Sh3bp2 Gain-Of-Function Mutation Ameliorates Lupus Phenotypes in B6.MRL-Faslpr Mice

SH3 domain-binding protein 2 (SH3BP2) is an adaptor protein that is predominantly expressed in immune cells, and it regulates intracellular signaling. We had previously reported that a gain-of-function mutation in SH3BP2 exacerbates inflammation and bone loss in murine arthritis models. Here, we explored the involvement of SH3BP2 in a lupus model. Sh3bp2 gain-of-function (P416R knock-in; Sh3bp2KI/+) mice and lupus-prone B6.MRL-Faslpr mice were crossed to yield double-mutant (Sh3bp2KI/+Faslpr/lpr) mice. We monitored survival rates and proteinuria up to 48 weeks of age and assessed renal damage and serum anti-double-stranded DNA antibody levels. Additionally, we analyzed B and T cell subsets in lymphoid tissues by flow cytometry and determined the expression of apoptosis-related molecules in lymph nodes. Sh3bp2 gain-of-function mutation alleviated the poor survival rate, proteinuria, and glomerulosclerosis and significantly reduced serum anti-dsDNA antibody levels in Sh3bp2KI/+Faslpr/lpr mice. Additionally, B220+CD4-CD8- T cell population in lymph nodes was decreased in Sh3bp2KI/+Faslpr/lpr mice, which is possibly associated with the observed increase in cleaved caspase-3 and tumor necrosis factor levels. Sh3bp2 gain-of-function mutation ameliorated clinical and immunological phenotypes in lupus-prone mice. Our findings offer better insight into the unique immunopathological roles of SH3BP2 in autoimmune diseases

SH3BP2 Deficiency Ameliorates Murine Systemic Lupus Erythematosus

Background: The adaptor protein Src homology 3 domain-binding protein 2 (SH3BP2) is widely expressed in immune cells. It controls intracellular signaling pathways. The present study was undertaken to investigate the role of SH3BP2 in a murine systemic lupus erythematosus model. Methods: For the lupus model, we used Faslpr/lpr mice. Clinical and immunological phenotypes were compared between Faslpr/lpr and SH3BP2-deficient Faslpr/lpr mice. Splenomegaly and renal involvement were assessed. Lymphocyte subsets in the spleen were analyzed by flow cytometry. To examine the role of SH3BP2 in specific cells, B cell-specific SH3BP2-deficient lupus mice were analyzed; T cells and bone marrow-derived dendritic cells and macrophages were analyzed in vitro. Results: SH3BP2 deficiency significantly reduced lupus-like phenotypes, presented as splenomegaly, renal involvement, elevated serum anti-dsDNA antibody, and increased splenic B220+CD4−CD8− T cells. Notably, SH3BP2 deficiency in B cells did not rescue the lupus-like phenotypes. Furthermore, SH3BP2 deficiency did not substantially affect the characteristics of T cells and macrophages in vitro. Interestingly, SH3BP2 deficiency suppressed the differentiation of dendritic cells in vitro and reduced the number of dendritic cells in the spleen of the lupus-prone mice. Conclusions: SH3BP2 deficiency ameliorated lupus-like manifestations. Modulating SH3BP2 expression could thus provide a novel therapeutic approach to autoimmune diseases

Infiltration of M1, but not M2, macrophages is impaired after unilateral ureter obstruction in Nrf2-deficient mice

Chronic inflammation can be a major driver of the failure of a variety of organs, including chronic kidney disease (CKD). The NLR family pyrin domain-containing 3 (NLRP3) inflammasome has been shown to play a pivotal role in inflammation in a mouse kidney disease model. Nuclear factor erythroid 2-related factor 2 (Nrf2), the master transcription factor for anti-oxidant responses, has also been implicated in inflammasome activation under physiological conditions. However, the mechanism underlying inflammasome activation in CKD remains elusive. Here, we show that the loss of Nrf2 suppresses fibrosis and inflammation in a unilateral ureter obstruction (UUO) model of CKD in mice. We consistently observed decreased expression of inflammation-related genes NLRP3 and IL-1β in Nrf2-deficient kidneys after UUO. Increased infiltration of M1, but not M2, macrophages appears to mediate the suppression of UUO-induced CKD symptoms. Furthermore, we found that activation of the NLRP3 inflammasome is attenuated in Nrf2-deficient bone marrow–derived macrophages. These results demonstrate that Nrf2-related inflammasome activation can promote CKD symptoms via infiltration of M1 macrophages. Thus, we have identified the Nrf2 pathway as a promising therapeutic target for CKD

Prevalence of anemia in patients with chronic kidney disease in Japan: A nationwide, cross-sectional cohort study using data from the Japan Chronic Kidney Disease Database (J-CKD-DB)

Background: The Japan Chronic Kidney Disease Database (J-CKD-DB) is a nationwide clinical database of patients with chronic kidney disease (CKD) based on electronic health records. The objective of this study was to assess the prevalence of anemia and the utilization rate of erythropoiesis-stimulating agents (ESAs) in Japanese patients with CKD. Methods: In total, 31, 082 adult outpatients with estimated glomerular filtration rates of 5–60 ml/min/1.73 m2 in seven university hospitals were included this analysis. The proportions of patients with CKD stages G3b, G4, and G5 were 23.5%, 7.6%, and 3.1%, respectively. Results: The mean (standard deviation) hemoglobin level of male patients was 13.6 (1.9) g/dl, which was significantly higher than the mean hemoglobin level of female patients (12.4 (1.6) g/dl). The mean (standard deviation) hemoglobin levels were 11.4 (2.1) g/dl in patients with CKD stage G4 and 11.2 (1.8) g/dl in patients with CKD stage G5. The prevalences of anemia were 40.1% in patients with CKD stage G4 and 60.3% in patients with CKD stage G5. Logistic regression analysis showed that diagnoses of CKD stage G3b (adjusted odds ratio [95% confidence interval]: 2.32 [2.09–2.58]), G4 (5.50 [4.80–6.31]), and G5 (9.75 [8.13–11.7]) were associated with increased prevalence of anemia. The utilization rates of ESAs were 7.9% in patients with CKD stage G4 and 22.4% in patients with CKD stage G5. Conclusions: We determined the prevalence of anemia and utilization rate of ESAs in Japanese patients with CKD using data from a nationwide cohort study

マウス横紋筋融解症誘発性急性腎障害モデルにおけるNrf2活性化の意義の検討

生体は親電子性物質，活性酸素種によって生成される酸化ストレスから生体を保護する応答システムを有している．Keap1（Kelch-like ECH-associated protein 1） -Nrf2（NF-E2 related factor2）システムがこの応答機構において重要な役割を果たす．核内移行したNrf2は転写因子として，NQO1，HO-1などの抗酸化遺伝子群の発現を制御する．　横紋筋融解症による急性腎障害（AKI: Acute Kidney Injury）の機序として，酸化ストレスが尿細管障害に大きく関与する．それ故，横紋筋融解症誘発性AKI においてもNrf2活性化による腎保護効果が期待される．横紋筋融解症誘発性AKI におけるNrf2活性化の意義と治療標的としての可能性を検討した．ヒト近位尿細管上皮細胞（hPTECs）を用いhemin 刺激に対するNrf2活性化の意義を検討した．hemin 刺激によりhPTECs におけるNrf2関連抗酸化遺伝子群の上昇，細胞障害を認めた．Nrf2-siRNA によるNrf2ノックダウン（KD）を行うことでhemin 刺激に対する抗酸化遺伝子群の発現上昇は抑制され，細胞障害が有意に増悪した．野生型マウス （WT），Nrf2欠損マウス（Nrf2KO）を用い，グリセロール筋注による横紋筋融解症モデルを作成した．（１）WT/Cont，（２）WT/ 横紋筋融解症（RM），（３）Nrf2KO/Cont，（４）Nrf2KO/RM の４群で比較検討した．結果は，WT/Cont に比べWT/RM 群で腎機能障害，尿細管障害，マクロファージ浸潤を認め，Nrf2KO/RM 群で有意に増悪した．抗酸化遺伝子群の発現はNrf2KO/RM 群で低下していた．　横紋筋融解症誘発性AKI において，Nrf2活性化が腎保護効果を有する事が示された．横紋筋融解症によるAKI に対して，Nrf2活性化が新たな治療標的となり得ることが明らかとなった．Cells are equipped with cytoprotective systems against oxidative stress caused by reactive oxygen species and electrophilic stress. The Keap1-Nrf2 pathway plays a central role in such mechanisms against oxidative and xenobiotic damage. Nrf2, as a transcription factor, activates a series of genes including NQO1 and HO-1.As the mechanism of acute kidney injury (AKI) due to rhabdomyolysis, renal tubule injury due to oxidative stress is the major component of the pathology. Therefore, in rhabdomyolysisinduced AKI, reno-protective effect of Nrf2 activation is expected. In the present study, the role of Nrf2 activation in rhabdomyolysis-induced AKI was investigated. In vitro, human proximal tubular epithelial cells (hPTECs) were used to determine the significance of Nrf2 for hemin stimulation. Hemin stimulation revealed elevation of Nrf2-related antioxidant gene group and cytotoxicity. Nrf2 knockdown (KD) with Nrf2-siRNA suppressed the rise of the expression of the antioxidant genes against hemin stimulation, and the cell damage was significantly exacerbated. A model of rhabdomyolysis by glycerol intramuscular injection was also prepared in vivo using wild type mice (WT) and Nrf2-deficient mice (Nrf2 KO). These mice were of the C57BL/6J background. We divided them into four groups: (1) WT/Cont, (2) WT/rhabdomyolysis (RM), (3) Nrf2 KO/Cont, and (4) Nrf2 KO/RM. Renal dysfunction and macrophage infiltration occurred more often in the WT/RM than in the WT/Cont, and it significantly worsened in the Nrf2 KO/RM group compared to the WT/RM. The expression of the antioxidant gene group was suppressed more in the Nrf2 KO/RM group compared with the WT/RM.These results indicate that Nrf2 activation exerts reno-protective effect in rhabdomyolysisinduced AKI. Nrf2 activation may be a new therapeutic target for rhabdomyolysis-induced AKI

Summary of the 2018 ISN Frontiers Meeting: Kidney Disease and Cardiovascular Disease

International Society of Nephrology (ISN) Frontiers meetings build on the success of the ISN Nexus and Forefronts series by bringing together basic scientists, clinicians, and practitioners in a unique setting. This new event was organized to make more innovative science available to a global audience by removing regional barriers in accessing the latest knowledge. The first ISN Frontiers meeting was organized in partnership between the Japanese Society of Nephrology and the Japanese Society for Dialysis Therapy, which was held in Tokyo in February 2018. The meeting focused on the topic “Kidney Disease & Cardiovascular Disease,” which covered a broad range of scientific and clinical fields, including nephrology, cardiovascular diseases, dialysis, transplantation, chronic kidney disease (CKD)–mineral bone disease (MBD), diabetes, pediatric nephrology, nutrition, pharmacology, and nursing. A total of 1584 active physicians and scientists from 64 countries attended the meeting, and a number of leading physician scientists from different and related disciplines of clinical and basic research described and reviewed recent discoveries. This report summarizes the main highlights of the meeting lectures. Keywords: acute kidney injury, cardiovascular disease, chronic kidney disease, CKD-MBD, diabetes, dialysis, nutrition, nursing science, pediatric nephrology, pharmacology, transplantatio

The Impact of Potassium Binders on Mortality in Patients with Hyperkalemia: A Single-Center Study

Hyperkalemia is associated with an increased risk of mortality and is a common complication in patients with chronic kidney disease (CKD). Despite the prevalence of hyperkalemia, current real-world data suggest that serum potassium levels are not effectively managed in clinical practice. The potential benefit of potassium binders in reducing the risk of death has not been thoroughly investigated. Therefore, this retrospective cohort study aimed to investigate the potential impact of potassium binders on mortality risk in patients with CKD by analyzing electronic medical records. The study included 1689 patients with CKD and hyperkalemia (serum potassium level > 5.0 mEq/L), who visited Kawasaki Medical School Hospital between January 2014 and December 2018. The patients were divided into two groups: those without CPS (calcium polystyrene sulphonate) treatment (CPS_OFF) and those with CPS treatment (CPS_ON). The results showed that the incidence of death was significantly higher in the CPS_OFF group than in the CPS_ON group (22.3% vs. 19.6%, p p = 0.020). These results suggest that potassium binders may reduce the risk of death in patients with CKD and hyperkalemia. We hope that the results of this cohort study will be confirmed in future RCTs

The eNOS-NO pathway attenuates kidney dysfunction via suppression of inflammasome activation in aldosterone-induced renal injury model mice.

Hypertension causes vascular complications, such as stroke, cardiovascular disease, and chronic kidney disease (CKD). The relationship between endothelial dysfunction and progression of kidney disease is well known. However, the relationship between the eNOS-NO pathway and chronic inflammation, which is a common pathway for the progression of kidney disease, remains unexplored. We performed in vivo experiments to determine the role of the eNOS-NO pathway by using eNOS-deficient mice in a hypertensive kidney disease model. All mice were unilateral nephrectomized (Nx). One week after Nx, the mice were randomly divided into two groups: the aldosterone infusion groups and the vehicle groups. All mice also received a 1% NaCl solution instead of drinking water. The aldosterone infusion groups were treated with hydralazine to correct blood pressure differences. After four weeks of drug administration, all mice were euthanized, and blood and kidney tissue samples were collected. In the results, NLRP3 inflammasome activation was elevated in the kidneys of the eNOS-deficient mice, and tubulointerstitial fibrosis was accelerated. Suppression of inflammasome activation by knocking out ASC prevented tubulointerstitial injury in the eNOS knockout mice, indicating that the eNOS-NO pathway is involved in the development of kidney dysfunction through acceleration of NLRP3 inflammasome in macrophages. We revealed that endothelial function, particularly the eNOS-NO pathway, attenuates the progression of renal tubulointerstitial injury via suppression of inflammasome activation. Clinically, patients who develop vascular endothelial dysfunction have lifestyle diseases, such as hypertension or diabetes, and are known to be at risk for CKD. Our study suggests that the eNOS-NO pathway could be a therapeutic target for the treatment of chronic kidney disease associated with endothelial dysfunction