Sodium glucose cotransporter 2 inhibitor suppresses renal injury in rats with renal congestion.

Renal congestion is an issue of cardiorenal syndrome in patients with heart failure. Recent clinical and basic studies suggest a renoprotective potential of sodium-glucose cotransporter (SGLT) 2 inhibitors. However, the effect on renal congestion and its mechanism is not fully understood. Thus, we aimed to clarify the effect of SGLT inhibition in a renal congestion model. Renal congestion was induced in the left kidney of male Sprague-Dawley rats by ligation of the inferior vena cava between the renal veins. The SGLT2 inhibitor tofogliflozin or vehicle was orally administered daily from the day before IVC ligation until two days after surgery. On the third postoperative day, both the right control kidney and the left congested kidney were harvested and analyzed. Kidney weight and water content was increased, and renal injury and fibrosis were observed in the left congested kidney. Kidney weight gain and hydration were improved with tofogliflozin treatment. Additionally, this treatment effectively reduced renal injury and fibrosis, particularly in the renal cortex. SGLT2 expression was observed in the congested kidney, but suppressed in the damaged tubular cells. Molecules associated with inflammation were increased in the congested kidney and reversed by tofogliflozin treatment. Mitochondrial dysfunction provoked by renal congestion was also improved by tofogliflozin treatment. Tofogliflozin protects against renal damage induced by renal congestion. SGLT2 inhibitors could be a candidate strategy for renal impairment associated with heart failure.

Association between an Antioxidant-Rich Japanese Diet and Chronic Kidney Disease: The Ohasama Study.

AIMS: Although physiological effects of hydrophilic- (H-) and lipophilic- (L-) antioxidant capacities (AOCs) are suggested to differ, the association of an antioxidant-rich diet and chronic kidney disease (CKD) incidence has not been examined. We therefore explored the association between the H- or L-AOC of a whole Japanese diet and CKD risk in a general population. METHODS: A total of 922 individuals without CKD (69.2% women; mean age, 59.5 years old) from Ohasama Town, Japan, were examined. CKD incidence was defined as the presence of proteinuria and/or an estimated glomerular filtration rate (eGFR) of ＜60 ml/min/1.73 m2. Consumption of H-/L-AOC was determined based on the oxygen radical absorbance capacity in a specially developed Japanese food AOC database. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for new-onset CKD using a Cox proportional hazards model. RESULTS: During the median follow-up of 9.7 years, 137 CKD incidents were recorded. After adjusting for potential confounding variables, the highest quartile of L-AOC was significantly associated with a 51% reduced CKD risk among only women. An increased L-AOC intake was more effective in preventing eGFR reduction than in preventing proteinuria in women. These associations were not seen for H-AOC intake in both sexes and L-AOC intake in men. CONCLUSIONS: A high intake of lipophilic antioxidants may be associated with a reduced CKD risk. The balance between dietary antioxidant intake and pro-oxidants induced by unhealthy lifestyles may be crucial for preventing future kidney deterioration.

NRIP1 regulates cell proliferation in lung adenocarcinoma cells.

Nuclear receptor interacting protein 1 (NRIP1) is a transcription cofactor that regulates the activity of nuclear receptors and transcription factors. Functional expression of NRIP1 has been identified in multiple cancers. However, the expression and function of NRIP1 in lung adenocarcinoma have remained unclear. Thus, we aimed to clarify the NRIP1 expression and its functions in lung adenocarcinoma cells. NRIP1 and Ki-67 were immunostained in the tissue microarray section consisting of 64 lung adenocarcinoma cases, and the association of NRIP1 immunoreactivity with clinical phenotypes was examined. Survival analysis was performed in lung adenocarcinoma data from The Cancer Genome Atlas (TCGA). Human A549 lung adenocarcinoma cell line with an NRIP1-silencing technique was used in vitro study. Forty-three of 64 cases were immunostained with NRIP1. Ki-67-positive cases were more frequent in NRIP1-positive cases as opposed to NRIP1-negative cases. Higher NRIP1 mRNA expression was associated with poor prognosis in the TCGA lung adenocarcinoma data. NRIP1 was mainly located in the nucleus of A549 cells. NRIP1 silencing significantly reduced the number of living cells, suppressed cell proliferation, and induced apoptosis. These results suggest that NRIP1 participates in the progression and development of lung adenocarcinoma. Targeting NRIP1 may be a possible therapeutic strategy against lung adenocarcinoma.

MPO-ANCA-positive conversion and microscopic polyangiitis development in idiopathic interstitial pneumonia: a case report.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a systemic autoimmune disease characterized by necrotizing inflammation of the small blood vessels. ANCA-associated vasculitis is subclassified into three variants: granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, and microscopic polyangiitis (MPA). Myeloperoxidase (MPO) ANCA is a marker antibody for MPA. Interstitial pneumonia (IP) is occasionally complicated with MPA. However, only a few cases of idiopathic IP develop MPO-ANCA-positive conversion and MPA. Therefore, we present a case of a 70-year-old Japanese man with idiopathic IP who developed MPO-ANCA-positive conversion and MPA. We performed renal biopsy, which revealed pauci-immune crescentic glomerulonephritis. The patient was treated with intravenous methylprednisolone pulse therapy and oral prednisone, and the patient's laboratory data gradually improved with steroid therapy. The association between the production of MPO-ANCA and IP remains unclear, and the present case suggests that IP plays a role in inducing MPO-ANCA production. Patients with idiopathic IP should be followed-up carefully for an examination of increased MPO-ANCA levels and MPA development. In addition, early gastric cancer was detected during upper gastrointestinal endoscopy in our case, and it could also be important not to miss malignancy in patients with ANCA-associated vasculitis.

Association Between Ambulatory Blood Pressure and Risk of Home Hypertension in a Normotensive Population: The Ohasama Study.

BACKGROUND: We investigated the association between ambulatory blood pressure (BP) and the risk of home hypertension in a normotensive population and whether considering ambulatory BP improves the 10-year prediction model for home hypertension risk, which was developed in the previous Ohasama Study. METHODS: In this prospective study, we followed up with 410 participants (83.2% women; age, 53.6 years) without a home and ambulatory hypertension in the general population of Ohasama, Japan. The Cox model was used to assess the hazard ratios (HRs) for home hypertension (home BP ≥ 135/≥85 mmHg or the initiation of antihypertensive treatment) and model improvement. RESULTS: During a mean 14.2-year follow-up, 225 home hypertension incidences occurred. The HR (95% confidence interval) for home hypertension incidence per 1-SD higher (=6.76 mmHg) 24-hour systolic BP (SBP) was 1.59 (1.33 to 1.90), after adjustments for possible confounding factors, including baseline home SBP. Harrell's C-statistics increased from 0.72 to 0.73 (P = 0.11) when 24-hour SBP was added to the basic 10-year home hypertension prediction model, which includes sex, age, body mass index, smoking status, office SBP, and baseline home SBP. Continuous net reclassification improvement (0.53, P < 0.0001) and integrated discrimination improvement (0.028, P = 0.0014) revealed improvement in the model. CONCLUSIONS: A total of 24-hour SBP could be an independent predictor of future home hypertension. Home BP and 24-hour BP can longitudinally influence each other in the long term.

Female Reproductive Events and Subclinical Atherosclerosis of the Brain and Carotid Arteriopathy: the Ohasama Study.

AIMS: Few studies have investigated the subclinical atherosclerotic changes in the brain and carotid artery, and in East Asian populations. We sought to investigate whether gravidity, delivery, the age at menarche and menopause and estrogen exposure period are associated with subclinical atherosclerosis of the brain and carotid arteriopathy. METHODS: This cross-sectional study formed part of a cohort study of Ohasama residents initiated in 1986. Brain atherosclerosis and carotid arteriopathy were diagnosed as white matter hyperintensity (WMH) and lacunae evident on brain magnetic resonance imaging (MRI) and carotid intimal media thickness (IMT) or plaque revealed by ultrasound, respectively. The effect of the reproductive events on brain atherosclerosis and carotid arteriopathy was investigated using logistic regression and general linear regression models after adjusting for covariates. RESULTS: Among 966 women aged ≥ 55 years in 1998, we identified 622 and 711 women (mean age: 69.2 and 69.7 years, respectively) who underwent either MRI or carotid ultrasound between 1992-2008 or 1993-2018, respectively. The highest quartile of gravidity (≥ 5 vs. 3) and delivery (≥ 4 vs. 2), and the highest and second highest (3 vs. 2) quartiles of delivery were associated with an increased risk of WMH and carotid artery plaque, respectively. Neither of age at menarche, menopause, and estrogen exposure period estimated by subtracting age at menarche from age at menopause was associated with atherosclerotic changes of brain and carotid arteries. CONCLUSIONS: Higher gravidity and delivery are associated with subclinical atherosclerosis of the brain and carotid plaque.

(Pro)renin receptor and insulin signalling regulate cell proliferation in MCF-7 breast cancer cells.

(Pro)renin receptor [(P)RR] is related to both the renin-angiotensin system and V-ATPase with various functions including stimulation of cell proliferation. (P)RR is implicated in the pathophysiology of diabetes mellitus and cancer. Hyperinsulinemia is observed in obesity-related breast cancer. However, the relationship between (P)RR and insulin has not been clarified. We have therefore studied the effect of insulin on (P)RR expression, cell viability and AKT phosphorylation under the conditions with and without (P)RR knockdown. Effects of insulin were studied in a human breast cancer cell line, MCF-7. Cell proliferation assay was performed by WST-8 assay. (P)RR expression was suppressed by (P)RR-specific siRNAs. The treated cells were analysed by western blotting and reverse transcriptase-quantitative polymerase chain reaction analysis. Insulin stimulated proliferation of MCF-7 cells and increased (P)RR protein expression, but not (P)RR mRNA levels. Moreover, autophagy flux was suppressed by insulin. Suppression of (P)RR expression reduced cell number of MCF-7 cells and AKT phosphorylation significantly in both the presence and the absence of insulin, indicating that (P)RR is important for cell viability and AKT phosphorylation. In conclusion, insulin upregulates the level of (P)RR protein, which is important for cell viability, proliferation, AKT phosphorylation and autophagy in breast cancer cells.

Inhibition of platelet-derived growth factor pathway suppresses tubulointerstitial injury in renal congestion.

OBJECTIVE: Increased central venous pressure in congestive heart failure is responsible for renal dysfunction, which is mediated by renal venous congestion. Pericyte detachment from capillaries after renal congestion might trigger renal fibrogenesis via pericyte-myofibroblast transition (PMT). Platelet-derived growth factor receptors (PDGFRs), which are PMT indicators, were upregulated in our recently established renal congestion model. This study was designed to determine whether inhibition of the PDGFR pathway could suppress tubulointerstitial injury after renal congestion. METHODS: The inferior vena cava between the renal veins was ligated in male Sprague-Dawley rats, inducing congestion only in the left kidney. Imatinib mesylate or vehicle were injected intraperitoneally daily from 1 day before the operation. Three days after the surgery, the effect of imatinib was assessed by physiological, morphological and molecular methods. The inhibition of PDGFRs against transforming growth factor-ß1 (TGFB1)-induced fibrosis was also tested in human pericyte cell culture. RESULTS: Increased kidney weight and renal fibrosis were observed in the congested kidneys. Upstream inferior vena cava (IVC) pressure immediately increased to around 20 mmHg after IVC ligation in both the imatinib and saline groups. Although vasa recta dilatation and pericyte detachment under renal congestion were maintained, imatinib ameliorated the increased kidney weight and suppressed renal fibrosis around the vasa recta. TGFB1-induced elevation of fibrosis markers in human pericytes was suppressed by PDGFR inhibitors at the transcriptional level. CONCLUSION: The activation of the PDGFR pathway after renal congestion was responsible for renal congestion-induced fibrosis. This mechanism could be a candidate therapeutic target for renoprotection against renal congestion-induced tubulointerstitial injury.

Impact of preoperative factors on catheter position in peritoneal dialysis: a prospective cohort study.

BACKGROUND: Peritoneal dialysis (PD) catheter malposition is one of the complications of renal replacement therapy. This study aimed to determine the preoperative factors that cause PD catheter malposition. METHODS: The prospective cohort study included patients who underwent PD catheter insertion surgery and had preoperative and postoperative computed tomography scans. We compared preoperative and intraoperative factors between the lower depth catheter group (group L) and upper depth catheter group (group U), and preoperative and intraoperative factors between the posterior catheter group (group P) and anterior catheter group (group A). In addition, PD catheter obstruction requiring surgical intervention in each group was followed up for 1 year. RESULTS: A total of 150 patients were categorized into groups L (n = 77) and U (n = 73), or groups P (n = 107) and A (n = 43). Body mass index (BMI; P = 0.02), subcutaneous fat area (P = 0.02), and rate of previous abdominal surgery (P = 0.01) were significantly lower in group L than in group U. In terms of anterior catheter position, females had more-anterior catheter positions. The time to PD catheter obstruction requiring surgical intervention (P = 0.03) was significantly lower in group U than in group L. CONCLUSIONS: High BMI, high subcutaneous fat area, high subcutaneous fat thickness, and previous abdominal surgery were identified as preoperative factors that cause the PD catheter to have an upper depth. Female sex was a preoperative influencing factor for the anterior PD catheter position.

Safety of peritoneal dialysis catheter surgery under dexmedetomidine and local anesthesia for elderly patients in Japan: a single-center prospective cohort study.

BACKGROUND: The number of patients aged ≥ 75 years and who need renal replacement therapy is steadily increasing. The study aimed to determine the safety of open surgery for peritoneal dialysis (PD) catheter placement in such patients. METHODS: This prospective cohort study included patients who underwent PD catheter placement by open surgery under dexmedetomidine (DEX) and local anesthesia at our institution from January 2015 to February 2021. Patients were divided into the following two groups according to age at the time of surgery: ≥ 75 years (group A) and < 75 years (group B). We compared the perioperative and postoperative complications (i.e., time to the first PD-related peritonitis and catheter obstruction requiring surgical intervention within 1 year) between the groups. RESULTS: A total of 118 patients were categorized into groups A (n = 65) and B (n = 53). No significant intergroup differences were observed in the postoperative fever, total duration of surgery, perioperative hemoglobin decrease, changes in the white blood cell count and C-reactive protein, postoperative catheter leakage, postoperative hospital stay, time to the first PD-related peritonitis, and catheter obstruction requiring surgical intervention within 1 year. CONCLUSIONS: The surgery for PD catheter placement by open surgery under DEX and local anesthesia in elderly patients is safe and effective.

The Impact of Preoperative Risk Factors on Peritoneal Dialysis-Related Peritonitis: A Single-Center Prospective Study in Japan.

Background and Objectives: Peritoneal dialysis (PD)-related peritonitis is a critical problem. However, preoperative risk factors for PD-related peritonitis have not been established. Thus, we aimed to determine the preoperative risk factors for PD-related peritonitis. Materials and Methods: This is a single-center prospective observational study. All peritonitis episodes during the study period were recorded, and preoperative and intraoperative clinical parameters were compared between patients with and without peritonitis to examine risk factors for PD-related peritonitis. Furthermore, subcutaneous and abdominal fat volumes were evaluated using computed tomography. Results: Among a total of 118 patients, 24 patients developed peritonitis. The proportion of male patients (83% vs. 61%, p = 0.04), body mass index (25 vs. 22 kg/m2, p = 0.04), and subcutaneous fat area (120 vs. 102 cm2, p = 0.01) were significantly higher and the proportion of patients living with family members (75% vs. 94%, p = 0.02) was significantly lower in the peritonitis group than in the non-peritonitis group. There were no significant differences in age, operation method, surgeon experience, previous abdominal surgery, medical history of diabetic nephropathy, serum albumin level, and renal function between the two groups. Conclusions: Male patients with high subcutaneous fat who are living alone might be at higher risk of PD-related peritonitis. These characteristics might be useful in risk assessment and patient education before PD induction.

Prediction Models for the 5- and 10-Year Incidence of Home Morning Hypertension: The Ohasama Study.

BACKGROUND: We aimed to develop risk prediction models for new-onset home morning hypertension. METHODS: We followed up 978 participants without home hypertension in the general population of Ohasama, Japan (men: 30.1%, age: 53.3 years). The participants were divided into derivation (n = 489) and validation (n = 489) cohorts by their residential area. The C-statistics and calibration plots were assessed after the 5- or 10-year follow-up. RESULTS: In the derivation cohort, sex, age, body mass index, smoking, office systolic blood pressure (SBP), and home SBP at baseline were selected as significant risk factors for new-onset home hypertension (≥135/85 mm Hg or the initiation of antihypertensive treatment) using the Cox model. In the validation cohort, Harrell's C-statistic for the 5-/10-year home hypertension was 0.7637 (0.7195-0.8100)/0.7308 (0.6932-0.7677), when we used the full model, which included the significant risk factors in the derivation cohort. The calibration test revealed good concordance between the observed and predicted 5-/10-year home hypertension probabilities (P ≥ 0.19); the regression slope of the observed probability on the predicted probability was 1.10/1.02, and the intercept was -0.04/0.06, respectively. A model without home SBP was also developed; for the 10-year home hypertension risk, the calibration test revealed a good concordance (P = 0.19) but Harrell's C-statistic was 0.6689 (0.6266-0.7067). CONCLUSIONS: The full model revealed good ability to predict the 5- and 10-year home morning hypertension risk. Although the model without home SBP is acceptable, the low C-statistic implies that home BP should be measured to predict home morning hypertension precisely.

Elevated (Pro)renin Receptor Expression by Anti-Cancer Drugs, Carboplatin and Paclitaxel, in Cultured Cancer Cells: Possible Involvement of Apoptosis and Autophagy.

(Pro)renin receptor [(P)RR] is a component of the renin-angiotensin system and plays an essential role in the activity of vacuolar H+-ATPase and autophagy. (P)RR is expressed in cancer cells. However, the relationship among (P)RR, apoptosis and autophagy in the treatment of anti-cancer drugs has not been clarified. The aim of this study was to clarify the effects of anti-cancer drugs with autophagy-promoting activity on (P)RR expression in cancer cells. MCF-7 breast cancer cells and A549 lung cancer cells were treated with carboplatin or paclitaxel, and the expression of (P)RR, apoptosis markers and autophagy markers were assessed by RT-qPCR, western blot analysis and immunocytochemistry. Expression levels of (P)RR mRNA and soluble (P)RR protein were increased by carboplatin or paclitaxel in a dose-dependent manner. Immunofluorescence staining of (P)RR was increased in both MCF-7 and A549 cells treated by carboplatin or paclitaxel. Apoptosis induction was shown by elevated BAX/BCL2 mRNA levels and increased active caspase3-positive cells. Moreover, autophagy induction was confirmed by increased levels of autophagy-associated mRNAs and LC3B-II proteins. (P)RR knockdown by (P)RR-specific siRNA suppressed the cell viability in MCF-7 cells and A549 cells under the treatment of carboplatin or paclitaxel, suggesting that (P)RR deficiency inhibits the proliferation of cancer cells in a pathway different from carboplatin or paclitaxel. The present study showed that the expression of (P)RR mRNA and soluble (P)RR was increased by anti-cancer drugs with autophagy-promoting activity. Upregulated (P)RR and autophagy may constitute a stress adaptation that protects cancer cells from apoptosis.

Metformin slows liver cyst formation and fibrosis in experimental model of polycystic liver disease.

Polycystic liver disease (PLD) is a hereditary liver disease in which the number of cysts increases over time, causing various abdominal symptoms and poor quality of life. Although effective treatment for PLD has not been established, we recently reported that long-term exercise ameliorated liver cyst formation and fibrosis with the activation of AMP-activated protein kinase (AMPK) in polycystic kidney (PCK) rats, a PLD model. Therefore, the aim of this study was to investigate whether metformin, an indirect AMPK activator, was effective in PCK rats. PCK rats were randomly divided into a control (Con) group and a metformin-treated (Met) group. The Met group was treated orally with metformin in drinking water. After 12 wk, liver function, histology, and signaling cascades of PLD were examined in the groups. Metformin did not affect the body weight or liver weight, but it reduced liver cyst formation, cholangiocyte proliferation, and fibrosis around the cyst. Metformin increased the phosphorylation of AMPK and tuberous sclerosis complex 2 and decreased the phosphorylation of mammalian target of rapamycin, S6, and extracellular signal-regulated kinase and the expression of cystic fibrosis transmembrane conductance regulator, aquaporin I, transforming growth factor-ß, and type 1 collagen without changes in apoptosis or collagen degradation factors in the liver. Metformin slows the development of cyst formation and fibrosis with the activation of AMPK and inhibition of signaling cascades responsible for cellular proliferation and fibrosis in the liver of PCK rats.NEW & NOTEWORTHY This study indicates that metformin, an indirect AMPK activator slows liver cyst formation and fibrosis in PLD rat model. Metformin attenuates excessive cell proliferation in the liver with the inactivation of mTOR and ERK pathways. Metformin also reduces the expression of proteins responsible for cystic fluid secretion and liver fibrosis. Metformin and AMPK activators may be potent drugs for polycystic liver disease.

Fabry Nephropathy in a Young Female Patient Presenting with Only Urinary Mulberry Bodies Treated with Chaperone Therapy.

Fabry disease (FD) is an X-linked disorder of the sphingolipid metabolism, caused by deficiency or decreased activity of α-galactosidase A. We report a rare case of Fabry nephropathy (FN) in a 21-year-old Japanese female patient presenting with only urinary mulberry bodies; she was treated with pharmacological chaperone therapy (PCT) after renal biopsy. The patient underwent a detailed examination because her mother was diagnosed with FD in the Division of Community Medicine of our hospital. She did not have renal dysfunction or proteinuria, and only mulberry bodies were detected in the urine. The activity of α-galactosidase A was low, and genetic analysis revealed the R301Q mutation. A percutaneous renal biopsy was performed, and the findings revealed enlargement and vacuolation of glomerular podocytes by light microscopy, and myelin and zebra bodies were detected in podocytes by electron microscopy. She was diagnosed with FN by renal biopsy and gene analysis. PCT was selected as the treatment to prevent cardiac events and renal dysfunction. The present case suggests that renal biopsy may be necessary even for young women with only mulberry bodies for the diagnosis of FN. It could be useful to evaluate the effect of treatment using the counts of mulberry bodies in the urine. In addition, due to its oral administration, PCT may be suitable for patients who are unable to visit the hospital frequently.

A case of light chain (AL) amyloidosis with heart failure, renal dysfunction, and heparin-induced thrombocytopenia successfully treated with peritoneal dialysis.

A 65-year-old woman was hospitalized for heart failure and pneumonia in a nearby hospital. She had been previously diagnosed as light chain (AL) amyloidosis and treated with melphalan plus dexamethasone (Mel-Dex), and lenalidomide plus dexamethasone (Len-Dex). She started treatment including antimicrobials and diuretics, but her renal function worsened progressively, and she was transferred to our hospital for nephrological care. She was treated with antimicrobials, noradrenaline, dobutamine, and continuous hemodiafiltration. Her general condition gradually stabilized, and she was switched to intermittent hemodialysis (HD). However, HD was discontinued due to intradialytic hypotension and the development of heparin-induced thrombocytopenia. Her renal replacement therapy was switched to peritoneal dialysis (PD), which enabled good volume control and stable cardiac function. She was discharged and is still in good condition, without serious complications and achieving a considerably better prognosis than was predicted. Our case suggests that PD is an effective modality for patients with AL amyloidosis with heart failure and renal dysfunction.

(Pro)renin receptor/ATP6AP2 is required for autophagy and regulates proliferation in lung adenocarcinoma cells.

(Pro)renin receptor ((P)RR)/ ATP6AP2 (ATPase, H+ transporting, lysosomal accessory protein 2) functions as an essential accessory subunit of vacuolar H+ -ATPase (V-ATPase). V-ATPase is necessary for lysosome function and autophagy. Autophagy is related to cell proliferation, migration and invasion of various cancer cells. In this study, we aim to clarify the relationship between (P)RR and autophagy in lung adenocarcinoma. Expression of (P)RR and Ki-67 (a proliferation marker) was studied in sixty-four adenocarcinoma cases by immunohistochemistry. Lung adenocarcinoma cell line, A549, was transfected with (P)RR-specific siRNA. Autophagy inhibitors, bafilomycin A1 and chloroquine, were used as positive controls. Cell proliferation and migration were measured by WST-8 assay and wound healing assay. Autophagosome markers, p62 and LC3, were analyzed by RT-qPCR, Western blot and immunocytochemistry. Immunohistochemistry showed that (P)RR was expressed in all adenocarcinoma tissues. The intensity of (P)RR immunoreactivity was significantly associated with Ki-67. Treatment of (P)RR-specific siRNA suppressed (P)RR expression and significantly reduced cell proliferation and migration as did the autophagy inhibitors. Western blot and immunocytochemistry showed that (P)RR-specific siRNA, as well as the autophagy inhibitors, induced p62 and LC3 accumulation in cytoplasmic granules. These results suggest that (P)RR is involved in cell proliferation and progression of lung adenocarcinoma via regulating autophagy.

Blood Pressure and Chronic Kidney Disease Stratified by Gender and the Use of Antihypertensive Drugs.

Background The present study assessed the association between blood pressure (BP) and the risk of chronic kidney disease (CKD) according to gender and the use of antihypertensive drugs using data from a large-scale health checkup. Methods and Results We conducted a retrospective cohort study using the JMDC database, which contains annual health checkup data of Japanese employees and their dependents aged <75 years. We included 154 692 participants (men, 69.68%; mean age, 44.74 years) without CKD. CKD was indicated by an estimated glomerular filtration rate <60 mL/min per 1.73 m2 or the presence of proteinuria. During the mean follow-up period of 4.78 years, new-onset CKD occurred in 14 888 participants. When the normal BP group (systolic/diastolic BP <120/<80 mm Hg) without treatment was used as a reference, the hazard ratios of the high BP (130-139/80-89 mm Hg) and grade 1 (140-159/90-99 mm Hg) and grade 2 or 3 hypertension (≥160/≥100 mm Hg) groups were 1.11 (95% CI, 1.06-1.17), 1.36 (95% CI, 1.28-1.45), and 1.76 (95% CI, 1.56-1.99) for untreated men, respectively. However, in treated men, even normal BP was associated with a 1.5-fold higher risk of CKD. The association between BP and the risk of CKD was weaker in untreated women than in untreated men. The risk of CKD in treated women with normal BP was similar to that of untreated women with normal BP. Conclusions Gender differences were found in the association between BP and CKD risk. Kidney function in treated individuals should be followed carefully, especially in men.

ATP6AP2 variant impairs CNS development and neuronal survival to cause fulminant neurodegeneration.

Vacuolar H+-ATPase-dependent (V-ATPase-dependent) functions are critical for neural proteostasis and are involved in neurodegeneration and brain tumorigenesis. We identified a patient with fulminant neurodegeneration of the developing brain carrying a de novo splice site variant in ATP6AP2 encoding an accessory protein of the V-ATPase. Functional studies of induced pluripotent stem cell-derived (iPSC-derived) neurons from this patient revealed reduced spontaneous activity and severe deficiency in lysosomal acidification and protein degradation leading to neuronal cell death. These deficiencies could be rescued by expression of full-length ATP6AP2. Conditional deletion of Atp6ap2 in developing mouse brain impaired V-ATPase-dependent functions, causing impaired neural stem cell self-renewal, premature neuronal differentiation, and apoptosis resulting in degeneration of nearly the entire cortex. In vitro studies revealed that ATP6AP2 deficiency decreases V-ATPase membrane assembly and increases endosomal-lysosomal fusion. We conclude that ATP6AP2 is a key mediator of V-ATPase-dependent signaling and protein degradation in the developing human central nervous system.