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.

The prorenin receptor is an accessory subunit of the vacuolar H ϩ -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 ϩ -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.

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.

ABSTRACT. To investigate the adverse effects of long-term administration of ketoprofen in dogs, ketoprofen (1 mg/kg) was administered to five clinically healthy beagle dogs (ketoprofen group) and gelatin capsules (control group) were administered to four clinically healthy beagle dogs for 30 days. We monitored the dogs through periodic physical examination, blood analyses, endoscopic examinations, fecal occult blood tests, renal function tests, urinalysis, urinary enzyme indices and cuticle bleeding time analysis. The lesions in the stomach, especially in the pyloric antrum, and fecal occult blood progressively worsened in the ketoprofen group. However, the differences between the ketoprofen group and the control group were not statistically significant. One dog in the ketoprofen group temporarily exhibited a decrease in renal plasma flow and two dogs exhibited enzymuria. However, these changes did not persist and the other examinations showed no significant difference between premedication and postmedication in the ketoprofen group. Therefore, the adverse effects of long-term administration of ketoprofen observed in this study were not clinically important in healthy dogs. Nevertheless, further investigation of adverse renal effects from long-term administration of ketoprofen is necessary in the dogs with subclinical renal disease. KEY WORDS: adverse effect, canine, Ketoprofen, long-term administration.

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. Hypertension Research (2010) 33, 177-180; doi:10.1038/hr.2009 published online 18 December 2009 Keywords: angiotensin; ATP6ap2; handle region peptide; prorenin; vacuolar H + -ATPase INTRODUCTIONThe pathophysiological roles of the (pro)renin receptor ((P)RR) are a growing concern because numerous experimental studies conducted since this receptor was first discovered in 2002 1 have suggested that the pro(renin) receptor has its own intracellular signaling pathways and is involved in the tissue renin-angiotensin system. However, the clinical relevance of the human (P)RR remains uncertain because only a few clinical studies examining the (P)RR have been performed. In this review article of previous studies and new findings, we attempt to elucidate the possible role of the (P)RR in humans. SUGGESTIONS FROM IN VITRO STUDIESThe (P)RR was first reported to be capable of binding both renin and prorenin in vitro. 1 However, Batenburg et al. 2 showed that prorenin, but not renin, was capable of binding to the (P)RR in cultured vascular smooth muscle cells, suggesting that prorenin is an endogenous agonist of the (P)RR. In addition, Nabi et al. 3 provided clear evidence that receptor-bound prorenin gains 'renin activity' without undergoing the proteolytic cleavage of the prosegment of prorenin as a result of a conformational change, although the enzymatic activity of receptor-bound renin is similar to that of free renin. On the basis of these findings, renin may be an endogenous inhibitor for the binding of prorenin to the (P)RR.Stimulation of the (P)RR by renin and prorenin reportedly results in the activation of intracellular signaling pathways, including MAP kinases, in mesangial cells, 4-6 vascular smooth muscle cells, 7 cardiomyocytes 8 and renal tubular epithelial cells. 9 However, the significance of the (P)RR-dependent intracellular signals in vivo remains undetermined. SUGGESTIONS FROM ANIMAL MODELS OF DIAB...

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.

RDKET induced mild to moderate gastric mucosal injuries especially in the pyloric antrum in healthy Beagles, whereas no adverse effects were observed in renal function or hemostasis. Fecal occult blood tests may be useful as screening tests for adverse gastrointestinal effects induced by RDKET in dogs.

ABSTRACT. The interaction between oral non-steroidal anti-inflammatory drugs (NSAIDs) and prednisolone administered concurrently for 30 days was studied in 18 healthy dogs divided into 3 groups of 6 dogs each: a drug-free negative control group (NC group) given 2 gelatin capsules; a group given meloxicam (0.1 mg/kg) and prednisolone (0.5 mg/kg) (MP group); and a group given a reduced dosage of ketoprofen (0.25 mg/kg, PO) and prednisolone (0.5 mg/kg, PO) (KP group). The dogs were periodically monitored by physical examinations, blood analyses, endoscopic examinations, fecal occult blood tests, renal function tests [effective renal plasma flow (ERPF) and glomerular filtration rate (GFR)], urinalyses [urinary sediments, and urinary micro-albumin to creatinine ratio (UAlb/Cre)], urinary enzyme indices, and haemostatic function tests [buccal mucosa bleeding time (BMBT), cuticle bleeding time (CBT)]. Significant changes were observed in the KP group, including a decrease of ERPF and GFR, an increased UAlb/Cre ratio, prolonged BMBT and CBT, as well as the presence of more severe grades of endoscopic lesions and fecal occult blood. In both the MP and KP groups, abnormal enzymuria with exfoliation of renal tubular epithelial cells in the urine was found. However, no significant changes in any of the other tests were observed in the MP group compared with the NC group. These findings suggest that the combination of NSAIDs, even selective COX-2 inhibitors, with prednisolone may be contraindicated due to the potential for serious adverse effects on the kidneys, the platelets, and the gastrointestinal tract.