MBL was much higher in dialysis-dependent patients than that in dialysis-independent patients. CONCLUSION: Complement activation was involved in renal damage of human ANCA-negative pauci-immune CrGN but with heterogeneous activation pathways. Positive staining of C4d and MBL might be associated with poor renal outcome.

Complement deposition in renal histopathology of patients with ANCA-associated pauci-immune glomerulonephritis.

BACKGROUND: The pathogenesis of ANCA-associated pauci-immune glomerulonephritis has not been fully elucidated. Several studies had suggested that complement deposition could be detected in renal histopathology. The current study investigated the clinical and pathological significance of complement deposition in renal histopathology of patients with ANCA-associated pauci-immune glomerulonephritis. METHODS: Renal biopsy specimens from 112 patients with ANCA-associated pauci-immune glomerulonephritis were investigated using direct immunofluorescence, light and electron microscopy. For direct immunofluorescence, IgG, IgA, IgM, C3c and C1q staining on fresh frozen renal tissue were routinely performed immediately after a renal biopsy. Complement deposition was defined as the presence of C3c or C1q for at least 1+ in a 0-4+ scale. Clinical and histopathological data between patients with and without complement deposition were compared. RESULTS: In direct immunofluorescence microscopy, C3c and C1q could be detected in glomerular capillary wall and/or mesangium in the specimens of 37/112 (33.0%), 7/112 (6.3%) patients, respectively. Compared with patients without C3c deposition, patients with C3c deposition had a higher level of urinary protein (P < 0.01) and poorer initial renal function (P < 0.05). CONCLUSION: Complement deposition was not rare in renal histopathology of human ANCA-associated pauci-immune glomerulonephritis, which was associated with more severe renal injury.

Complement activation is involved in renal damage in human antineutrophil cytoplasmic autoantibody associated pauci-immune vasculitis.

OBJECTIVE: This study was to investigate the evidence for complement activation in renal biopsy specimens of patients with myeloperoxidase (MPO)-antineutrophil cytoplasmic autoantibody (ANCA)-associated pauci-immune vasculitis. METHODS: Renal biopsy specimens from seven patients with MPO-ANCA positive pauci-immune necrotizing crescentic glomerulonephritis (NCGN) were used to detect the staining of membrane attack complex (MAC), C3d, C4d, mannose-binding lectin (MBL), factor B and factor P using immunohistochemistry and immunofluorescence. Renal tissue from seven patients with minimal change disease (MCD) and two normal renal tissue were used as controls. RESULTS: MAC, C3d, factor B and factor P could be detected in glomeruli and small blood vessels with active vasculitis of patients with pauci-immune AAV, but not or scarcely in patients with MCD and in normal renal tissue. C3d and factor B co-localized with MAC, factor P colocalized with C3d. MBL and C4d were not detected in patients with AAV. CONCLUSION: The alternative pathway of the complement system is involved in renal damage of human pauci-immune AAV.

Angiotensin II-induced insulin resistance is enhanced in adrenomedullin-deficient mice.

Insulin resistance and hypertension are common disorders that are closely related. Among several factors, oxidative stress has been reported to be intimately related to these diseases. To elucidate the involvement of oxidative stress in the development of insulin resistance in a hypertensive model, we administered angiotensin II (Ang II), which raises blood pressure and induces reactive oxygen radicals, to adrenomedullin (AM)-knockout heterozygous mice and examined the resulting changes in blood pressure and insulin resistance. Ang II was administered ip at a dosage of 640 ng/kg.min for 4 wk. The systolic blood pressure was significantly elevated in both AM-knockout heterozygous and wild-type mice to the same extent. On the other hand, Ang II attenuated insulin sensitivity more strongly in AM-knockout heterozygous mice than in wild-type mice, when measured using 2- deoxyglucose uptakes in the soleus muscle. Ang II also induced a higher urinary excretion of isoprostane, a marker of oxidative stress. Furthermore, the production of oxidative stress in the soleus muscles of angiotensin-treated mice, measured using electronic spin resonance, was significantly higher than that in AM-knockout heterozygous mice. Moreover, 4-hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl, a superoxide scavenger mimetic, normalized the insulin resistance induced by Ang II without affecting the blood pressure in both groups. The present results suggest that, in an Ang II-treated mouse model, insulin resistance is induced by oxidative stress through a mechanism that is independent of blood pressure, and that AM can act as a protective peptide against insulin resistance via its intrinsic antioxidant effect.

Organ-protective effects of adrenomedullin.

Adrenomedullin (AM), a vasodilatory peptide, has recently been shown to have multipotent properties. Among its other pharmacological actions, AM has been hypothesized to protect organs from hypertension, hypoxia, or infection. In vitro studies have shown that AM has an inhibitory effect on vascular smooth muscle cell proliferation and oxidative stress, but that it enhances nitric oxide (NO) production, which in turn is thought to protect against organ damage. Recent advances in genetic engineering have made it possible to investigate the chronic effects of AM in vivo. Applying genetic engineering, it is revealed that adrenomedullin was shown to protect liver, kidney, vasculature, and heart from septic shock, ischemia and hypertension. However, speculation as to the mechanism of its organ-protective effect varies from report to report. Possible mechanisms include preservation of blood flow, interaction with NO and/or oxidative stress. And although there continue to be technical limitations to the use of these genetically modified models, their application in further investigations should help to clarify the potential efficacy of AM as a new therapeutic agent.