Sodium-glucose cotransporter-2 inhibitors increase urinary tract infections?-a cross sectional analysis of a nationwide Japanese claims database.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a novel class of antidiabetic drugs. Guidelines for the proper use of SGLT2 inhibitors recommend caution regarding urinary tract infections (UTIs). However, little evidence has been reported on the relationship between SGLT2 inhibitors and UTIs in large epidemiological studies. We investigated (1) the relationship between diabetes mellitus (DM) and UTIs and (2) the relationship between SGLT2 inhibitor prescriptions and the likelihood of developing UTIs in patients with DM, using a nationwide Japanese health insurance claims database by MDV analyzer®. We found that the incidence of UTIs was significantly higher among patients with DM than among those without DM (odds ratio (OR), 1.71; 95% confidence interval (CI), 1.69-1.72, for male; OR, 1.90; 95% CI, 1.89-1.92 for female). In contrast, in male patients with DM, the prescription of SGLT2 inhibitors was negatively associated with the likelihood of developing UTIs (OR, 0.74; 95% CI, 0.72-0.75). Among female patients with DM, there was no significant difference in the incidence of UTIs with or without an SGLT2 inhibitor prescription (OR, 0.99; 95% CI, 0.96-1.01). Subgroup analyses by age confirmed similar relationships between SGLT2 inhibitor prescriptions and UTIs, except for female patients aged ≤39 years, in whom SGLT2 inhibitor prescription was negatively associated with the likelihood of developing UTIs. In conclusion, our analysis of a nationwide claims database found no evidence that SGLT2 inhibitors increase UTIs in Japanese patients with DM, regardless of sex or age.

The sexual dimorphism of kidney growth in mice and humans.

Kidney mass and function are sexually determined, but the cellular events and the molecular mechanisms involved in this dimorphism are poorly characterized. By combining female and male mice with castration/replacement experiments, we showed that male mice exhibited kidney overgrowth from five weeks of age. This effect was organ specific, since liver and heart weight were comparable between males and females, regardless of age. Consistently, the androgen receptor was found to be expressed in the kidneys of males, but not in the liver. In growing mice, androgens led to kidney overgrowth by first inducing a burst of cell proliferation and then an increase of cell size. Remarkably, androgens were also required to maintain cell size in adults. In fact, orchiectomy resulted in smaller kidneys in a matter of few weeks. These changes paralleled the changes of the expression of ornithine decarboxylase and cyclin D1, two known mediators of kidney growth, whereas, unexpectedly, mTORC1 and Hippo pathways did not seem to be involved. Androgens also enhanced kidney autophagy, very likely by increasing transcription factor EB nuclear translocation. Functionally, the increase of tubular mass resulted in increased sodium/phosphate transport. These findings were relevant to humans. Remarkably, by studying living gender-paired kidney donors-recipients, we showed that tubular cell size increased three months after transplantation in men as compared to women, regardless of the donor gender. Thus, our results identify novel signaling pathways that may be involved in androgen-induced kidney growth and homeostasis and suggest that androgens determine kidney size after transplantation.

Inhibition of sodium-glucose cotransporter 2 suppresses renal stone formation.

BACKGROUND AND AIMS: Nephrolithiasis is a common renal disease with no effective medication. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, an anti-diabetic agent, have diuretic and anti-inflammatory properties and could prevent nephrolithiasis. Here, we investigated the potential of SGLT2 inhibition against nephrolithiasis using large-scale epidemiological data, animal models, and cell culture experiments. METHODS: This study included the data of diabetic patients (n = 1,538,198) available in the Japanese administrative database and divided them according to SGLT2 inhibitor prescription status. For animal experiments, renal calcium oxalate stones were induced by ethylene glycol in Sprague-Dawley rats, and phlorizin, an SGLT1/2 inhibitor, was used for the treatment. The effects of SGLT2-specific inhibition for renal stone formation were assessed in SGLT2-deficient mice and a human proximal tubular cell line, HK-2. RESULTS: Nephrolithiasis prevalence in diabetic men was significantly lower in the SGLT2 inhibitor prescription group than in the non-SGLT2 inhibitor prescription group. Phlorizin attenuated renal stone formation and downregulated the kidney injury molecule 1 (Kim1) and osteopontin (Opn) expression in rats, with unchanged water intake and urine volume. It suppressed inflammation and macrophage marker expression, suggesting the role of the SGLT2 inhibitor in reducing inflammation. SGLT2-deficient mice were resistant to glyoxylic acid-induced calcium oxalate stone formation with reduced Opn expression and renal damages. High glucose-induced upregulation of OPN and CD44 and cell surface adhesion of calcium oxalate reduced upon SGLT2-silencing in HK-2 cells. CONCLUSION: Overall, our findings identified that SGLT2 inhibition prevents renal stone formation and may be a promising therapeutic approach against nephrolithiasis.

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.

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.

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.

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.

(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.

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.

Blood Pressure Phenotypes Defined by Ambulatory Blood Pressure Monitoring and Carotid Artery Changes in Community-Dwelling Older Japanese Adults: The Ohasama Study.

White coat hypertension is defined as elevated blood pressure in the office, but a normal blood pressure out-of-office, whereas masked hypertension is defined as elevated blood pressure in the office, but normal out-of-office blood pressure. The objective was to investigate the associations between these blood pressure phenotypes and carotid artery changes. Conventional blood pressure, ambulatory blood pressure, and carotid ultrasonography were evaluated in 851 Ohasama residents (31.8% men; mean age 66.3 years). The blood pressure phenotypes were defined by the ordinary thresholds (140/90 mmHg for conventional blood pressure, 135/85 mmHg for daytime blood pressure) and then by the 2017 American College of Cardiology/American Heart Association (ACC/AHA) thresholds for hypertension (130/80 mmHg for both conventional and daytime blood pressure), irrespective of antihypertensive medication treatment status. Blood pressure phenotypes were linearly associated with the mean intima-media thickness of the carotid artery in ascending order for sustained normal blood pressure, white coat hypertension, masked hypertension, and sustained hypertension according to the ordinary thresholds and the 2017 ACC/AHA thresholds (both linear trends P < 0.0001) after adjustments for possible confounding factors. The odds ratios for the presence of carotid plaques showed similar linear trends with the blood pressure phenotypes according to the 2017 ACC/AHA thresholds (linear trend P < 0.0191). In conclusion, there was a close relationship between blood pressure phenotypes and carotid artery changes, suggesting that blood pressure phenotypes as defined by ambulatory blood pressure are potentially useful for risk stratification of carotid artery changes in the Japanese general population.

Hydrochlorothiazide ameliorates polyuria caused by tolvaptan treatment of polycystic kidney disease in PCK rats.

BACKGROUND: Tolvaptan is an effective treatment for polycystic kidney disease (PKD), but also causes unfortunate polyuria. Hydrochlorothiazide (HCTZ) has been shown to reduce urine volume in nephrogenic diabetes insipidus, raising the possibility that HCTZ could also be effective in reducing tolvaptan-induced polyuria. In this study, we examined the combined administration of HCTZ and tolvaptan. METHODS: Male PCK rats were divided into four groups of normal chow (Cont), normal chow plus tolvaptan, gavage HCTZ treatment, and tolvaptan + HCTZ. Biochemical examinations of the plasma and urine were performed as well as histological and molecular (mRNA and protein expression) analyses. RESULTS: Groups treated with tolvaptan had significantly higher 24 h urine excretion, which was significantly reduced in the tolvaptan + HCTZ group after 2 weeks. Cyst size, pERK protein expression, and Cyclin D1 mRNA expression were all significantly reduced in both the tolvaptan and tolvaptan + HCTZ groups, indicating that HCTZ did not affect the beneficial functions of tolvaptan. Notably, aquaporin 2 redistribution from the apical to intracellular domains was observed in tolvaptan-treated rats and was partially reversed in the tolvaptan + HCTZ group. The renal glomerular filtration rate was reduced in the tolvaptan + HCTZ group. Significantly lowered mRNA expression of neuronal nitric oxide synthase, prostaglandin E synthase 2 and renin were also found in the medulla, but not in the cortex. CONCLUSION: HCTZ reduces tolvaptan-induced polyuria without altering its beneficial effects on PKD. This novel therapeutic combination could potentially lead to better PKD treatments and improved quality of life for the affected patients.

N-Terminal Pro-B-Type Natriuretic Peptide Is Not a Significant Predictor of Stroke Incidence After 5 Years　- The Ohasama Study.

BACKGROUND: N-terminal pro-B-type natriuretic peptide (NT-proBNP) has been used for risk stratification in heart failure or acute coronary syndrome, but the beyond 5-year predictive value of NT-proBNP for stroke remains an unsettled issue in Asian patients. The aim of the present study was to clarify this point.Methods and Results:We followed 1,198 participants (33.4% men; mean age, 60.5±11.1 years old) in the Japanese general population for a median of 13.0 years. A first stroke occurred in 93 participants. Referencing previous reports, we stratified participants according to NT-proBNP 30.0, 55.0, and 125.0 pg/mL. Using the NT-proBNP <30.0 pg/mL group as a reference, adjusted HR for stroke (95% CI) in the NT-proBNP 30.0-54.9-pg/mL, 55.0-124.9-pg/mL, and ≥125.0-pg/mL groups were 1.92 (0.94-3.94), 1.77 (0.85-3.66), and 1.99 (0.86-4.61), respectively. With the maximum follow-up period set at 5 years, the hazard ratio of the NT-proBNP≥125.0-pg/mL group compared with the <30.0-pg/mL group increased significantly (HR, 4.51; 95% CI: 1.03-19.85). On extension of the maximum follow-up period, however, the association between NT-proBNP and stroke risk weakened. CONCLUSIONS: NT-proBNP was significantly associated with an elevated stroke risk. Given, however, that the predictive power decreased with the number of years after NT-proBNP measurement, NT-proBNP should be re-evaluated periodically in Asian patients.

Genome-wide association study for white coat effect in Japanese middle-aged to elderly people: The HOMED-BP study.

BACKGROUND: White coat effect (WCE), the blood pressure (BP) difference between clinical and non-clinical settings, can lead to clinical problems such as misdiagnosis of hypertension. Etiology of WCE has been still unclear, especially from genetic aspects. The present article investigated association between genome-wide single nucleotide polymorphisms (SNPs) and WCE in patients with essential hypertension. METHODS: The present cross-sectional analyses were based on 295 Japanese essential hypertensive outpatients aged ≧40 years enrolled in randomized control study, Hypertension Objective Treatment Based on Measurement by Electrical Devices of Blood Pressure (HOMED-BP) study, who were not taking antihypertensive medications before the randomization. Home and clinic BP were measured. WCE was defined by subtracting home BP from clinic BP. Genotyping was conducted with 500K DNA microarray chips. Association between genome-wide SNPs and WCE were analyzed. For replication (p < 10-4), we analyzed participants from Ohasama study who took no antihypertension medications and whose SNPs were collected. RESULTS: Genome-wide SNPs were not significantly associated with WCE of systolic and diastolic BP after corrections of multiple comparisons (p < 2 × 10-7). We found suggestive SNPs associated with WCE of systolic and diastolic BP (p < 10-4). However, the consistent results were not obtained in the replication study. CONCLUSION: The present article showed no significant association between genome-wide SNPs and WCE. Since there were several suggestive SNPs associated with WCE, the present study warrants a further study with bigger sample size for investigating the genetic influence on WCE.

Better Healing of the Exit Site with Negative-Pressure Wound Therapy.

Exit-site infection poses a risk for peritonitis and can shorten peritoneal dialysis (PD) vintage. A loose fit of the skin around the catheter at the exit site can push bacteria surrounding the catheter into the subcutaneous tunnel. Negative-pressure wound therapy (NPWT) has been used to hasten healing of the wound after an operation or to treat pressure ulcers. We hypothesized that NPWT could speed the healing of the exit site and tighten the fit of the skin around the catheter. Using a V.A.C. Therapy system [vacuum-assisted closure (KCI, San Antonio, TX, U.S.A.)], NPWT was therefore applied in 9 patients for 1 - 2 weeks after the PD catheter insertion operation. Results in those patients were compared with results in patients who did not receive NPWT.The healed exit site was classified as either tightly fitted (when the skin was tightly connected around the PD catheter) or loosely fitted (when the skin was not tightly connected around the catheter). The relevant data were retrieved from the medical record and analyzed retrospectively.Patients who received NPWT had a tight exit site after 1 - 2 weeks. Those who did not receive NPWT did not have a tight exit site after 1 - 2 weeks. No bleeding was observed in patients receiving NPWT. Bleeding from the exit site after the catheter insertion operation was observed in 3 patients not receiving NPWT.Because we use a fine trocar to make the subcutaneous catheter tunnel, bleeding from the vasculature can often be observed. That bleeding could be minimized with the application of NPWT. Negative pressure could also hasten wound healing and result in a tight fit of the skin around the catheter within in 1 - 2 weeks compared with the 1 month typically required with the use of conventional film dressings.Negative-pressure wound therapy is beneficial for creating a tight fit of the skin to the catheter within 1 - 2 weeks and might reduce the number of exit-site and tunnel infections, which could result in a reduction in the peritonitis rate.

Expression of (Pro)renin Receptor During Rapamycin-Induced Erythropoiesis in K562 Erythroleukemia Cells and Its Possible Dual Actions on Erythropoiesis.

(Pro)renin receptor ((P)RR), a specific receptor for renin and prorenin, is expressed in erythroblastic cells. (P)RR has multiple biological actions: prorenin activation, stimulation of the intracellular signaling including extracellular signal-regulated kinases, and functional complex formation with vacuolar H+-ATPase (v-ATPase). However, the functional implication of (P)RR in erythroblast cells has not been clarified. The aim of the present study was to clarify changes of (P)RR expression during erythropoiesis and a role of (P)RR in the heme synthesis. (P)RR expression was studied during rapamycin-induced erythropoiesis in a human erythroleukemia cell line, K562. Treatment with rapamycin (100 nM) for 48 hours significantly increased %number of hemoglobin-producing cells, γ-globin mRNA levels, erythroid specific 5-aminolevulinate synthase (ALAS2) mRNA levels, and heme content in K562 cells. Both (P)RR protein and mRNA levels increased about 1.4-fold during rapamycin-induced erythropoiesis. Suppression of (P)RR expression by (P)RR-specific small interference RNA increased ALAS2 mRNA levels about 1.6-fold in K562 cells, compared to control using scramble RNA, suggesting that (P)RR may down-regulate ALAS2 expression. By contrast, treatment with bafilomycin A1, an inhibitor of v-ATPase, decreased greatly % number of hemoglobin-producing cells and heme content in K562 cells, indicating that the v-ATPase function is essential for hemoglobinization and erythropoiesis. Treatment with bafilomycin A1 increased (P)RR protein and mRNA levels. In conclusion, we propose that (P)RR has dual actions on erythropoiesis: the promotion of erythropoiesis via v-ATPase function and the down-regulation of ALAS2 mRNA expression. Thus, (P)RR may contribute to the homeostatic control of erythropoiesis.

Water Deprivation Increases (Pro)renin Receptor Levels in the Kidney and Decreases Plasma Concentrations of Soluble (Pro)renin Receptor.

Water deprivation activates the renin-angiotensin system. We have hypothesized that the renal expression of (pro)renin receptor ((P)RR), a specific receptor for renin and prorenin, could be changed under dehydration. Moreover, plasma levels of soluble (P)RR (s(P)RR) comprising of the extracellular domain of (P)RR may reflect the renal (P)RR expression. In the present study, we therefore aimed to clarify changes of plasma s(P)RR concentrations and kidney tissue (P)RR levels using rats with dehydration. Male Wister-Kyoto rats were divided into two groups; dehydrated (DH) rats deprived of water for 72 hours with free access to food, and control rats. Plasma s(P)RR concentrations measured by enzyme-linked immunosorbent assay were significantly lower in DH rats (6.94 ± 2.08 ng/mL, mean ± SD, n = 5) than in control (12.54 ± 2.00 ng/mL, n = 5) (p < 0.05). Western blot analysis confirmed lower expression levels of s(P)RR in plasma in DH rats than in control. By contrast, western blot analysis showed higher levels of full-length (P)RR and lower levels of furin (an enzyme responsible for generation of s(P)RR from full-length (P)RR) in the kidney tissues obtained from DH rats compared to control. There was no significant difference in the renal (P)RR mRNA levels between DH rats and control. These findings suggest that water deprivation may elevate the renal full-length (P)RR levels via reducing the expression of furin. Increased full-length (P)RR may contribute to the up-regulation of the renal renin-angiotensin system and the production of concentrated urine under dehydration.

A functional (pro)renin receptor is expressed in human lymphocytes and monocytes.

The renin-angiotensin system (RAS) is involved in inflammation. The signaling via the ANG II type 1 receptor in human lymphocytes and monocytes, which play key roles in pathophysiology of glomerulonephritis (GN), can enhance inflammation. However, the role of the (pro)renin receptor [(P)RR], a component of the RAS, in inflammatory reactions is unknown. We assessed whether (P)RR is expressed in human lymphocytes and monocytes by RT-PCR, Western blotting, flow cytometry, and immunohistochemistry, and whether (P)RR functions in inflammation. (P)RR mRNA and protein were expressed in human peripheral blood mononuclear cells (PBMCs). Flow cytometric analysis revealed high expression of (P)RR on monocytes. (P)RR was present on PBMCs, infiltrating lymphocytes, and macrophages around glomeruli with a crescent in anti-neutrophil cytoplasmic antibody (ANCA)-associated GN. Renin stimulation of PBMCs from healthy subjects in the presence of the ANG II type 1 receptor and ANG II type 2 receptor blockers induced ERK1/2 phosphorylation and release of IL-6 and expression of cyclooxygenase-2 (COX-2). The increases in cytokine release and COX-2 expression were inhibited in the presence of an ERK1/2 inhibitor. (P)RR knockdown by small interfering RNA in U937 cells, a human leukemic monocyte lymphoma cell line, significantly decreased ERK1/2 phosphorylation after renin stimulation. Thus (P)RR expressed in human inflammatory cells might contribute to inflammation in ANCA-associated GN.

Aldosterone-to-renin ratio and nocturnal blood pressure decline assessed by self-measurement of blood pressure at home: the Ohasama Study.

Based on ambulatory blood pressure (BP) monitoring, the aldosterone-to-renin ratio (ARR) has been reported to be associated with a diminished nocturnal decline in BP, generally referred to as a "non-dipping" pattern. The objective of this cross-sectional study was to investigate the association between ARR and the non-dipping pattern based on home BP measurements. This study included 177 participants≥55 years from the general population of Ohasama (mean age: 67.2 years; 74.6% women); no patient was receiving antihypertensive treatment. The median plasma renin activity (PRA), plasma aldosterone concentration (PAC) and ARR were 0.8 ng/mL/h, 8.1 ng/dL and 9.7 ng/dL per ng/mL/h, respectively. Each 1 SD increase in log-transformed (ln) ARR was significantly associated with the prevalence of the non-dipping pattern after adjustments for possible confounding factors including home morning systolic BP (odds ratio, 1.45; p=0.049). However, no significant associations of PRA or PAC with the non-dipping pattern were observed (p≥0.2). When participants were divided into four groups according to median levels of home morning and night-time systolic BPs, the group with a higher home morning systolic BP (≥128.4 mmHg) with a higher home night-time systolic BP (≥114.4 mmHg) had the greatest ARR levels (ANCOVA p=0.01). These results support the hypothesis that relative aldosterone excess may be related to a non-dipping pattern in a general population and suggest that a non-dipping pattern can be accurately observed by home BP measurements.

Personality traits as predictors of decline in higher-level functional capacity over a 7-year follow-up in older adults: the Ohasama study.

Numerous factors that affect functional decline have been identified, and personality traits are considered to be an important factor in functional decline risk. The Tokyo Metropolitan Institute of Gerontology Index of Competence (TMIG) was developed to measure three higher-level functional capacities, instrumental activities of daily living, intellectual activity, and social roles, in Japanese elderly, which were previously not assessed adequately with existing scales of functional decline. The objective of this study was to explore the effect of personality traits as predictors of higher-level functional decline over a 7-year follow-up in a rural Japanese community. Data on 676 participants (mean 67.1 years) who were free of functional decline and had completed questionnaires at baseline and 7 years later, were analyzed. Demographic characteristics, lifestyle and personality characteristics were obtained from a self-administered questionnaire at baseline. Higher-level functional decline was examined using the subscales of the TMIG at baseline and at a 7-year follow-up examination. Over the 7-year study period, 21.7% of eligible participants reported decline in higher-level functional capacity. After adjustment for putative confounding factors, the traits that were significant predictors of decline in higher-level functional capacity at the 7-year follow-up had higher psychoticism scores [odds ratio (95% confidence interval) 2.12 (1.23-3.66)] and lower extraversion scores [1.89 (1.01-3.56)]. The personality traits of higher psychoticism and lower extraversion were significantly associated with a risk of future functional decline. A better understanding of these personality traits may help identify of at-risk individuals and could help reduce functional decline in older adults.