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The aim of the case study is to examine the association between hypertension and the level of bone metabolism markers in newly diagnosed osteoporotic patients. A cross-sectional study of 518 subjects was done to see the association between hypertension and the level of osteocalcin (OC), bone-specific alkaline phosphatase (B-ALP), Tartrate-resistant acid phosphatase (TRAP.5B), and 25-hydroxy vitamin D (25-OHD). There were 243 (46.9%) osteoporosis patients with hypertension. Both univariate and multivariate analysis have suggested that lower OC and 25-OHD levels were associated with hypertension. The potential confounders-adjusted OC level was significantly lower in hypertensive female group than that in the female without hypertension group [β = -0.20, 95% confidence interval (95% CI) = -0.37 to -0.03, P = .02 in final adjust model]. The potential confounders-adjusted 25-OHD level was significantly lower in hypertensive male group than that in male without hypertension group (β = -0.34, 95% CI = -0.58 to -0.10, P = .01 in final adjust model). The B-ALP and TRACP.5B levels were positively associated with hypertension in all patients or subgroup analysis. However, all the correlations had no statistical significance for the B-ALP and TRACP.5B. In conclusion, the hypertension was associated with low level of OC and 25-OHD. Hypertension probably led to low bone turnover, which may be one of the mechanisms of hypertension-related osteoporosis.

The antidiuretic hormone vasopressin (VP) is produced by the hypothalamus and is stored and secreted from the posterior pituitary. VP acts via VP type 2 receptors (V2Rs) on the basolateral membrane of principal cells of the collecting duct (CD) to regulate fluid permeability. The VP-evoked endocrine pathway is essential in determining urine concentrating capability. For example, a defect in any component of the VP signaling pathway can result in polyuria, polydipsia, and hypotonic urine, collectively termed diabetes insipidus (DI). A lack of VP production precipitates central diabetes insipidus (CDI), which can be managed effectively by VP supplementation. A majority of cases of nephrogenic diabetes insipidus (NDI) result from V2R mutations that impair receptor sensitivity. No specific therapy is currently available for management of NDI. Evidence is evolving that (pro)renin receptor (PRR), a newly identified member of the renin-angiotensin system, is capable of regulating VP production and action. As such, PRR should be considered strongly as a therapeutic target for treating CDI and NDI. The current review will summarize recent advances in understanding the physiology of renal and central PRR as it relates to the two types of DI.

Adriamycin (ADR) administration in susceptible rodents such as the BALB/c mouse strain produces injury to the glomerulus mimicking human chronic kidney disease due to primary focal segmental glomerulosclerosis. The goal of the present study was to use this model to investigate antiproteinuric actions of the (pro)renin receptor decoy inhibitor PRO20. BALB/c mice were pretreated for 1 day with PRO20 at 500 μg·kg−1·day−1 via an osmotic minipump followed by a single injection of vehicle or ADR (10 mg/kg) via the tail vein. Albuminuria and renal function were analyzed at the fourth week post-ADR administration. ADR-treated mice exhibited severe proteinuria, hypoalbuminemia and hyperlipidemia, glomerulosclerosis, podocyte loss, tubulointerstitial fibrosis, and oxidative stress, accompanied by elevated urinary neutrophil gelatinase-associated lipocalin and kidney injury molecule-1, all of which were significantly attenuated by PRO20. Urinary and renal renin activity and angiotensin II were elevated by ADR and suppressed by PRO20. In parallel, urinary and renal H2O2 levels and renal NADPH oxidase 4 (Nox4) and transient receptor potential channel C6 (TRPC6) expression in response to ADR were all similarly suppressed. Taken together, the results of the present study provide the first evidence that PRO20 can protect against podocyte damage and interstitial fibrosis in ADR nephropathy by preventing activation of the intrarenal renin-angiotensin system and upregulation of Nox4 and TRPC6 expression. PRO20 may have a potential application in the treatment of ADR nephropathy.

Thiazolidinediones, the PPARgamma agonists, represent a unique class of insulin sensitizers for management of hyperglycemia in type 2 diabetes but are limited by the side effect of fluid retention. Here we report therapeutic potential of histidine-tagged recombinant soluble (pro)renin receptor (sPRR), termed as sPRR-His, in a mouse obesity model induced by 9-month high fat diet (DIO) for management of glucose dysregulation. In the DIO mice, a 2-wk administration of sPRR-His lowered body weight (47.0 ± 1.4 vs. 52.8 ± 1.2 g) and remarkably improved multiple metabolic parameters including hyperglycemia (serum glucose: 148.8 ± 19.1 vs. 224.8 ± 12.5 mg/dL), hyperinsulinemia (serum insulin: 3.7 ± 0.4 vs. 10.9 ± 0.9 ng/ml), glucose intolerance, albuminuria (urine albumin/ Creatinine: 63.4 ± 3.5 vs. 97.7 ± 10.2 mg/g), and glomerular hyperfiltration (GFR: 264.7 ± 12.2 vs. 521.3 ± 18.2 μl/min) in the absence of fluid retention (plasma volume: 28.7 ± 1.2 vs. 27.8 ± 0.9 μl/g). GFR and plasma volume were measured by using FITC-sinistrin (7.5mg/100g i.v.) and FITC-dextran (2 mg/100 g i.v.) respectively. Conversely, inhibition of endogenous sPRR production by PF429242, an inhibitor of site-1 protease induced diabetes and insulin resistance which were reversed by sPRR-His supplement. At cellular level, sPRR-His enhanced insulin-induced increases in glucose uptake via upregulation of phosphorylated AKT and protein abundance of Glut4. Promoter and gene expression analysis revealed PRR as a direct target gene of PPARγ. Adipocyte-specific PPARγ deletion induced severe diabetes (blood glucose: 243.6 ± 39.8 vs. 108.4 ± 2.1 mg/dL) and insulin resistance (plasma insulin: 48.9 ± 4 vs. 1.5 ± 0.2 ng/ml) associated with reduced adipose PRR expression and circulating sPRR (plasma sPRR: 265.7 ± 14 vs. 893.0 ± 86.8 pg/ml). sPRR-His supplement in the null mice nearly normalized blood glucose (142.4 ± 12.2 mg/dL) and insulin level (14.3 ± 7.9 ng/ml). Additionally, sPRR-His treatment suppressed DIO-induced renal sodium-glucose cotransporter-2 (SGLT2) expression. Overall, sPRR-His exerts potent hypoglycemic action via serving as a mediator of insulin-sensitizing action of thiazolidinedione as well as a negative regulator of renal SGLT2 in the absence of fluid retention side effect.

Background Extensive myocardial calcification has a low incidence rate, but when the patients do have extensive myocardial cases, the prognosis is usually poor. Several sepsis-related extensive myocardial calcification cases have been reported, but there are cases of biventricular calcifications that are caused by multiple cases besides bacteremia and the treatment for it has a low percentage of success. Case presentation A 9 year old girl had an extensive biventricular calcification which is caused by multiple factors including multiple organ failure (heart, lung, liver, and kidney), aseptic cardiomyopathy, systemic inflammatory response syndrome, pulmonary hemorrhage, viral encephalitis. In this case study, the massive myocardial calcification present in the patient was classified as dystrophic. After the patient was transferred to the Intensive care unit, a series of rescue treatments such as anti-inflammatory factor storm were implemented to protect the organs. In the end, the patient was rescued from the rescue treatment procedure. After 18 months of follow-up, it was observed that the patient’s heart function returned to normal and it was observed that there was no change in myocardial calcification in the patient. Conclusion In this case study, it showcased a case of the diffused biventricular calcification that caused by multiple factors. Furthermore, the precise role of calcification on cardiac function was largely unknown and there has to be further follow-up observation on the patient.

The therapies available for management of obesity and associated conditions are limited, because they are often directed toward an individual component of metabolic syndrome and are associated with adverse effects. Here, we report the multifaceted therapeutic potential of histidine-tagged recombinant soluble (pro)renin receptor (sPRR), termed sPRR-His, in a mouse model of diet-induced obesity (DIO). In the DIO model, 2-week administration of sPRR-His lowered body weight and remarkably improved multiple metabolic parameters in the absence of fluid retention. Conversely, inhibition of endogenous sPRR production by PF429242 induced diabetes and insulin resistance, both of which were reversed by the sPRR-His supplement. At the cellular level, sPRR-His enhanced insulin-induced increases in glucose uptake via upregulation of phosphorylated AKT and protein abundance of glucose transporter 4. Promoter and gene expression analysis revealed PRR as a direct target gene of PPARγ. Adipocyte-specific PPARγ deletion induced severe diabetes and insulin resistance associated with reduced adipose PRR expression and circulating sPRR. The sPRR-His supplement in the null mice nearly normalized blood glucose and insulin levels. Additionally, sPRR-His treatment suppressed DIO-induced renal sodium-glucose cotransporter-2 (SGLT2) expression. Overall, sPRR-His exhibits a therapeutic potential in management of metabolic syndrome via interaction with PPARγ.

Within the kidney, the (pro)renin receptor (PRR) is predominantly expressed in the collecting duct (CD), particularly in intercalated cells, and it is regulated by the PGE2 receptor EP4 Notably, EP4 also controls urinary concentration through regulation of aquaporin 2 (AQP2). Here, we tested the hypothesis that sequential activation of EP4 and PRR determines AQP2 expression in the CD, thus mediating the antidiuretic action of vasopressin (AVP). Water deprivation (WD) elevated renal PRR expression and urinary soluble PRR excretion in rats. Intrarenal infusion of a PRR decoy peptide, PRO20, or an EP4 antagonist partially prevented the decrease in urine volume and the increase in urine osmolality and AQP2 expression induced by 48-hour WD. In primary cultures of rat inner medullary CD cells, AQP2 expression induced by AVP treatment for 24 hours depended on sequential activation of the EP4 receptor and PRR. Additionally, mice lacking PRR in the CD exhibited increased urine volume and decreased urine osmolality under basal conditions and impaired urine concentrating capability accompanied by severe volume loss and a dangerous level of plasma hyperosmolality after WD. Together, these results suggest a previously undescribed linear AVP/PGE2/EP4/PRR pathway in the CD for regulation of AQP2 expression and urine concentrating capability.

Dahl salt-sensitive (SS) hypertensive rats exhibit increased expression of renal (pro)renin receptor (PRR) and aberrant activation of the intrarenal renin-angiotensin system (RAS) with unclear functional implication. Recent evidence demonstrates that soluble PRR (sPRR) serves as a potential regulator of tubular transport via activating Wnt/ β-catenin pathway in the distal nephron and is derived from the cleavage by site-1 protease (S1P). The present study attempted to define the role of sPRR during salt-sensitive hypertension in SS rats. The effect of S1P inhibitor PF-429242 (PF at 20 mg/kg/d via mini-pump) on blood pressure, proteinuria, and urinary renin were tested in SS rats during high salt loading. In a separate group, a recombinant sPRR (sPRR-His at 20 μg/kg/d) was infused via catheterization of jugular vein to SS rats during PF treatment. In High sodium (HS)-loaded SS rats, administration of PF attenuated the hypertension development (MAP on day 10, HS+PF group: 124.5 ± 4.6 mmHg vs. HS group: 144.1 ± 8.2 mmHg) as assessed by radiotelemetry and proteinuria (HS+PF group: 50.9 ± 5.5 μg/24h vs. HS group: 105.3 ± 7.4 μg/24h). PF treatment reduced HS-stimulated urinary sPRR excretion by 65% in SS rats. Supplement of sPRR restored HS-induced hypertension during PF treatment (MAP on day 10, HS+PF+sPRR-His group: 138.7 ± 6.1 vs. HS+PF group: 124.5 ± 4.6 mmHg) and proteinuria (HS+PF+sPRR-His group: 79.0 ± 5.8 μg/24h vs. HS+PF group: 50.9 ± 5.5 μg/24h) in SS rats. Concurrently, PF treatment reduced HS-stimulated urinary renin activity (by 80%), aldosterone excretion (by 36%) and renal medullary prorenin and renin (by 60%), which were all restored by sPRR-His infusion (1.5- to 3-fold). Indices of Wnt/β-catenin pathway including protein levels of renal cytosolic Axin-2 and nuclear β-catenin as assessed by immunoblotting were elevated by HS (3.4-fold, 2.2-fold respectively) in SS but not SR rats, which were all suppressed by S1P inhibition (by 80% and 50% respectively) and restored by sPRR-His infusion. Given β-catenin signaling as a known regulator of intrarenal RAS, our results suggest that S1P-derived sPRR plays a pathogenic role in salt-sensitive hypertension in SS rats via β-catenin/intrarenal RAS pathway.

Thiazolidinediones (TZDs), which are synthetic peroxisome proliferator-activated receptor subtype-γ (PPARγ), agonists are highly effective for treatment of type 2 diabetes. However, the side effect of fluid retention has significantly limited their application. Most of the previous studies addressing TZD-induced fluid retention employed healthy animals. The underlying mechanism of this phenomenon is still incompletely understood, particularly in the setting of disease state. The present study was undertaken to examine rosiglitazone (RGZ)-induced fluid retention in db/db mice and to further investigate the underlying mechanism. In response to RGZ treatment, db/db mice exhibited an accelerated plasma volume expansion as assessed by hematocrit (Hct) and fluorescent nanoparticles, in parallel with a greater increase in body weight, compared with lean controls. In response to RGZ-induced fluid retention, urinary Na+ excretion and urine volume were significantly increased in lean mice. In contrast, the natriuretic and diuretic responses were significantly blunted in db/db mice. RGZ db/db mice exhibited a parallel decrease in plasma Na+ concentration and plasma osmolality, contrasting to unchanged levels in lean controls. Imunoblotting analysis showed downregulation of renal aquaporin (AQP) 2 expression in response to RGZ treatment in lean mice but not in db/db mice. Renal AQP3 protein expression was unaffected by RGZ treatment in lean mice but was elevated in db/db mice. In contrast, the expression of Na+/H+ exchanger-3 (NHE3) and NKCC2 was unchanged in either mouse strain. Together these results suggest that compared with the lean controls, db/db mice exhibited accelerated plasma volume expansion that was in part due to the inappropriate response of renal water transporters.

The extracellular domain of the (pro)renin receptor (PRR) is cleaved to produce a soluble (pro)renin receptor (sPRR) that is detected in biological fluid and elevated under certain pathological conditions. The present study was performed to define the antidiuretic action of sPRR and its potential interaction with liver X receptors (LXRs), which are known regulators of urine-concentrating capability. Water deprivation consistently elevated urinary sPRR excretion in mice and humans. A template-based algorithm for protein-protein interaction predicted the interaction between sPRR and frizzled-8 (FZD8), which subsequently was confirmed by coimmunoprecipitation. A recombinant histidine-tagged sPRR (sPRR-His) in the nanomolar range induced a remarkable increase in the abundance of renal aquaporin 2 (AQP2) protein in primary rat inner medullary collecting duct cells. The AQP2 up-regulation relied on sequential activation of FZD8-dependent β-catenin signaling and cAMP-PKA pathways. Inhibition of FZD8 or tankyrase in rats induced polyuria, polydipsia, and hyperosmotic urine. Administration of sPRR-His alleviated the symptoms of diabetes insipidus induced in mice by vasopressin 2 receptor antagonism. Administration of the LXR agonist TO901317 to C57/BL6 mice induced polyuria and suppressed renal AQP2 expression associated with reduced renal PRR expression and urinary sPRR excretion. Administration of sPRR-His reversed most of the effects of TO901317. In cultured collecting duct cells, TO901317 suppressed PRR protein expression, sPRR release, and PRR transcriptional activity. Overall we demonstrate, for the first time to our knowledge, that sPRR exerts antidiuretic action via FZD8-dependent stimulation of AQP2 expression and that inhibition of this pathway contributes to the pathogenesis of diabetes insipidus induced by LXR agonism.

Earlier we reported that the recombinant soluble (pro) renin receptor sPRR‐His upregulates renal aquoporin‐2 (AQP2) expression, and attenuates polyuria associated with nephrogenic diabetes insipidus (NDI) induced by vasopressin type 2 receptor (V2R) antagonism. Patients that receive lithium therapy develop polyuria associated NDI that might be secondary to downregulation of renal AQP2. We hypothesized that sPRR‐His attenuates indices of NDI associated with lithium treatment. Eight‐week‐old male C57/BL6 mice consumed chow supplemented with LiCl (40 mmol/kg diets) for 14 days. For the last 7 days mice received either sPRR‐His [30 μg/(kg day), i.v.; sPRR] or vehicle (Veh) via minipump. Control (Con) mice consumed standard chow for 14 days. Compared to Con mice, 14‐d LiCl treatment elevated water intake and urine volume, and decreased urine osmolality, regardless of sPRR‐His or Veh administration. These data indicate that sPRR‐His treatment does not attenuate indices of NDI evoked by lithium. Unexpectedly, epididymal fat mass was lower, adipocyte UCP1 mRNA and protein expression were higher, and multilocular lipid morphology was enhanced, in LiCl‐fed mice treated with sPRR‐His versus vehicle. The beiging of white adipose tissue is a novel metabolic benefit of manipulating the sPRR in the context of lithium‐induced NDI.

The collecting duct (CD) has been recognized as an important source of prorenin/renin, and it also expresses (pro)renin receptor (PRR). The goal of this study was to examine the hypothesis that prorenin or renin via PRR regulates epithelial Na+channel (ENaC) activity in mpkCCD cells. Transepithelial Na+transport was measured by using a conventional epithelial volt-ohmmeter and was expressed as the calculated equivalent current ( Ieq). Amiloride-inhibitable Ieqwas used as a reflection of ENaC activity. Administration of prorenin in the nanomolar range induced a significant increase in Ieqthat was detectable as early as 1 min, peaked at 5 min, and gradually returned to baseline within 15 min. These changes in Ieqwere completely prevented by a newly developed PRR decoy inhibitor, PRO20. Prorenin-induced Ieqwas inhibitable by amiloride. Compared with prorenin, renin was less effective in stimulating Ieq. Prorenin-induced Ieqwas attenuated by apocynin but enhanced by tempol, the latter effect being prevented by catalase. In response to prorenin treatment, the levels of total reactive oxygen species and H2O2were both increased, as detected by spin-trap analysis and reactive oxygen species (ROS)-Glo H2O2assay, respectively. Both siRNA-mediated Nox4 knockdown and the dual Nox1/4 inhibitor GKT137892 attenuated prorenin-induced Ieq. Overall, our results demonstrate that activation of PRR by prorenin stimulates ENaC activity in CD cells via Nox4-derived H2O2.

Background & Aims Microsomal prostaglandin E synthase-2 (mPGES-2) deletion does not influence in vivo PGE 2 production and the function of this enzyme remains elusive. The present study was undertaken to investigate the role of mPGES-2 in streptozotocin (STZ)-induced type-1 diabetes and organ injuries. Methods mPGES-2 wild type (WT) and knockout (KO) mice were treated by a single intraperitoneal injection of STZ at the dose of 120mg/kg to induce type-1 diabetes. Subsequently, glycemic status and organ injuries were evaluated. Results Following 4days of STZ administration, mPGES-2 KO mice exhibited severe lethality in contrast to the normal phenotype observed in WT control mice. In a separate experiment, the analysis was performed at day 3 of the STZ treatment in order to avoid lethality. Blood glucose levels were similar between STZ-treated KO and WT mice. However, the livers of KO mice were yellowish with severe global hepatic steatosis, in parallel with markedly elevated liver enzymes and remarkable stomach expansion. However, the morphology of the other organs was largely normal. The STZ-treated KO mice displayed extensive hepatocyte apoptosis compared with WT mice in parallel with markedly enhanced inflammation and oxidative stress. More interestingly, a liver-specific 50% upregulation of GLUT2 was found in the KO mice accompanied with a markedly enhanced STZ accumulation and this induction of GLUT2 was likely to be associated with the insulin/SREBP-1c pathway. Primary cultured hepatocytes of KO mice exhibited an increased sensitivity to STZ-induced injury and higher cellular STZ content, which was markedly blunted by the selective GLUT2 inhibitor phloretin. Conclusions mPGES-2 deletion enhanced STZ-induced liver toxicity possibly via GLUT2-mediated STZ uptake, independently of diabetes mellitus.