Renin Receptor Research Articles

Endothelial cell polarity and extracellular matrix composition require functional ATP6AP2 during developmental and pathological angiogenesis.

The (Pro)renin receptor ([P]RR), also known as ATP6AP2, is a single-transmembrane protein that is implicated in a multitude of biological processes. However, the exact role of ATP6AP2 during blood vessel development remains largely undefined. Here, we use an inducible endothelial cell-specific (EC-specific) Atp6ap2-KO mouse model to investigate the role of ATP6AP2 during both physiological and pathological angiogenesis in vivo. We observed that postnatal deletion of Atp6ap2 in ECs results in cell migration defects, loss of tip cell polarity, and subsequent impairment of retinal angiogenesis. In vitro, Atp6ap2-deficient ECs similarly displayed reduced cell migration, impaired sprouting, and defective cell polarity. Transcriptional profiling of ECs isolated from Atp6ap2 mutant mice further indicated regulatory roles in angiogenesis, cell migration, and extracellular matrix composition. Mechanistically, we provided evidence that expression of various extracellular matrix components is controlled by ATP6AP2 via the ERK pathway. Furthermore, Atp6ap2-deficient retinas exhibited reduced revascularization in an oxygen-induced retinopathy model. Collectively, our results demonstrate a critical role of ATP6AP2 as a regulator of developmental and pathological angiogenesis.

Targeting the (pro)renin receptor in cancers: from signaling to pathophysiological effects.

Cancer is a major public health problem, currently affecting hundreds of millions of people worldwide, and its clinical results are unpredictable, partly due to the lack of reliable biomarkers of cancer progression. Recently, it has been reported that (pro)renin receptor (PRR), as a new biomarker, plays an important role in different types of cancer, such as colorectal cancer, breast cancer, glioma, aldosterone-producing adenoma, endometrial cancer, urothelial cancer, and pancreatic ductal adenocarcinoma. In order to comprehensively and systematically understand the relationship and role of PRR with various cancers, this review will summarize the current research on targeting PRR in cancer from signaling to pathophysiological effects,including the correlation between PRR/sPRR expression level and different cancers, potential mechanisms regulated by PRR in the progress of cancers, and PRR in cancer treatment. PRR can be a novel and promising biomarker and potential therapeutic target for diagnosis, treatment, and prognosis in cancer, which is worthy of extensive development and application in clinics.

Potential of soluble (pro)renin receptor in kidney disease: can it go beyond a biomarker?

(Pro)renin receptor (PRR), also termed ATPase H+-transporting accessory protein 2 (ATP6AP2), is a type I transmembrane receptor and is capable of binding and activating prorenin and renin. Apart from its association with the renin-angiotensin system, PRR has been implicated in diverse developmental, physiological, and pathophysiological processes. Within the kidney, PRR is predominantly expressed in the distal nephron, particularly the intercalated cells, and activation of renal PRR contributes to renal injury in various rodent models of chronic kidney disease. Moreover, recent evidence demonstrates that PRR is primarily cleaved by site-1 protease to produce 28-kDa soluble PRR (sPRR). sPRR seems to mediate most of the known pathophysiological functions of renal PRR through modulating the activity of the intrarenal renin-angiotensin system and provoking proinflammatory and profibrotic responses. Not only does sPRR activate renin, but it also directly binds and activates the angiotensin II type 1 receptor. This review summarizes recent advances in understanding the roles and mechanisms of sPRR in the context of renal pathophysiology.

(Pro)renin receptor and insulin signalling regulate cell proliferation in MCF-7 breast cancer cells.

(Pro)renin receptor [(P)RR] is related to both the renin-angiotensin system and V-ATPase with various functions including stimulation of cell proliferation. (P)RR is implicated in the pathophysiology of diabetes mellitus and cancer. Hyperinsulinemia is observed in obesity-related breast cancer. However, the relationship between (P)RR and insulin has not been clarified. We have therefore studied the effect of insulin on (P)RR expression, cell viability and AKT phosphorylation under the conditions with and without (P)RR knockdown. Effects of insulin were studied in a human breast cancer cell line, MCF-7. Cell proliferation assay was performed by WST-8 assay. (P)RR expression was suppressed by (P)RR-specific siRNAs. The treated cells were analysed by western blotting and reverse transcriptase-quantitative polymerase chain reaction analysis. Insulin stimulated proliferation of MCF-7 cells and increased (P)RR protein expression, but not (P)RR mRNA levels. Moreover, autophagy flux was suppressed by insulin. Suppression of (P)RR expression reduced cell number of MCF-7 cells and AKT phosphorylation significantly in both the presence and the absence of insulin, indicating that (P)RR is important for cell viability and AKT phosphorylation. In conclusion, insulin upregulates the level of (P)RR protein, which is important for cell viability, proliferation, AKT phosphorylation and autophagy in breast cancer cells.

(Pro)renin receptor inhibition attenuated liver steatosis, inflammation, and fibrosis in mice with steatohepatitis.

The (Pro)renin receptor (PRR) is reportedly involved in hepatic lipid metabolism and hepatocyte PRR knockdown protects mice against hepatosteatosis. However, the impact of PRR inhibition on liver inflammation and fibrosis in nonalcoholic steatohepatitis (NASH) remains unclear. Herein, C57BL/6 mice were fed a normal chow diet or fast food diet (FFD) for 24 weeks. Lentivirus-mediated PRR short hairpin RNA (shRNA) or handle region peptide (HRP), a PRR blocker, was administered for PRR inhibition. Mouse primary hepatocytes were cultured with palmitic acid, prorenin, siRNA-targeted PRR, and HRP. In FFD-fed mice, PRR inhibition via lentivirus-mediated PRR knockdown or HRP significantly attenuated liver steatosis, inflammation, and fibrosis. Mechanistically, PRR knockdown or HRP decreased hepatic acetyl-CoA carboxylase (ACC) abundance and upregulated peroxisome proliferator-activated receptor-alpha (PPARα). HRP treatment also decreased hepatic PRR expression. In addition, intrahepatic oxidative stress, apoptosis and inflammatory cell recruitment were ameliorated by PRR knockdown or HRP treatment, along with suppression of proinflammatory cytokine expression. PRR inhibition downregulated the hepatic expression of profibrotic factors, as well as TGF-β1/SMAD3 pathway. In primary mouse hepatocytes, PRR knockdown with siRNA or HRP downregulated cellular ACC and increased PPARα expression. In conclusion, our findings revealed that PRR inhibition attenuated hepatic steatosis, inflammation, and fibrosis in mice with NASH. Accordingly, targeting PRR signaling may serve as a potential treatment for NASH.

Abstract 042: A Novel (pro)renin Receptor Variant Prr24 As A Specific Renin Receptor And Key Regulator Of Nkcc2 And Urine Concentrating Capability

(Pro)renin receptor (PRR) has emerged as a key regulator of renal handling of Na + and water, and blood pressure (BP). Renal action of PRR is at least in part mediated through its ability to activate tissue prorenin and renin. In preliminary studies, investigation of a “non-specific” protein band recognized by an anti-PRR antibody against the extracellular domain led to identification of a novel 24-kDa isoform of PRR, termed as PRR24. PRR24 was encoded by a novel cDNA with part of 5’UTR arising from retention of intron 3 and an ATG in exon 5 as an alternative start codon so that this isoform overlaps completely with PRR except that N-terminal 136 amino acids are missing. PRR24 selectively bound and activated renin but not prorenin whereas PRR non-selectively interacted both prorenin and renin. PRR24 protein and mRNA expression was exclusively detected in the renal medulla but not renal cortex or extrarenal organs. Within the kidney, PRR24 mRNA was restricted to medullary thick ascending limb (mTAL) as assessed by RT-PCR on microdissected nephron segments. Using CRISP/Cas9 strategy, we generated a mouse model with mutagenesis of the start codon in exon 5 (termed PRR24 mut ) by replacing methionine with glutamine in PRR. Renal medullary protein expression of PRR24 was barely detectable contrasting unchanged PRR abundance in the null mice. PRR24 mut mice was born at Mendelian ratio and didn’t exhibit developmental abnormalities or mortality as seen in systemic PRR KO mice. PRR24 mut mice developed polyuria, hypoosmotic urine, polydipsia, hypotension (radiotelemetry MAP: WT 120 + 0.8 vs. Mutant 112 + 1.4 mmHg; p<0.05). Plasma volume assessed indirectly by hematocrit and directly assessed by using a fluorescent tracer was consistently reduced by 5-10%. Renal expression of NKCC2 was downregulated by 70% in parallel with reduced diuretic response to furosemide. Following 24-h water deprivation, the upregulation of NKCC2 expression was blunted in PRR24 mut mice associated with impaired urine concentrating capability as assessed by urine volume and osmolality. Overall, PRR24 is a novel PRR variant and serves as a specific renin receptor to regulate renal NKCC2 expression to ultimately determine urine concentrating capability.

Abstract 043: Prorenin Reduces Spontaneous Firing Rate In Cells Expressing Tyrosine Hydroxylase In The Hypothalamic Paraventricular Nucleus

The (pro)renin receptor (PRR) plays essential roles in cardiovascular and metabolic physiology. The tyrosine hydroxylase (TH) neurons in the paraventricular nucleus of the hypothalamus (PVN) have recently emerged as a key metabolic regulator that play functional roles in the regulation of the energy expenditure and metabolism. Using RNAScope in situ hybridization, we found that 95% of TH-containing neurons in the PVN (n=872 cells/3 mice) express the PRR. In this study, we aimed to examine the effects of PRR activation on the firing activity of the TH-containing neurons in the PVN (TH PVN ). We hypothesized that prorenin activation of the PRR increases firing activity of the TH PVN neuron. To test this hypothesis, we performed electrophysiological recordings in loose cell-attached voltage-clamp configuration in PVN slices from mice expressing TdTomato reporter for TH neurons (TH-cre-TdTomato mice). These experiments were carried out to isolate and record spontaneous firing rate (SFR). We abolished all the synaptic transmission by adding a GABA A receptor antagonist (picrotoxin, 50 μM), an antagonist of AMPA/kainate receptors (CNQX, 5 μM), and an NMDA receptor antagonist (D-APV, 50 μM) throughout the recording. The cells were discarded if the access resistance was >15 MΩ or fluctuated more than 15%. At the end of the experiments, tetrodotoxin (1 μM) was added to abolish and confirm neuronal activity. The SFR in TH PVN neurons was significantly decreased after application of prorenin (PR) (4.9 ± 0.87 and 3.2 ± 1.07 Hz, before and after PR, respectively; n = 10, p = 0.006, paired t -test) indicating that PR reduces spontaneous firing activity of the TH PVN neurons. To determine if this effect was due to the prorenin activation of the PRR, we recorded SFR in the presence of PRR antagonist (PRO20). There was no difference in the SFR (5.8 ± 1.58 Hz and 5.9 ± 1.7 Hz, n = 5, p = 0.903, paired t -test) in the TH PVN neurons between PRO20 and PRO20+PR group respectively suggesting that PRO20 blocks the effect of PR in reducing SFR in TH PVN neurons. Our results showed that the prorenin acts on the PRR to reduce the SFR of the TH PVN neurons. We conclude that PRR signaling in the TH PVN neurons might play a role in cardiovascular and metabolic regulation by the modulating the TH PVN neuronal plasticity.

Abstract 031: Mutagenesis Of The Cleavage Site Of (pro)renin Receptor Abrogates Aldosterone-salt-induced Hypertension And Renal Injury In Mice

Soluble (pro)renin receptor (sPRR), the extracellular domain of (pro)renin receptor (PRR), is primarily generated by site-1 protease (S1P) and furin. It has been reported that sPRR functions as an important regulator of intrarenal renin contributing to angiotensin II (Ang II)-induced hypertension. Relatively, less is known for the function of sPRR in Ang II-independent hypertension such as mineralocorticoid excess. In the present study, we employed a novel mouse model with mutagenesis of the cleavage site in PRR (termed as Mutant mice) to examine the phenotype during aldosterone (Aldo)-salt treatment. The hypertensive response of Mutant mice to Aldo-salt treatment was blunted (day 12, delta MAP: WT/Aldo-salt 22.4±4.1 mm Hg vs. Mutant/Aldo-salt 11.7±2.5 mm Hg, n=6, p<0.05), in parallel with attenuated response of plasma volume expansion and sodium-water retention. Renal cortical and inner medullary mRNA and protein expression of α-, β-, and γ-subunits of epithelial sodium channel (ENaC) were all increased in WT mice after Aldo-salt treatment but only the increase of α-ENaC in inner medulla was blunted in Mutant mice. The plasma sPRR was increased 1.5-fold after Aldo-salt treatment, which was reduced by 57% in Mutant mice. Moreover, Aldo-salt-induced hypertrophy in the heart and kidney, which were improved in Mutant mice (Heart Weight/Body Weight: WT/Aldo-salt 5.8±0.4 mg/g vs. Mutant/Aldo-salt 4.2±0.3 mg/g; Kidney Weight/Body Weight: WT/Aldo-salt 9.9±0.4 mg/g vs. Mutant/Aldo-salt 7.3±0.4 mg/g, n=6, p<0.01), accompanied with blunted polydipsia and polyuria in Mutant mice. Furthermore, the urinary albumin was increased 8.3-fold after Aldo-salt treatment, which was reduced by 32% in Mutant mice. The mRNA levels of Fibronectin, α-SMA, IL-6, MCP-1 and TGF-β were increased in Aldo-salt/WT mice, which were prevented almost 60% in Aldo-salt/Mutant mice. Together, these results represent strong evidence favoring endogenous sPRR as a mediator of Aldo-salt-induced hypertension and renal injury. Here, we firstly report that sPRR-dependent pathway medicates the Na + -retaining action of Aldo in the distal nephron, which opens up a new area for a better understanding of the molecular basis of renal handling of Na + balance and blood pressure.

Abstract 063: Soluble (Pro)renin Receptor Acts Via Direct Activation Of Angiotensin Type 1 Receptor To Enhance Renal Aquaporin-2 Expression And Urine Concentrating Capability

Abundant evidence has established an essential role of collecting duct (pro)renin receptor (PRR) in regulation of aquaporin-2 (AQP-2) expression and urine concentrating capability. Moreover, such AQP2-regulating and antidiuretic action of PRR is mediated by its cleavage product, the soluble PRR (sPRR). However, the mechanism of action of sPRR in this setting remains incompletely understood. In light of our recent report of direct interaction of sPRR and angiotensin type 1 receptor (AT1R) in the vascular endothelial cells, we examined the hypothesis that sPRR signals via AT1R in the kidney. In primary rat inner medullary collecting duct cells, exposure to a recombinant sPRR (termed as sPRR-His) at 10 nM for 24 h induced 4 fold increase in AQP2 protein abundance, which was blunted by `~50% by pretreatment with losartan. In C57/BL6 mice, administration of the V2R antagonist (OPC at 30 mg/kg/d via gavage for 3 days) resulted in symptoms of nephrogenic diabetes insipidus (NDI), including polydipsia, polyuria, and hypoosmotic urine, all of which were improved by subcutaneous infusion of sPRR-His at 30 μg/kg/d via minipump (urine volume [ml]: 5.3 ± 0.2 vs. 3.3 ± 0.3, n =5, p < 0.01; urine osmolality [Osm/kg. H2O]: 428.6 ± 29.2 vs. 704.6 ± 24.2, n =5, p < 0.01). Administration of losartan (5 mg/kg/d) almost completely reversed the therapeutic effect of sPRR-His (urine volume [ml]: 4.7 ± 0.2; urine osmolality [Osm/kg. H2O]: 486 ± 16.1). Immunoblotting demonstrated that sPRR-His treatment restored OPC-induced reduction of AQP2 protein abundance, which was reversed by losartan. Together, sPRR interacted with AT1R to control renal AQP2 expression and urine concentrating capability.

Abstract 041: Renal-derived Human Sprr Increases Blood Pressure In Female Mice But Not In Male Mice

The soluble prorenin receptor (sPRR) plays an important role in blood pressure regulation. In rodent models, sPRR contributes to Ang II production by increasing renin activity and systolic blood pressure (SBP). However, there is a gap of knowledge concerning the functional role of locally produced human sPRR from the kidney in blood pressure regulation. Therefore, we evaluated the role of renal-derived human sPRR in SBP control.Human sPRR-Myc-tag transgenic mice were bred with mice expressing Hoxb7/Cre to selectively express human sPRR in the collecting duct (RHsPRR). RHsPRR and control (CTL) male and female mice were fed a standard diet for 10 months (n=8-11/group). Body weight was examined weekly and SBP measured by radio-telemetry. Western blot analysis depicted the presence of human sPRR-Myc-tag (28 KDa) in the cortex and medulla of RHsPRR male mice which validated the humanized mouse model. Renal-derived human sPRR did not change body weight in male or female mice (M: CTL: 34±1, RHsPRR: 33±1 g; F: CTL: 28±1, RHsPRR: 30±1 g). Circulating sPRR was also unchanged in male and female mice (M: 3995±643 and 4342±500pg/ml, F: 3479±194 and 3948±238pg/ml). SBP increased significantly in female RHsPRR mice compared to CTL (F: 118.7±2 and 127.2±3 mmHg, P<0.05) but not in male mice (M: 123.8±2 and 119.9±6 mmHg). In female mice, renal-derived human sPRR increased significantly renal AT1R gene expression (F: 1.7±0.5 and 2.6±0.4 2 -ΔΔCT , P<0.05) and stimulated ERK1/2 (F: 0.3±0.0 and 0.6±0.1 AU, P<0.05) suggesting that human sPRR increases blood pressure in female mice likely via AT1R-ERK1/2 pathway activation. In contrast, in male mice, AT1R-ERK1/2 pathway was not up-regulated and renal ACE2 gene expression was significantly increased in RHsPRR males (M: 1.0±0.2 and 3.3±1.1 2 -ΔΔCT , P<0.05). Mechanistically, in male mice, our results indicated that the lack of activation of AT1R-ERK1/2 pathway combined with the increase of ACE2 could have prevented RHsPRR-induced increase in SBP. Together, our data highlighted the contribution of renal human sPRR to blood pressure control in a sex-dependent manner and a new mechanism of blood pressure control that involved the renin angiotensin system.

Abstract 066: Renal-derived Human Sprr Induces Hypernatremia And Water Retention In Male Mice But Not Female Mice

The soluble prorenin receptor (sPRR) plays an important role in fluid and electrolyte balance. In rodent models, sPRR contributes to aquaporin2(AQP2)-dependent antidiuretic action. However, there is a gap of knowledge concerning the functional role of locally produced human sPRR from the kidney. Hence, we evaluated the role of renal-derived human sPRR in fluid and electrolyte homeostasis.Human sPRR-Myc-tag transgenic mice were bred with mice expressing Hoxb7/Cre to selectively express human sPRR in the collecting duct (RHsPRR). RHsPRR and control (CTL) male and female mice were fed a standard diet for 10 months (n=8-11/group). Body weight was examined weekly, body composition monthly and water balance at study endpoint. Western blot analysis depicted the presence of human sPRR-Myc-tag (28 KDa) in the cortex and medulla of RHsPRR male and female mice validating the humanized mouse model.Renal-derived human sPRR did not change body weight in male or female mice (Male: CTL: 34±1, RHsPRR: 33±1 g; Female: CTL: 28±1, RHsPRR: 30±1 g) nor kidney function assessed by GFR (Male: CTL: 817±83, RHsPRR: 1088±163 μl/min/100gBW; Female: CTL: 1057±75, RHsPRR: 875±89 μl/min/100gBW). In male mice, renal-derived human sPRR significantly elevated plasma sodium (Male: CTL: 115±4, RHsPRR: 127±3 mmol/L; P<0.05) and ENaC gene expression (M: 1.7±0.7 and 3.7±0.9 2 -ΔΔCT , P<0.05). Urine flow rate was decreased (Male: CTL: 1.0±0.2, RHsPRR: 0.6±0.2 ml; P<0.05) and AQP2 protein expression was increased in male RHsPRR mice compared to CTL (M: 0.13±0.05 and 0.44±0.12 AU, P<0.05), suggesting that renal-derived human sPRR elicits hypernatremia by stimulating sodium reabsorption via ENaC-dependent mechanism and water reabsorption by AQP2 expression.In female mice, renal-derived human sPRR did not change plasma sodium (Female: CTL: 120±7, RHsPRR: 118±5 mmol/L), ENaC gene expression (F: 1.2±0.2 and 1.4±0.1 2 -ΔΔCT ), urine flow rate (Female: CTL: 0.4±0.1, RHsPRR: 0.5±0.1 ml) or AQP2 protein expression (F: 0.20±0.03 and 0.20±0.06 AU, P<0.05).Our data suggest that renal cortical and medullary human sPRR regulates water and electrolyte balance in a sex specific-manner. Translationally, human sPRR could be a promising therapeutic target to treat hypernatremia in men.

Abstract 115: Soluble (pro)renin Receptor Contributes To Endotoxin-induced Septic Shock And Aki In Mice

Sepsis associated acute kidney injury (S-AKI) is a life-threating disease with poorly defined mechanisms and limited therapeutic options. Here we examined the role of site-1 protease (S1P)-derived soluble PRR (sPRR) in the S-AKI model induced by lipopolysaccharide (LPS). Male 10-week-old B6129SF1/J mice were pretreated with a S1P inhibitor PF-429242 (PF) at 20 mg/kg/day via minipump and treated with a single s.c. injection of LPS at 10 mg/kg and monitored for 24 hours. By radiotelemetry, LPS induced fall in mean arterial pressure (MAP) (Δ mmHg: -14.98 ± 4.13 in LPS+PF group vs . -23.15 ± 1.82 in LPS+ Vehicle group; n = 6, p < 0.05) and heart rate (HR) (Beats/min: -78.60 ± 20.73 in LPS+PF group vs . -133.35 ± 30.92 in LPS group, n = 6, p < 0.05), which was significantly attenuated by PF treatment. In parallel, renal dysfunction as reflected by the rises in plasma creatinine and BUN along with albuminuria, urinary excretion of NGAL and Kim-1 were all improved. Similar improvement was observed for infiltration of macrophage as assessed by immunofluorescence detection of F4/80 as well as renal mRNA expression of M1 markers such as iNOS, IL-1β, IL-6, and TNFα. The results from the pharmacological study were validated using a recently generated mouse model of mutagenesis of the cleavage site of PRR (termed Mutant mice). LPS-induced hypotensive response, renal dysfunction, the markers of renal injury and inflammation and M1 activation were all improved in Mutant mice as seen with PF treatment. LPS induced a 3.35-fold increase in plasma sPRR which was attenuated by PF or in Mutant mice. By immunofluorescence, LPS-induced PRR expression was largely restricted to renal medullary intercalated dells. In cultured RAW264.7 macrophage cells, recombinant sPRR treatment at 30 nM directly promoted macrophage migration and stimulated mRNA levels of M1 markers, all of which were attenuated by losartan. Taken together, the present study suggests that (1) S1P-derived sPRR contributes to LPS-induced septic shock and AKI, and (2) within the kidney, LPS-induced sPRR originates from intercalated cells and may act in a paracrine manner to activate AT1R on macrophages to induce pro-inflammatory response.

Inhibitory effect of (pro)renin receptor decoy inhibitor PRO20 on endoplasmic reticulum stress during cardiac remodeling.

Background: Ectopic activation of renin-angiotensin-system contributes to cardiovascular and renal diseases. (Pro)renin receptor (PRR) binds to renin and prorenin, participating in the progression of nephrology. However, whether PRR could be considered as a therapeutic target for cardiac remodeling and heart failure remains unknown. Materials and methods: Transverse aortic constriction (TAC) surgery was performed to establish a mouse model of chronic pressure overload-induced cardiac remodeling. Neonatal rat cardiomyocytes (CMs) and cardiac fibroblasts (CFs) were isolated and stimulated by Angiotensin II (Ang II). PRR decoy inhibitor PRO20 was synthesized and used to evaluate its effect on cardiac remodeling. Results: Soluble PRR and PRR were significantly upregulated in TAC-induced cardiac remodeling and Ang II-treated CMs and CFs. Results of In vivo experiments showed that suppression of PRR by PRO20 significantly retarded cardiac remodeling and heart failure indicated by morphological and echocardiographic analyses. In vitro experiments, PRO20 inhibited CM hypertrophy, and also alleviated CF activation, proliferation and extracellular matrix synthesis. Mechanically, PRO20 enhanced intracellular cAMP levels, but not affected cGMP levels in CMs and CFs. Moreover, treatment of PRO20 in CFs markedly attenuated the production of reactive oxygen species and phosphorylation of IRE1 and PERK, two well-identified markers of endoplasmic reticulum (ER) stress. Accordingly, administration of PRO20 reversed ER stressor thapsigargin-induced CM hypertrophy and CF activation/migration. Conclusion: Taken together, these findings suggest that inhibition of PRR by PRO20 attenuates cardiac remodeling through increasing cAMP levels and reducing ER stress in both CMs and CFs.

Soluble (Pro)Renin Receptor Levels Are Regulated by Plasma Renin Activity and Correlated with Edema in Mice and Humans with HFrEF

Symptomatic heart failure with reduced ejection fraction (HFrEF) is characterized by edema and chronic pathological activation of the classical renin–angiotensin–aldosterone system (RAAS). The soluble (pro)renin receptor (s(P)RR) is released into circulation by proteolytic cleavage of tissue expressed (P)RR and is a candidate biomarker of RAAS activation. However, previous studies linked elevated levels of s(P)RR in patients with HFrEF to renal dysfunction. Utilizing prospectively enrolled patients with comparable rEF, we show that increased plasma levels of s(P)RR are associated with symptomatic HF (characterized by edema), independent of chronic renal dysfunction. We also found that s(P)RR levels were positively correlated with patient plasma renin activity (PRA). Normotensive mice with dilated cardiomyopathy (DCM) and HFrEF, without renal dysfunction, showed plasma s(P)RR and PRA patterns similar to human HFrEF patients. Plasma s(P)RR levels positively correlated with PRA and systemic edema, but not with EF, resembling findings in patients with HFrEF without chronic kidney dysfunction. In female DCM mice with elevated PRA levels and plasma s(P)RR levels, a randomized, blinded trial comparing the direct renin inhibitor, aliskiren vs. vehicle control, showed that direct renin inhibition normalized PRA, lowered s(P)RR, and prevented symptomatic HFrEF. Considered in light of previous findings, these data suggest that, in HFrEF, in the absence of renal dysfunction, elevation of plasma s(P)RR levels is caused by increased PRA and associated with the development of systemic edema.

(Pro)renin Receptor and Blood Pressure Regulation: A Focus on the Central Nervous System.

The renin-angiotensin system (RAS) is classically described as a hormonal system in which angiotensin II (Ang II) is one of the main active peptides. The action of circulating Ang II on its cognate Ang II type-1 receptor (AT1R) in circumventricular organs has important roles in regulating the autonomic nervous system, blood pressure (BP) and body fluid homeostasis, and has more recently been implicated in cardiovascular metabolism. The presence of a local or tissue RAS in various tissues, including the central nervous system (CNS), is well established. However, because the level of renin, the rate-limiting enzyme in the systemic RAS, is very low in the brain, how endogenous angiotensin peptides are generated in the CNS-the focus of this review-has been the subject of considerable debate. Notable in this context is the identification of the (pro)renin receptor (PRR) as a key component of the brain RAS in the production of Ang II in the CNS. In this review, we highlight cellular and anatomical locations of the PRR in the CNS. We also summarize studies using gain- and loss-of function approaches to elucidate the functional importance of brain PRR-mediated Ang II formation and brain RAS activation, as well as PRR-mediated Ang II-independent signaling pathways, in regulating BP. We further discuss recent developments in PRR involvement in cardiovascular and metabolic diseases and present perspectives for future directions.

Hormone-Dependent Regulation of Renin and Effects on Prorenin Receptor Signaling in the Collecting Duct.

The production of renin by the principal cells of the collecting duct has widened our understanding of the regulation of intrarenal angiotensin II (Ang II) generation and blood pressure. In the collecting duct, Ang II increases the synthesis and secretion of renin by mechanisms involving the activation of Ang II type 1 receptor (AT1R) via stimulation of the PKCα, Ca2+, and cAMP/PKA/CREB pathways. Additionally, paracrine mediators, including vasopressin (AVP), prostaglandins, bradykinin (BK), and atrial natriuretic peptide (ANP), regulate renin in principal cells. During Ang II-dependent hypertension, despite plasma renin activity suppression, renin and prorenin receptor (RPR) are upregulated in the collecting duct and promote de novo formation of intratubular Ang II. Furthermore, activation of PRR by its natural agonists, prorenin and renin, may contribute to the stimulation of profibrotic factors independent of Ang II. Thus, the interactions of RAS components with paracrine hormones within the collecting duct enable tubular compartmentalization of the RAS to orchestrate complex mechanisms that increase intrarenal Ang II, Na+ reabsorption, and blood pressure.

Molecules related to diabetic retinopathy in the vitreous and involved pathways.

Diabetic retinopathy (DR) is one of the most common complications of diabetes and major cause of blindness among people over 50 years old. Current studies showed that the vascular endothelial growth factor (VEGF) played a central role in the pathogenesis of DR, and application of anti-VEGF has been widely acknowledged in treatment of DR targeting retinal neovascularization. However, anti-VEGF therapy has several limitations such as drug resistance. It is essential to develop new drugs for future clinical practice. The vitreous takes up 80% of the whole globe volume and is in direct contact with the retina, making it possible to explore the pathogenesis of DR by studying related factors in the vitreous. This article reviewed recent studies on DR-related factors in the vitreous, elaborating the VEGF upstream hypoxia-inducible factor (HIF) pathway and downstream pathways phosphatidylinositol diphosphate (PIP2), phosphoinositide-3-kinase (PI3K), and mitogen-activated protein kinase (MAPK) pathways. Moreover, factors other than VEGF contributing to the pathogenesis of DR in the vitreous were also summarized, which included factors in four major systems, kallikrein-kinin system such as bradykinin, plasma kallikrein, and coagulation factor XII, oxidative stress system such as lipid peroxide, and superoxide dismutase, inflammation-related factors such as interleukin-1β/6/13/37, and interferon-γ, matrix metalloproteinase (MMP) system such as MMP-9/14. Additionally, we also introduced other DR-related factors such as adiponectin, certain specific amino acids, non-coding RNA and renin (pro) receptor in separate studies.

Prize‐winning abstracts from BSACI/WAO 2022 meeting

Prize‐winning abstracts from <scp>BSACI</scp>/<scp>WAO</scp> 2022 meeting

Angiotensin-(1-7): A novel therapeutic target for preventing cardiovascular disease

Angiotensin-(1-7) is a vasoactive heptapeptide of renin-angiotensin system which is usually produced by angiotensin converting enzyme 2 and exhibits activity through activation of Mitochondrial assembly (Mas) receptor. In present scenario, the Ang-(1-7)/ACE2/Mas axis has tendency to counterbalance many vasoconstrictor biomolecules such as classical renin angiotensin system that includes ACE, ANG, renin, AT1 and AT2 receptors. Ang (1-7) is a vasodilator substance that shows significant roles in cardiovascular system. Because of the protective roles of Ang-(1-7) in cardiomyocytes and endothelial tissues, it is also known to evoke anti- arrhythmogenic effects as well as endogenous inducer for the release of vasodilators like nitric oxide and prostanoids. Moreover, the heptapeptide Ang-(1-7) is also being explored against organ failure, renal diseases, preeclampsia and even against carcinoma. This review circumscribes many pharmacological potentials of Ang-(1-7) against various physiological conditions.

Practical Applications of The Unreasonable Attractiveness of More ESG Data

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 V₀ 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.