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.soluble (pro)renin receptor | liver X receptor | aquaporin-2 | frizzled-8 | β-catenin F ull-length (Pro)renin receptor (PRR), a 350-amino acid transmembrane receptor for prorenin and renin, is subjected to protease-mediated cleavage to produce a 28-kDa protein of the N-terminal extracellular domain, the soluble (pro)renin receptor (sPRR), and the 8.9-kDa C-terminal intracellular domain called "M8.9" (1, 2). Before the cloning of full-length PRR in mesangial cells as an integral 39-kDa membrane protein (3), M8.9 was identified as a truncated protein associated with the vacuolar H + -ATPase (V-ATPase) from bovine chromatin granules (4). The cleavage occurs in Golgi apparatus through furin (5) or ADMA19 (6). An sPRR ELISA kit has been developed to detect sPRR in plasma and urine samples (7) . With this assay, increased serum sPRR levels have been demonstrated in patients with heart failure (8), kidney disease (9, 10), hypertension (11), and preeclampsia (2). Moreover, serum sPRR is positively associated with serum creatinine, blood urea nitrogen, and urine protein and is inversely associated with the estimated glomerular filtration rate in patients with chronic kidney disease caused by hypertension...
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 PGE receptor EP Notably, EP also controls urinary concentration through regulation of aquaporin 2 (AQP2). Here, we tested the hypothesis that sequential activation of EP 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 EP 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 EP 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/PGE/EP/PRR pathway in the CD for regulation of AQP2 expression and urine concentrating capability.
Until now, renin-angiotensin system (RAS) hyperactivity was largely thought to result from angiotensin II (Ang II) dependent stimulation of the Ang II type 1 receptor (AT1R). Here we assessed the role of soluble (pro)renin receptor (sPRR), a product of site-1 protease-mediated cleavage of (pro)renin receptor (PRR), as a possible ligand of the AT1R in mediating: (i) endothelial cell dysfunction in vitro; and (ii) arterial dysfunction in mice with diet-induced obesity. Primary human umbilical vein endothelial cells (HUVECs) treated with a recombinant histidine-tagged sPRR (sPRR-His) exhibited IκBα degradation concurrent with NF-κB p65 activation. These responses were secondary to sPRR-His evoked elevations in Nox4-derived H2O2 production that resulted in inflammation, apoptosis and reduced NO production. Each of these sPRR-His-evoked responses was attenuated by AT1R inhibition using Losartan (Los) but not ACE inhibition using captopril (Cap). Further mechanistic exploration revealed that sPRR-His activated AT1R downstream Gq signaling pathway. Immunoprecipitation coupled with autoradiography experiments and radioactive ligand competitive binding assays indicate sPRR directly interacts with AT1R via Lysine199 and Asparagine295. Important translational relevance was provided by findings from obese C57/BL6 mice that sPRR-His evoked endothelial dysfunction was sensitive to Los. Besides, sPRR-His elevated blood pressure in obese C57/BL6 mice, an effect that was reversed by concurrent treatment with Los but not Cap. Collectively, we provide solid evidence that the AT1R mediates the functions of sPRR during obesity-related hypertension. Inhibiting sPRR signaling should be considered further as a potential therapeutic intervention in the treatment and prevention of cardiovascular disorders involving elevated blood pressure.
Normal aging of the brain differs from pathological conditions and is associated with increased risk for psychiatric and neurological disorders. In addition to its role in the etiology and treatment of mood disorders, altered serotonin (5-HT) signaling is considered a contributing factor to aging; however, no causative role has been identified in aging. We hypothesized that a deregulation of the 5-HT system would reveal its contribution to agerelated processes and investigated behavioral and molecular changes throughout adult life in mice lacking the regulatory presynaptic 5-HT 1B receptor (5-HT 1B R), a candidate gene for 5-HTmediated age-related functions. We show that the lack of 5-HT 1B R (Htr1b KO mice) induced an early age-related motor decline and resulted in decreased longevity. Analysis of life-long transcriptome changes revealed an early and global shift of the gene expression signature of aging in the brain of Htr1b KO mice. Moreover, molecular changes reached an apparent maximum effect at 18-months in Htr1b KO mice, corresponding to the onset of early death in that group. A comparative analysis with our previous characterization of aging in the human brain revealed a phylogenetic conservation of age-effect from mice to humans, and confirmed the early onset of molecular aging in Htr1b KO mice. Potential mechanisms appear independent of known central mechanisms (Bdnf, inflammation), but may include interactions with previously identified age-related systems (IGF-1, sirtuins). In summary, our findings suggest that the onset of age-related events can be influenced by altered 5-HT function, thus identifying 5-HT as a modulator of brain aging, and suggesting age-related consequences to chronic manipulation of 5-HT.
Background: Recently, subjective cognitive decline (SCD) has been described as the earliest at-risk state of Alzheimer's disease (AD), and drawn attention of investigators. Studies suggested that SCD-community individuals may constitute a more vulnerable population than SCD-clinic patients, therefore, to investigate the early changes of the brain may provide guidance for treatment of the disease. We sought to investigate the changes of structure and functional connectivity alternation of the hippocampus in individuals with SCD recruited from the community using structural and resting-state functional MRI (fMRI).Methods: Thirty-five SCD patients and 32 healthy controls were recruited. Resting-state fMRI data and high-resolution T1-weighted images were collected. Whole-brain voxelbased morphometry was used to examine the brain structural changes. We also used the hippocampal tail and the whole hippocampus as seeds to investigate functional connectivity alternation in SCD.Results: Individuals with SCD showed significant gray matter volume decreases in the bilateral hippocampal tails and enlargement of the bilateral paracentral lobules. We also found that individuals with SCD showed decreased hippocampal tail resting-state functional connectivity (rsFC) with the right medial prefrontal cortex (mPFC) and the left temporoparietal junction (TPJ), and decreased whole hippocampus rsFC with the bilateral mPFC and TPJ. These brain region and FC showing significant differences also showed significantly correlation with Montreal Cognitive Assessment (MoCA) scores.Conclusion: Individuals with SCD recruited from the community is associated with structural and functional changes of the hippocampus, and these changes may serve as potential biomarkers of SCD.
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