Usefulness of random-start progestin-primed ovarian stimulation for fertility preservation.

BACKGROUND: Progestin-primed ovarian stimulation (PPOS) has been used in infertility cases in recent years, and several reports have stated that it has oocyte collection results similar to those of gonadotropin-releasing hormone antagonist (GnRH-ant) protocol. For emergency fertility preservation, random-start ovarian stimulation is usually recommended. Therefore we compared the clinical outcomes of random-start PPOS with those of conventional random-start GnRH-ant protocols in fertility-preserving cases. METHODS: We retrospectively examined 86 cycles of oocyte collection, of which 56 were random-start GnRH-ant and 30 were random-start PPOS for fertility preservation at our hospital between January 2016 and April 2021. The primary outcome was the number of mature oocytes per cycle. The secondary outcome was the number of vitrified blastocysts per cycle for embryo freezing cases. RESULTS: No significant differences were noted in the number of days of stimulation, total dose of gonadotropin preparation, and the number of mature oocytes and vitrified blastocysts. The number of hospital visits for monitoring was significantly lower in the PPOS group. The start of menstruation before oocyte collection was significantly less in the PPOS group. CONCLUSIONS: Random-start PPOS and GnRH-ant were similar in oocyte collection results. PPOS can reduce the number of hospital visits, thus reducing patient stress. PPOS at the start of the luteal phase can prevent the start of menstruation during ovarian stimulation.

Severe hemoperitoneum resulting from restart of letrozole after oocyte retrieval procedure: a case report.

BACKGROUND: In the field of oncofertility, patients with breast cancer are often administered letrozole as an adjuvant drug before and after oocyte retrieval to prevent an increase in circulating estradiol. CASE PRESENTATION: We report a case of abdominal hemorrhage due to an ovarian rupture in a 29-year-old Japanese patient who restarted letrozole 2 days after an oocyte retrieval procedure in which 14 mature oocytes were retrieved. The patient had sought embryo cryopreservation as a fertility preservation option before undergoing treatment for recurrent breast cancer. A day after restarting letrozole treatment, the patient unexpectedly developed severe abdominal pain. Laparoscopic hemostasis was performed to manage the ovarian swelling and hemorrhage. CONCLUSIONS: The ovaries can be restimulated by restart letrozole after an oocyte retrieval procedure. Therefore, reproductive-medicine practitioners should understand the potential complications of letrozole administration in such cases and take steps to ensure that they are minimized.

Safety of transvaginal aspiration of cysts in pregnancies complicated with ovarian endometrioma.

OBJECTIVES: Pregnancy complicated with ovarian endometrioma is a risk factor for preterm delivery and rupture or infection during pregnancy. This study aimed to clarify the effectiveness and safety of transvaginal aspiration during pregnancy for endometrioma diagnosed in the first trimester. DESIGN: This retrospective observational study included 8 pregnant women with endometrioma who underwent transvaginal cyst aspiration at 12-14 weeks (aspiration group) between March 2011-March 2018 and 23 pregnant women with endometrioma who refused aspiration during the same period (observation group). METHODS: Characteristics of patients were compared in both groups. Safety, feasability and complications of transvaginal cyst aspiration were reported. Complications and obstetrical outcomes were reported and compared in both groups. RESULTS: The maximum cyst diameter was 8.9 ± 1.5 cm (mean ± standard deviation) in the aspiration group, which was significantly larger than that in the observation group (4.7 ± 0.2 cm). Four preterm deliveries (17.3%) occurred in the observation group and none in the aspiration group. The emergency cesarean section rate during delivery was 14.2% in the aspiration group and 43.7% in the observation group. CONCLUSIONS: The aspiration group tended to have lower rate of preterm deliveries and emergency cesarean sections, suggesting that cyst aspiration could be an effective, minimally invasive, and safe management option for endometrioma during pregnancy.

Late-onset ovarian hyperstimulation syndrome developing during ovarian stimulation in an ectopic pregnancy: a case report.

BACKGROUND: Ovarian hyperstimulation syndrome is normally induced by ovarian stimulation drugs. Severe cases of ovarian hyperstimulation syndrome involve complications such as renal failure and thrombosis. Evidence has recently been developed for a method to prevent ovarian hyperstimulation syndrome. Most cases of ovarian hyperstimulation syndrome are of an early-onset type, which occurs shortly after injection of human chorionic gonadotropin. However, late-onset ovarian hyperstimulation syndrome, which occurs in a pregnancy cycle, also requires caution. We report our experience in treating a woman who was transported to our hospital with a severe case of ovarian hyperstimulation syndrome occurring during ovarian stimulation and who was determined to have an ectopic pregnancy. CASE PRESENTATION: Assisted reproductive technology was planned for a 29-year-old nulligravida Japanese woman diagnosed with bilateral fallopian tube obstruction and right-sided hydrosalpinx. On day 1 of controlled ovarian stimulation, the result of her human chorionic gonadotropin urine test was negative, and her serum levels of luteinizing hormone, estradiol, and progesterone were normal. On day 11 of controlled ovarian stimulation, the levels of estradiol and progesterone had risen to 9679 pg/ml and 16 ng/ml, respectively, prompting suspension of controlled ovarian stimulation. Eleven days after controlled ovarian stimulation was suspended, the patient demonstrated ascites that did not improve despite administration of cabergoline, and she was transported to our hospital 2 days after. Late-onset ovarian hyperstimulation syndrome suggested that she was pregnant, and her serum human chorionic gonadotropin level was 27,778 IU/ml. She underwent laparoscopic bilateral salpingectomy and was diagnosed with right tubal pregnancy. CONCLUSION: In an ectopic pregnancy, human chorionic gonadotropin sometimes increases later than in an intrauterine pregnancy. In our patient's case, endogenous human chorionic gonadotropin following the start of controlled ovarian stimulation may have caused late-onset ovarian hyperstimulation syndrome. The key to early detection of similar cases may be to suspect pregnancy in the event of unexpectedly high progesterone levels during ovarian stimulation.

Associations between the levels of soluble (pro)renin receptor in maternal and umbilical cord blood and hypertensive disorder of pregnancy.

INTRODUCTION: The prorenin (PR) receptor [(P)RR] contributes to the regulation of the tissue renin-angiotensin system (RAS) and Wnt signaling, which is involved in embryogenesis and the pathological progression of malignant tumors and diabetes mellitus. Placental (P)RR is significantly upregulated in placental tissues from preeclamptic women. However, because it cannot be examined during pregnancy, the chronological relationship between the acceleration of tissue RAS and the disease state of hypertensive disorder of pregnancy (HDP) has not been reported. In this study, we examined whether chronological changes in placental tissue RAS can be assessed by measuring soluble (P)RR [s(P)RR]. METHODS: We obtained maternal and umbilical cord blood samples from 517 pregnant women (441 singleton and 76 twin pregnancies). The concentrations of s(P)RR and prorenin (PR) were measured using enzyme-linked immunosorbent assays. RESULTS: Multivariate analysis showed that maternal serum s(P)RR levels were significantly higher in patients with HDP or fetal growth restriction (FGR) and were positively correlated with serum PR levels. Furthermore, the maternal s(P)RR level was significantly higher in HDP with severe hypertension and after the onset of HDP. However, maternal s(P)RR levels were not affected by the severity of proteinuria. Serum s(P)RR levels in umbilical cord blood of singleton pregnancies were significantly correlated with gestational week at delivery and PR level. DISCUSSION: Maternal serum s(P)RR concentrations may reflect acceleration of tissue RAS in the placenta and blood pressure severity; however, the umbilical serum s(P)RR concentration was not affected by maternal HDP.

Functional expression of BMP7 receptors in oral epithelial cells. Interleukin-17F production in response to BMP7.

BACKGROUND: Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-ß (TGF-ß) superfamily. Recently, BMP7 has been demonstrated to be produced by salivary glands and contribute to embryonic branching in mice. The BMP7 in saliva is thought to be delivered to the oral cavity and is expected to contact with stratified squamous epithelial cells which line the surface of oral mucosa. In this study, we attempted to investigate the effects of BMP7 on oral epithelial cells. METHODS: The expression of BMP receptors was examined by reverse transcriptase-polymerase chain reaction (RT-PCR). OSCCs were stimulated with human recombinant BMP7 (hrBMP7) and the phosphorylation status of Smad1/5/8 was examined by western blotting. For microarray analysis, Ca9-22 cells were stimulated with 100 ng/mL of hrBMP7 and total RNA was extracted and subjected to real-time PCR. The 5'-untranslated region (5'-UTR) of IL-17 F gene was cloned to pGL4-basic vector and used for luciferase assay. Ca9-22 cells were pre-incubated with DM3189, a specific inhibitor of Smad1/5/8, for inhibition assay. RESULTS: All isoforms of type I and type II BMP receptors were expressed in both Ca9-22 and HSC3 cells and BMP7 stimulation resulted in the phosphorylation of Smad1/5/8 in both cell lines. The microarray analysis revealed the induction of interleukin-17 F (IL-17 F), netrin G2 (NTNG2) and hyaluronan synthase 1 (HAS1). Luciferase assay using the 5'-UTR of the IL-17 F gene revealed transcriptional regulation. Induced IL-17 F production was further confirmed at the protein level by ELISA. Smad1/5/8 inhibitor pretreatment decreased IL-17 F expression levels in the cells.

Prevalence and distribution of anomalies of permanent dentition in 9584 Japanese high school students.

This study investigated the prevalence and distribution of anomalies of permanent dentition in the current Japanese population by examining an unbiased sample. We conducted a survey of dental anomalies by mass dental screening at eight high schools in 2012. Participants were all students with permanent dentition. Dental anomalies were classified as hypodontia, supernumerary teeth, peg-shaped teeth, fused teeth, and talon cusps. Students with one or more dental anomalies on oral examination were given a differential diagnosis by three specialists. The final sample comprised 9584 participants (5062 boys, 4522 girls). Hypodontia was present in 372 students (3.88 %) with no significant sex difference (191 boys, 181 girls). Frequent sites were the right or left mandibular second premolar, right or left maxillary second premolar, and right or left maxillary lateral incisor. Supernumerary teeth were observed in three boys (0.06 %) and one girl (0.02 %). Peg-shaped teeth were observed in 74 students (0.77 %; 27 boys, 47 girls), differing significantly between sexes; they were most prevalent among maxillary lateral incisors. Of affected students, 18 students (0.19 %) also had hypodontia (3 boys, 15 girls). Fused teeth were present in two boys (0.04 %) and three girls (0.07 %) (gemination in one boy and fusion in the remaining four students). Sites were limited to maxillary and mandibular central and lateral incisors. Talon cusps were observed in two boys (0.04 %) and four girls (0.09 %). The present survey of a large unbiased sample can be considered to reflect the prevalence and distribution of anomalies of permanent dentition in the current Japanese population.

Placental (pro)renin receptor expression and plasma soluble (pro)renin receptor levels in preeclampsia.

INTRODUCTION: The prorenin receptor ((P)RR) contributes to the regulation of the tissue renin-angiotensin system (RAS) and the function of V-ATPase, which are essential for Wnt signaling. Thus, (P)RRs may be involved in the control both of feto-placental and maternal circulation during pregnancy. This study was conducted to clarify how placental (P)RR expression and plasma soluble (P)RR [s(P)RR] levels are associated with blood pressure elevations and renal function during pregnancy. METHODS: We conducted a cross-sectional study, conducted at Saitama medical center in 2010-2013. Preeclamptic women (n = 16) diagnosed according to the criteria of Japan Society of Obstetrics and Gynecology and normotensive pregnant women (n = 15) participated in the study. We measured the expression of (P)RR in the placenta, plasma s(P)RR levels, systolic blood pressure (SBP), and estimated glomerular filtration rate (eGFR). RESULTS: Placental expression of (P)RR was significantly higher in preeclamptic women than in normotensive pregnant women. The plasma s(P)RR levels were significantly higher in preeclamptic women than in normotensive pregnant women. Systolic blood pressure (SBP) was positively correlated with placental (P)RR levels (P = 0.0001) and plasma s(P)RR levels (P = 0.005) in all pregnant women. In preeclamptic women, SBP was positively correlated with placental (P)RR levels (P = 0.004), but not with plasma s(P)RR levels (P = 0.15). The eGFR was negatively correlated with placental (P)RR levels (P = 0.02) and plasma s(P)RR levels (P = 0.0002) in all pregnant women. In preeclamptic women, eGFR was negatively correlated with plasma s(P)RR levels (P = 0.006), but not with placental (P)RR levels (P = 0.93). DISCUSSION: Placental (P)RR can be involved in blood pressure regulation via the tissue RAS. On the other hand, plasma s(P)RR may be involved in the pathogenesis of decreased renal function in preeclampsia.

Current status of implant prosthetics in Japan: a survey among certified dental lab technicians.

BACKGROUND: There are many implant cases in which dental technicians take initiative with regard to the design of implant prostheses, and to a certain extent, this area of care is one in which dentists do not necessarily play the leading role. Moreover, inadequate communication between dental technicians and dentists and insufficient instructions for technicians has been highlighted as issues in the past. The purpose of this questionnaire is to improve the quality of implant prostheses and thereby contribute to patient service by clarifying, among other aspects of treatment, problem areas and considerations in the fabrication of implant prostheses, conceptual-level knowledge, and awareness of prosthodontics on the part of the dentists in charge of treatment and methods for preventing prosthetic complications. METHODS: A cross-sectional survey was given to 120 certified dental technicians. To facilitate coverage of a broad range of topics, we classified the survey content into the following four categories and included detailed questions for (1) the conditions under which implant technicians work, (2) implant fixed prostheses, (3) implant overdentures, and (4) prosthetic complications. RESULTS: Out of 120 surveys sent, 74 technicians responded resulting in a response rate of 61.6%. CONCLUSIONS: This survey served to clarify the current state of implant prosthodontics, issues, and considerations in the fabrication of implant prostheses, and the state of prosthetic complications and preventive initiatives, all from a laboratory perspective. The results of this survey suggested that, to fabricate prostheses with a high level of predictability, functional utility, and aesthetic satisfaction, it is necessary to reaffirm the importance for dentists to increase their prosthetic knowledge and work together with dental technicians to develop comprehensive treatment plans, implement an organized approach to prosthesis design, and accomplish occlusal reconstruction.

Repair of a multiple implant-supported fixed superstructure with a metal-ceramic resin-bonded fixed partial denture: a clinical report.

Even in the case of implant loss, replacement of the implant and refabrication of the superstructure are often sufficient, as long as the bone and soft tissue are in good condition. However, if implant loss accompanied by serious bone resorption occurs with a fixed implant superstructure supported by multiple implants, it is very difficult to treat. This clinical report describes the process by which multiple implant-supported fixed metal ceramic restorations were repaired with a metal ceramic resin-bonded fixed partial denture without complete refabrication after removal of one of the implants due to severe bone resorption. The 3-year follow-up indicated excellent serviceability and a well-satisfied patient.

Prorenin receptor is essential for normal podocyte structure and function.

The prorenin receptor is an accessory subunit of the vacuolar H(+)-ATPase, suggesting that it has fundamental functions beyond activation of the local renin-angiotensin system. Podocytes express the prorenin receptor, but its function in these cells is unknown. Here, podocyte-specific, conditional, prorenin receptor-knockout mice died of kidney failure and severe proteinuria within 4 weeks of birth. The podocytes of these mice exhibited foot process effacement with reduced and altered localization of the slit-diaphragm proteins nephrin and podocin. Furthermore, the podocytes contained numerous autophagic vacuoles, confirmed by enhanced accumulation of microtubule-associated protein 1 light chain 3-positive intracellular vesicles. Ablation of the prorenin receptor selectively suppressed expression of the V(0) c-subunit of the vacuolar H(+)-ATPase in podocytes, resulting in deacidification of intracellular vesicles. In conclusion, the prorenin receptor is important for the maintenance of normal podocyte structure and function.

Involvement of activated prorenin in the pathogenesis of slowly progressive nephropathy in the non-clipped kidney of two kidney, one-clip hypertension.

The handle region peptide (HRP), a (pro)renin receptor (P)RR blocker, did not prevent the acute nephropathy occurring 2 weeks after clipping in renovascular hypertensive rats. This study was performed to examine the effects of HRP, its scramble peptide, or a saline vehicle on slowly progressive nephropathy occurring in the kidneys of two-kidney, one-clip Goldblatt hypertensive rats. At 2 weeks after clipping, the renal morphology in the clipped and non-clipped kidneys was similar in the three groups of rats. At 12 weeks after clipping, however, the glomerulosclerosis index (GI) and the tubulointerstitial damage (TD) of the non-clipped kidneys of the HRP-treated rats were significantly lower than those of vehicle-treated rats, although the GI and the TD were similar in the rats treated with scramble peptide and vehicle. The GI and the TD of the clipped kidneys were similar in the three groups of rats at 12 weeks after clipping. In the non-clipped kidneys at 12 weeks after clipping, activated prorenin levels, angiotensin II levels and transforming growth factor (TGF)-ß mRNA levels of HRP-treated rats were significantly lower than those of vehicle-treated rats, although they were similar in the non-clipped kidneys from the rats treated with scramble peptide and vehicle. In the clipped kidneys at 12 weeks after clipping, activated prorenin levels, angiotensin II levels and TGF-ß mRNA levels were similar in the three groups of rats. These results suggest that the ((P)RR)-dependent activation of prorenin contributes to the pathogenesis of slowly progressive nephropathy in the intact kidney in a rat model of renovascular hypertension.

New approaches to blockade of the renin-angiotensin-aldosterone system: characteristics and usefulness of the direct renin inhibitor aliskiren.

Since renin inhibition interferes with the first and rate-limiting steps in the renin-angiotensin system, the renin step is a very attractive target for lowering blood pressure and minimizing target-organ damage. The newly developed direct renin inhibitor aliskiren has several attractive characteristics: it definitively reduces plasma renin activity among inhibitors of the renin-angiotensin system, is remarkably specific for human renin, exhibits a long half-life in plasma comparable to that of amlodipine, and has a high affinity for renal glomeruli and vasculature. Although these characteristics suggest the clinical usefulness and safety of aliskiren, several problems remain unsolved. Why does aliskiren have beneficial effects on the heart and kidneys of patients treated with angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II type 1-receptor blockers (ARBs)? Is the blood-pressure-lowering effect of aliskiren dependent on the plasma renin activity? Does aliskiren exert a possible adverse effect via (pro)renin receptor-dependent intracellular signals? Here, we review the characteristics and usefulness of aliskiren and discuss the current issues associated with this direct renin inhibitor.

Add-on blockade of (pro)renin receptor in imidapril-treated diabetic SHRsp.

To examine the involvement of (pro)renin receptor in the accelerated organ damage in streptozotocin-induced diabetic male SHRsp, the rats fed a high-salt diet were divided into 5 groups: a group treated with the vehicle, a group treated with 15 mg/kg/day of imidapril (ACEi), a group treated with 60 mg/kg/day of imidapril (High ACEi), a group treated with handle region peptide (HRP), and a group treated with both ACEi and HRP (ACEi+HRP). After 8 weeks, the arterial pressure was similar in the vehicle and HRP groups and decreased in the ACEi-treated groups. The renal angiotensin II content decreased similarly in the groups treated with ACEi and/or HRP. Urinary protein excretion also decreased in the ACEi, High ACEi, and HRP groups and significantly further decreased in the ACEi+HRP group. The heart weight of the ACEi+HRP group was significantly lower than that of any other groups, although the cardiac angiotensin II levels decreased similarly in the groups treated with ACEi and/or HRP. Thus, (pro)renin receptor contributes to the accelerated pathogenesis in the heart and kidneys of diabetic SHRsp.

The (pro)renin receptor/ATP6AP2 is essential for vacuolar H+-ATPase assembly in murine cardiomyocytes.

RATIONALE: The (pro)renin receptor [(P)RR], encoded in ATP6AP2, plays a key role in the activation of local renin-angiotensin system (RAS). A truncated form of (P)RR, termed M8.9, was also found to be associated with the vacuolar H(+)-ATPase (V-ATPase), implicating a non-RAS-related function of ATP6AP2. OBJECTIVE: We investigated the role of (P)RR/ATP6AP2 in murine cardiomyocytes. METHODS AND RESULTS: Cardiomyocyte-specific ablation of Atp6ap2 resulted in lethal heart failure; the cardiomyocytes contained RAB7- and lysosomal-associated membrane protein 2 (LAMP2)-positive multivesicular vacuoles, especially in the perinuclear regions. The myofibrils and mitochondria remained at the cell periphery. Cardiomyocyte death was accompanied by numerous autophagic vacuoles that contained undigested cellular constituents, as a result of impaired autophagic degradation. Notably, ablation of Atp6ap2 selectively suppressed expression of the V(O) subunits of V-ATPase, resulting in deacidification of the intracellular vesicles. Furthermore, the inhibition of intracellular acidification by treatment with bafilomycin A1 or chloroquine reproduced the phenotype observed for the (P)RR/ATP6AP2-deficient cardiomyocytes. CONCLUSIONS: Genetic ablation of Atp6ap2 created a loss-of-function model for V-ATPase. The gene product of ATP6AP2 is considered to act as in 2 ways: (1) as (P)RR, exerting a RAS-related function; and (2) as the V-ATPase-associated protein, exerting a non-RAS-related function that is essential for cell survival.

Renoprotective effects of mineralocorticoid receptor blockade in heminephrectomized (pro)renin receptor transgenic rats.

1. Nephropathy and elevated plasma aldosterone concentrations (PAC) have been observed in (pro)renin receptor transgenic (TG) rats. In the present study, we hypothesized that PAC and/or mineralocorticoid receptor contribute to the nephropathy of TG rats. To test this hypothesis, the effects of a high-sodium (8% NaCl) diet and heminephrectomy on PAC were examined. 2. Feeding of the high-sodium diet for 12 weeks similarly decreased PAC in TG and wild-type (WT) rats. Heminephrectomy further reduced PAC in TG rats fed a high-sodium diet, but had no effect on PAC in WT rats fed a high-sodium diet. 3. Next, the effects of eplerenone (125 mg/kg per day) and dietary salt restriction (0.36% NaCl diet) on proteinuria and renal morphology were examined in rats fed a high-sodium diet or subjected to heminephrectomy. Both eplerenone and dietary sodium restriction significantly reduced the arterial pressure of TG rats, but had no effect in WT rats. In TG rats, treatment with eplerenone significantly decreased urinary protein excretion, but dietary sodium restriction did not. 4. Nephrin and podocin mRNA levels, as determined by real-time quantitative reverse transcription-polymerase chain reaction, were significantly lower in TG rats than in WT rats. In TG rats, eplerenone treatment significantly increased nephrin mRNA levels, but not podocin mRNA levels. Dietary salt restriction significantly increased mRNA levels of both nephrin and podocin. Although zonula occludens (ZO)-1 mRNA levels were similar in both WT and TG rats, eplerenone treatment significantly decreased ZO-1 mRNA levels in TG rats. 5. The results of the present study suggest that the improvement in proteinuria following eplerenone treatment is independent of its effects on sodium balance and may be mediated by effects on the expression of slit diaphragm proteins.

Aliskiren inhibits intracellular angiotensin II levels without affecting (pro)renin receptor signals in human podocytes.

BACKGROUND: A direct renin inhibitor (DRI) had a benefit in decreasing albuminuria in type 2 diabetic patients having already been treated with angiotensin (Ang) II type 1 receptor blocker (ARB), suggesting that aliskiren may have another effect other than blockade of the traditional renin-angiotensin system (RAS). Recently, prorenin bound to (pro)renin receptor ((P)RR) was found and shown to evoke two pathways; the generation of Ang peptides and the receptor-dependent activation of extracellular signal-related protein kinase (ERK). Because (P)RR is present in the podocytes, a central component of the glomerular filtration barrier, we hypothesized that aliskiren influences the (P)RR-induced two pathways in human podocytes. METHODS: Human podocytes were treated with 2 nmol/l prorenin in the presence and absence of an angiotensin-converting enzyme inhibitor (ACEi) imidaprilat, an ARB candesartan, a DRI aliskiren, or the siRNA knocking down the (P)RR mRNA and the intracellular AngII levels and the phosphorylation of ERK were determined. RESULTS: The expression of (P)RR mRNA of human podocytes was unaffected by the treatment with RAS inhibitors, but decreased by 69% with the siRNA treatment. The basal levels of intracellular AngII and the prorenin-induced increase in intracellular AngII were significantly reduced by aliskiren and siRNA treatment, compared with imidaprilat and candesartan. The prorenin-induced ERK activation was reduced to control level by the siRNA treatment, but it was unaffected by imidaprilat, candesartan, or aliskiren. CONCLUSIONS: Aliskiren is the most potent inhibitor of intracellular AngII levels of human podocytes among RAS inhibitors, although it is incapable of inhibiting the (P)RR-dependent ERK phosphorylation.

Possible roles of human (pro)renin receptor suggested by recent clinical and experimental findings.

Numerous in vitro and in vivo animal studies using the (pro)renin receptor (P)RR blocker handle region peptide have suggested an important role of (P)RR in the pathogenesis of end-stage organ damage in patients with diabetes and hypertension. In addition, a limited number of clinical studies have suggested an association between (P)RR gene polymorphisms and blood pressure levels and between (P)RR mRNA levels and angiotensin-converting enzyme mRNA levels in human arteries. However, recent studies have shown that the (P)RR is divided into its soluble form and a residual hydrophobic part, which includes ATPase 6 associated protein 2, within cells. Therefore, the (P)RR may have a more complex function than previously thought. In addition, the physiological roles of the (P)RR remain undetermined, because the construction of (P)RR null mice has not been successful. As a next step for research in this area, a method for determining the soluble (P)RR levels in plasma and urine and the construction of tissue-specific (P)RR-knockout mice are needed to elucidate the roles of the (P)RR in physiology and pathophysiology.

Association of (pro)renin receptor mRNA expression with angiotensin-converting enzyme mRNA expression in human artery.

BACKGROUND/AIMS: A significant role of (pro)renin receptor in the pathogenesis of end-organ damage has been suggested only in animal studies. This study was conducted to examine the mRNA expression of (pro)renin receptor in human artery. METHODS: In 141 kidney failure patients, the mRNA was harvested from arterial fragments obtained during surgery constructing an arteriovenous access for hemodialysis therapy, and expression levels of (pro)renin receptor and other components of the renin-angiotensin system were determined. RESULTS: Arterial (pro)renin receptor expression was similar in diabetic and non-diabetic patients, although plasma prorenin levels were significantly higher in the diabetic patients than in the non-diabetic patients. The arterial (pro)renin receptor mRNA levels of the hypertensive patients, who had not been treated with either angiotensin-converting enzyme (ACE) inhibitors or angiotensin II type 1 receptor blockers, were significantly lower than those of the patients who had been treated with either drug. Multiple regression analyses showed a significant association with a large coefficient between the arterial mRNA level of the (pro)renin receptor and the arterial mRNA level of ACE; this significant association disappeared in patients who had been treated with either drug. CONCLUSION: (Pro)renin receptor may contribute to the generation of arterial angiotensin II in kidney failure patients.

Drug discovery for overcoming chronic kidney disease (CKD): new therapy for CKD by a (pro)renin-receptor-blocking decoy peptide.

Discovery of the (pro)renin receptor uncovered a novel function of renin/prorenin as the receptor ligands in addition to the enzyme and its precursor. The bindings of renin and prorenin to the (pro)renin receptor trigger two major pathways: the angiotensin II-dependent pathway as a result of the enzymatic activation of renin/prorenin and the angiotensin II-independent intracellular pathway involving hypertrophic, hyperplastic, and profibrotic signals. A specific blocker of the receptor was discovered through identification of the amino acid sequence of prorenin prosegment that binds to the receptor and leads to non-proteolytic conversion of prorenin to its active form. A peptide containing this sequence was found to block the binding of prorenin to its receptor. Its infusion in animal models of diabetes and low-renin hypertension significantly inhibited the development and progression of nephropathy, but (pro)renin receptor blockade had no benefit in the clipped kidney of 2K1C rats or rat models of high-renin hypertension. Since renin is still active without a (pro)renin receptor, (pro)renin-receptor blockade elicits a maximum benefit under low-renin conditions. Thus, (pro)renin-receptor blockade can be a useful therapy for chronic kidney disease with low renin levels in the plasma.