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 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 used a novel mouse model with mutagenesis of the cleavage site in PRR (termed as PRRR279V/L282V or mutant) to examine the phenotype during aldosterone (Aldo)-salt treatment. The hypertensive response of mutant mice to Aldo-salt treatment was blunted in parallel with the attenuated response of plasma volume expansion and renal medullary α-epithelial Na+ channel expression. Moreover, Aldo-salt-induced hypertrophy in the heart and kidney as well as proteinuria were improved, accompanied by blunted polydipsia and polyuria. Together, these results represent strong evidence favoring endogenous sPRR as a mediator of Aldo-salt-induced hypertension and renal injury.NEW & NOTEWORTHY We used a novel mouse model with mutagenesis of the cleavage site of PRR to support soluble PRR as an essential mediator of aldosterone-salt-induced hypertension and also as a potential therapeutic target for patients with mineralocorticoid excess. We firstly report that soluble PRR-dependent pathway medicates the Na+-retaining action of aldosterone 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.

Measurement and multiplexing of ultra-low duty cycle Nyquist pulse sequences.

In this paper, we propose a novel, to the best of our knowledge, method to our knowledge for generating and accurately measuring Nyquist pulse sequences with an ultra-low duty cycle of only 0.037, which breaks the limitations caused by the noise and bandwidth of the optical sampling oscilloscope (OSO) by using a narrow-bandwidth real-time oscilloscope (OSC) and an electrical spectrum analyzer (ESA). By this method, it is found that the bias point drift of the dual parallel Mach-Zehnder modulator (DPMZM) is the main cause of the distortion of the waveform. In addition, we increase the repetition rate of Nyquist pulse sequences by a factor of 16 by multiplexing the unmodulated Nyquist pulse sequences.

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.

Role of (pro)renin receptor in cyclosporin A-induced nephropathy.

Calcineurin inhibitors such as cyclosporin A (CsA) have been widely used to improve graft survival following solid-organ transplantation. However, the clinical use of CsA is often limited by its nephrotoxicity. The present study tested the hypothesis that activation of the (pro)renin receptor (PRR) contributes to CsA-induced nephropathy by activating the renin-angiotensin system (RAS). Renal injury in male Sprague-Dawley rats was induced by a low-salt diet combined with CsA as evidenced by elevated plasma creatinine and blood urea nitrogen levels, decreased creatinine clearance and induced renal inflammation, apoptosis and interstitial fibrosis, and elevated urinary N-acetyl-ß-d-glucosaminidase activity and urinary kidney injury molecule-1 content. Each index of renal injury was attenuated following 2 wk of treatment with the PRR decoy inhibitor PRO20. Although CsA-treated rats with kidney injury displayed increased renal soluble (s)PRR abundance, plasma sPRR, renin activity, angiotensin II, and heightened urinary total prorenin/renin content, RAS activation was attenuated by PRO20. Exposure of cultured human renal proximal tubular HK-2 cells to CsA induced expression of fibronectin and sPRR production, but the fibrotic response was attenuated by PRO20 and siRNA-mediated PRR knockdown. These findings support the hypothesis that activation of PRR contributes to CsA-induced nephropathy by activating the RAS in rats. Of importance, we provide strong proof of concept that targeting PRR offers a novel therapeutic strategy to limit nephrotoxic effects of immunosuppressant drugs.NEW & NOTEWORTHY The present study reports, for the first time, that activation of the (pro)renin receptor drives the renin-angiotensin system to induce renal injury during cyclosporin A administration. More importantly, our study has identified that antagonism with PRO20 offers a novel intervention in the management of side effects of cyclosporin A.

Revisiting the relationship between (Pro)Renin receptor and the intrarenal RAS: focus on the soluble receptor.

PURPOSE OF REVIEW: The (pro)renin receptor (PRR), also termed as ATPase H+ transporting accessory protein 2 (ATP6AP2), was originally cloned as a specific receptor for prorenin and renin [together called (pro)renin]. Given the wide tissue distribution of PRR, PRR was further postulated to act as a regulator of tissue renin. However, assigning a physiological role of PRR within the renin-angiotensin system (RAS) has been challenging largely due to its pleotropic functions in regulation of embryogenesis, autophagy, and H+ transport. The current review will summarize recent advances in understanding the roles of sPPR within the intrarenal RAS as well as those outside this local system. RECENT FINDINGS: Site-1 protease (S1P) is a predominant source of sPPR at least in the kidney. So far most of the known physiological functions of PRR including renal handling of electrolytes and fluid and blood pressure are mediated by sPRR. In particular, sPRR serves as a positive regulator of collecting duct renin to activate the intrarenal RAS during water deprivation or angiotensin-II (AngII) infusion. However, PRR/sPRR can act in renin-independent manner under other circumstances. SUMMARY: S1P-derived sPRR has emerged as a key regulator of kidney function and blood pressure and its relationship with the intrarenal RAS depends on the physiological context.

Neurokinin-1 receptor is an effective target for treating leukemia by inducing oxidative stress through mitochondrial calcium overload.

Substance P (SP) regulates multiple biological processes through its high-affinity neurokinin-1 receptor (NK-1R). While the SP/NK-1R signaling axis is involved in the pathogenesis of solid cancer, the role of this signaling pathway in hematological malignancy remains unknown. Here, we demonstrate that NK-1R expression is markedly elevated in the white blood cells from acute myeloid leukemia patients and a panel of human leukemia cell lines. Blocking NK-1R induces apoptosis in vitro and in vivo via increase of mitochondrial reactive oxygen species. This oxidative stress was triggered by rapid calcium flux from the endoplasmic reticulum into mitochondria and, consequently, impairment of mitochondrial function, a mechanism underlying the cytotoxicity of NK-1R antagonists. Besides anticancer activity, blocking NK-1R produces a potent antinociceptive effect in myeloid leukemia-induced bone pain by alleviating inflammation and inducing apoptosis. These findings thus raise the exciting possibility that the NK-1R antagonists, drugs currently used in the clinic for preventing chemotherapy-induced nausea and vomiting, may provide a therapeutic option for treating human myeloid leukemia.

Serine Protease HTRA1 as a Novel Target Antigen in Primary Membranous Nephropathy.

BACKGROUND: Identification of target antigens PLA2R, THSD7A, NELL1, or Semaphorin-3B can explain the majority of cases of primary membranous nephropathy (MN). However, target antigens remain unidentified in 15%-20% of patients. METHODS: A multipronged approach, using traditional and modern technologies, converged on a novel target antigen, and capitalized on the temporal variation in autoantibody titer for biomarker discovery. Immunoblotting of human glomerular proteins followed by differential immunoprecipitation and mass spectrometric analysis was complemented by laser-capture microdissection followed by mass spectrometry, elution of immune complexes from renal biopsy specimen tissue, and autoimmune profiling on a protein fragment microarray. RESULTS: These approaches identified serine protease HTRA1 as a novel podocyte antigen in a subset of patients with primary MN. Sera from two patients reacted by immunoblotting with a 51-kD protein within glomerular extract and with recombinant human HTRA1, under reducing and nonreducing conditions. Longitudinal serum samples from these patients seemed to correlate with clinical disease activity. As in PLA2R- and THSD7A- associated MN, anti-HTRA1 antibodies were predominantly IgG4, suggesting a primary etiology. Analysis of sera collected during active disease versus remission on protein fragment microarrays detected significantly higher titers of anti-HTRA1 antibody in active disease. HTRA1 was specifically detected within immune deposits of HTRA1-associated MN in 14 patients identified among three cohorts. Screening of 118 "quadruple-negative" (PLA2R-, THSD7A-, NELL1-, EXT2-negative) patients in a large repository of MN biopsy specimens revealed a prevalence of 4.2%. CONCLUSIONS: Conventional and more modern techniques converged to identify serine protease HTRA1 as a target antigen in MN.

Soluble (pro)renin receptor induces endothelial dysfunction and hypertension in mice with diet-induced obesity via activation of angiotensin II type 1 receptor.

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.

Observation of square- and h-shaped pulse from a mode-locked erbium-doped fiber laser.

We demonstrate the generation of a type of square-shaped pulse in a passively mode-locked erbium-doped fiber laser based on the nonlinear optical loop mirror technique. Through adjusting the pump power and polarization state, square-shaped pulses are generated. Furthermore, we investigate the pulse profile in relation to the optical spectrum. By filtering out short-wavelength spectrum components gradually, pulse shaping is achieved, and the top of the square-shaped pulse becomes flat. Subsequently, by filtering out long-wavelength spectrum components, a type of h-shaped pulse is obtained and the formation reason is also investigated.

Temperature-dependent characteristics of infrared photodetectors based on surface-state absorption in silicon.

At various temperatures, ranging from 25°C to 50°C, we characterized two types of photodetectors based on surface-state absorption in silicon: (1) contactless integrated photonic probes (CLIPPs) and (2) normal-incidence photoconductors. Both types of photodetectors exhibited temperature-dependent AC admittance without illumination. With illumination at telecommunication wavelengths near 1550 nm, in the temperature range we measured, the photoresponse of CLIPPs, i.e., the variance of admittance due to illumination, was relatively insensitive to temperature changes; in comparison, the temperature dependence of the photoresponse of normal-incidence photoconductors was more pronounced-their responsivity increased as temperature raised.

(Pro)renin receptor decoy peptide PRO20 protects against adriamycin-induced nephropathy by targeting the intrarenal renin-angiotensin system.

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.

COX-2-independent activation of renal (pro)renin receptor contributes to DOCA-salt hypertension in rats.

It has been shown that cyclooxygenase (COX)-2-dependent activation of renal (pro)renin receptor (PRR) contributes to angiotensin II (ANG II)-induced hypertension. However, less is known about the involvement of this mechanism in ANG II-independent hypertension. The goal of the present study was to test whether or not COX-2-dependent upregulation of PRR serves as a universal mechanism contributing to ANG II-dependent and -independent hypertension. Here, we examined the association between renal COX-2 and PRR during deoxycorticosterone acetate (DOCA)-salt hypertension in rats. By immunoblot analysis and immunofluorescence, renal protein expression of PRR was remarkably upregulated by DOCA-salt treatment. Surprisingly, this upregulation of renal PRR expression was unaffected by a COX-2 inhibitor, celecoxib. To address the role of renal PRR to the pathogenesis of DOCA-salt hypertension, a decoy PRR inhibitor, PRO20, was infused to the renal medulla of uninephrectomized Sprague-Dawley rats for 14 days. Radiotelemetry demonstrated effective attenuation of DOCA-salt hypertension by intramedullary infusion of a PRR inhibitor, PRO20. In parallel, DOCA-salt-induced hypertrophy in the heart and kidney as well as proteinuria were improved, accompanied with blunted polydipsia and polyuria. In contrast, intravenous infusion of PRO20 was less effective in attenuating DOCA-salt hypertension and cardiorenal injury. Together, these results suggest that COX-2-independent activation of renal PRR contributes to DOCA-salt hypertension.

Soluble (pro)renin receptor regulation of ENaC involved in aldosterone signaling in cultured collecting duct cells.

We have previously shown that activation of (pro)renin receptor (PRR) induces epithelial Na+ channel (ENaC) activity in cultured collecting duct cells. Here, we examined the role of soluble PRR (sPRR), the cleavage product of PRR in ENaC regulation, and further tested its relevance to aldosterone signaling. In cultured mpkCCD cells, administration of recombinant histidine-tagged sPRR (sPRR-His) at 10 nM within minutes induced a significant and transient increase in the amiloride-sensitive short-circuit current as assessed using the Ussing chamber technique. The acute ENaC activation was blocked by the NADPH oxidase 1/4 inhibitor GKT137892 and siRNA against Nox4 but not the ß-catenin inhibitor ICG-001. In primary rat inner medullary collecting duct cells, administration of sPRR-His at 10 nM for 24 h induced protein expression of the α-subunit but not ß- or γ-subunits of ENaC, in parallel with upregulation of mRNA expression as well as promoter activity of the α-subunit. The transcriptional activation of α-ENaC was dependent on ß-catenin signaling. Consistent results obtained by epithelial volt ohmmeter measurement of equivalent current and Ussing chamber determination of short-circuit current showed that aldosterone-induced transepithelial Na+ transport was inhibited by the PRR decoy inhibitor PRO20 and PF-429242, an inhibitor of sPRR-generating enzyme site-1 protease, and the response was restored by the addition of sPRR-His. Medium sPRR was elevated by aldosterone and inhibited by PF-429242. Taken together, these results demonstrate that sPRR induces two phases of ENaC activation via distinct mechanisms and functions as a mediator of the natriferic action of aldosterone.

Soluble (pro)renin receptor promotes the fibrotic response in renal proximal tubule epithelial cells in vitro via the Akt/ß-catenin/Snail signaling pathway.

Tubulointerstitial fibrosis has been regarded as a critical event in the pathogenesis of chronic kidney disease. The soluble form of (pro)renin receptor (sPRR), generated by site-1 protease (S1P) cleavage of full-length PRR, can be detected in biological fluid and elevated under certain pathological conditions. The present study was designed to evaluate the potential role of sPRR in the regulation of the fibrotic response in a cultured human renal proximal tubular cell line (HK-2 cells) in the setting of transforming growth factor (TGF)-ß or sPRR-His treatment. The TGF-ß-induced fibrotic response of HK-2 cells was indicated by upregulation of fibronectin (FN) expression; meanwhile, TGF-ß could also induce the generation of sPRR, due to enhanced cleavage of full-length PRR. To explore the role of sPRR in the fibrotic response of HK-2 cells, we blocked the production of sPRR with a the S1P inhibitor PF429242 and found that PF429242 remarkably suppressed TGF-ß-induced sPRR generation and FN expression in HK-2 cells. Administration of sPRR-His restored the PF429242-attenuated FN expression in HK-2 cells, indicating that sPRR could promote the TGF-ß-induced fibrotic response. Furthermore, sPRR-His alone also increased the abundance of FN in HK-2 cells. These data suggested that sPRR was sufficient and necessary for the TGF-ß-induced fibrotic response of HK-2 cells. Mechanistically, sPRR activated the AKT and ß-catenin pathway in HK-2 cells, and blockade of the AKT or ß-catenin pathway significantly abrogated sPRR-induced FN and Snail expression. Taking together, sPRR promoted the fibrotic response of HK-2 cells by activating Akt/ß-catenin/Snail signaling, and it may serve as a potential therapeutic target in renal fibrosis.

ELABELA antagonizes intrarenal renin-angiotensin system to lower blood pressure and protects against renal injury.

Emerging evidence has demonstrated that (pro)renin receptor (PRR)-mediated activation of intrarenal renin-angiotensin system (RAS) plays an essential role in renal handling of Na+ and water balance and blood pressure. The present study tested the possibility that the intrarenal RAS served as a molecular target for the protective action of ELABELA (ELA), a novel endogenous ligand of apelin receptor, in the distal nephron. By RNAscope and immunofluorescence, mRNA and protein expression of endogenous ELA was consistently localized to the collecting duct (CD). Apelin was also found in the medullary CDs as assessed by immunofluorescence. In cultured CD-derived M1 cells, exogenous ELA induced parallel decreases of full-length PRR (fPRR), soluble PRR (sPRR), and prorenin/renin protein expression as assessed by immunoblotting and medium sPRR and prorenin/renin levels by ELISA, all of which were reversed by 8-bromoadenosine 3',5'-cyclic monophosphate. Conversely, deletion of PRR in the CD or nephron in mice elevated Apela and Apln mRNA levels as well as urinary ELA and apelin excretion, supporting the antagonistic relationship between the two systems. Administration of exogenous ELA-32 infusion (1.5 mg·kg-1·day-1, minipump) to high salt (HS)-loaded Dahl salt-sensitive (SS) rats significantly lowered mean arterial pressure, systolic blood pressure, diastolic blood pressure, and albuminuria, accompanied with a reduction of urinary sPRR, angiotensin II, and prorenin/renin excretion. HS upregulated renal medullary protein expression of fPRR, sPRR, prorenin, and renin in Dahl SS rats, all of which were significantly blunted by exogenous ELA-32 infusion. Additionally, HS-induced upregulation of inflammatory cytokines (IL-1ß, IL-2, IL-6, IL-17A, IFN-γ, VCAM-1, ICAM-1, and MCP-1), fibrosis markers (TGF-ß1, FN, Col1A1, PAI-1, and TIMP-1), and kidney injury markers (NGAL, Kim-1, albuminuria, and urinary NGAL excretion) were markedly blocked by exogenous ELA infusion. Together, these results support the antagonistic interaction between ELA and intrarenal RAS in the distal nephron that appears to exert a major impact on blood pressure regulation.

Hydrogen sulfide upregulates renal AQP-2 protein expression and promotes urine concentration.

Increasing evidence supports the important role of H2S in renal physiology and the pathogenesis of kidney injury. Whether H2S regulates water metabolism in the kidney and the potential mechanism are still unknown. The present study was conducted to determine the role of H2S in urine concentration. Inhibition of both cystathionine-γ-lyase (CSE) and cystathionine-ß-synthase (CBS), 2 major enzymes for endogenous H2S production, with propargylglycine (PPG) and amino-oxyacetate (AOAA), respectively, caused increased urine output and reduced urine osmolality in mice that was associated with decreased expression of aquaporin (AQP)-2 in the renal inner medulla. Mice treated with both PPG and AOAA developed a urine concentration defect in response to dehydration that was accompanied by reduced AQP-2 protein expression. Inhibition of CSE alone was associated with a mild decrease in AQP-2 protein level in the renal medulla of heterozygous CBS mice. GYY4137, a slow H2S donor, markedly improved urine concentration and prevented the down-regulation of renal AQP-2 protein expression in mice with lithium-induced nephrogenic diabetes insipidus (NDI). GYY4137 significantly increased cAMP levels in cell lysates prepared from inner medullary collecting duct (IMCD) suspensions. AQP-2 protein expression was also upregulated, but was significantly inhibited by the adenyl cyclase inhibitor MDL12330A or the PKA inhibitor H89, but not the vasopressin 2 receptor (V2R) antagonist tolvaptan. Inhibition of endogenous H2S production impaired urine concentration in mice, whereas an exogenous H2S donor improved urine concentration in lithium-induced NDI by increasing AQP-2 expression in the collecting duct principal cells. H2S upregulated AQP-2 protein expression, probably via the cAMP-PKA pathway.-Luo, R., Hu, S., Liu, Q., Han, M., Wang, F., Qiu, M., Li, S., Li, X., Yang, T., Fu, X., Wang, W., Li, C. Hydrogen sulfide upregulates renal AQP-2 protein expression and promotes urine concentration.

Protein spectrum changes in exosomes after therapeutic plasma exchange in patients with neuromyelitis optica.

INTRODUCTION: Neuromyelitis optica (NMO) is an autoimmune disease with a high rate of blindness and positive for the detection of aquaporin-4 antibody (AQP4) in most patients. NMO acute attacks are managed by high-doses of intravenous methylprednisolone followed by oral taper, and if symptoms fail to resolve, therapeutic plasma exchange (TPE) is added. TPE can remove pathological antibodies and inflammatory factors leading to clinical improvement. METHODS: A total of 40 TPE fluid collections from the first to fifth TPE treatments were obtained from eight patients. Exosomes were isolated by ultracentrifugation. Mass spectrometry analyses were used to compare protein change in TPE fluid collection exosomes after the first to the fifth TPE treatments in these patients. RESULTS: We detected 647 exosome proteins through data-independent acquisition analysis. It was found that some unknown functional antibody fragments and complement pathway proteins decreased after TPE treatment. The results revealed a significant involvement of the following two key pathways: the primary immunodeficiency and systemic lupus erythematosus that may be associated with NMO pathophysiology and TPE treatment efficacy (P < .05). A series of complement proteins may contribute to NMO; in addition, the following proteins increased with plasma exchange: complement factor H-related protein 5, bridging integrator 2, neuroplastin, pigment epithelium-derived factor, ficolin-1, extracellular matrix protein 1, and fatty acid-binding protein 5. CONCLUSION: Our study may provide a new perspective on the pathogenesis and treatment efficacy of NMO.

A Novel Method of Measuring Instantaneous Frequency of an Ultrafast Frequency Modulated Continuous-Wave Laser.

Ultrafast linear frequency modulated continuous-wave (FMCW) lasers are a special category of CW lasers. The linear FMCW laser is the light source for many sensing applications, especially for light detection and ranging (LiDAR). However, systems for the generation of high quality linear FMCW light are limited and diverse in terms of technical approaches and mechanisms. Due to a lack of characterization methods for linear FMCW lasers, it is difficult to compare and judge the generation systems in the same category. We propose a novel scheme for measuring the mapping relationship between instantaneous frequency and time of a FMCW laser based on a modified coherent optical spectrum analyzer (COSA) and digital signal processing (DSP) method. Our method has the potential to measure the instantaneous frequency of a FMCW laser at an unlimited sweep rate. In this paper, we demonstrate how to use this new method to precisely measure a FMCW laser at a large fast sweep rate of 5000 THz/s by both simulation and experiments. We find experimentally that the uncertainty of this method is less than 100 kHz and can be improved further if a frequency feedback servo system is introduced to stabilize the local CW laser.

Sodium butyrate attenuates angiotensin II-induced cardiac hypertrophy by inhibiting COX2/PGE2 pathway via a HDAC5/HDAC6-dependent mechanism.

Sodium butyrate (NaBu) is reported to play important roles in a number of chronic diseases. The present work is aimed to investigate the effect of NaBu on angiotensin II (Ang II)-induced cardiac hypertrophy and the underlying mechanism in in vivo and in vitro models. Sprague Dawley rats were infused with vehicle or Ang II (200 ng/kg/min) and orally administrated with or without NaBu (1 g/kg/d) for two weeks. Cardiac hypertrophy parameters and COX2/PGE2 pathway were analysed by real-time PCR, ELISA, immunostaining and Western blot. The cardiomyocytes H9C2 cells were used as in vitro model to investigate the role of NaBu (2 mmol/L) in inhibition of Ang II-induced cardiac hypertrophy. NaBu significantly attenuated Ang II-induced increase in the mean arterial pressure. Ang II treatment remarkably increased cardiac hypertrophy as indicated by increased ratio of heart weight/body weight and enlarged cardiomyocyte size, extensive fibrosis and inflammation, as well as enhanced expression of hypertrophic markers, whereas hearts from NaBu-treated rats exhibited a significant reduction in these hypertrophic responses. Mechanistically, NaBu inhibited the expression of COX2/PGE2 along with production of ANP and phosphorylated ERK (pERK) stimulated by Ang II in in vivo and in vitro, which was accompanied by the suppression of HDAC5 and HDAC6 activities. Additionally, knocking down the expression of HDAC5 and HDAC6 via gene-editing strategy dramatically blocked Ang II-induced hypertrophic responses through COX2/PGE2 pathway. These results provide solid evidence that NaBu attenuates Ang II-induced cardiac hypertrophy by inhibiting the activation of COX2/PGE2 pathway in a HDAC5/HDAC6-dependent manner.

(Pro)renin receptor contributes to pregnancy-induced sodium-water retention in rats via activation of intrarenal RAAS and α-ENaC.

The (pro)renin receptor (PRR) is a new component of the renin-angiotensin-aldosterone system (RAAS) and regulates renin activity. The objective of the present study was to test potential roles of the renal PRR and intrarenal RAAS in the physiological status of late pregnancy. Late pregnant Sprague-Dawley rats were studied 19-21 days after sperm was observed in vaginal smears. Experiments were performed using age-matched virgin rats and late pregnant rats treated with the specific PRR inhibitor PRO20 (700 µg·kg-1·day-1 sc for 14 days, 3 times/day for every 8 h) or vehicle. The indices of RAAS, including PRR, renin, angiotensin II, and aldosterone levels, were examined by immunoblotting, qRT-PCR, or ELISA. Further analyses of renal epithelial sodium channel (ENaC) expression, sodium-water retention, and plasma volume were performed. We first present evidence for the activation of intrarenal RAAS in late pregnant rats, including increases in urinary renin activity, active and total renin content, and prorenin content, angiotensin II and aldosterone excretion, in parallel with increased renal PRR expression and urinary soluble PRR excretion. Functional evidence demonstrated that PRR antagonism with PRO20 effectively suppressed the indices of intrarenal RAAS in late pregnant rats. In addition, our results revealed that renal α-ENaC expression, sodium-water retention, and plasma volume were elevated during late pregnancy, which were all attenuated by PRO20. In summary, the present study examined the renal mechanism of sodium-water retention and plasma volume expansion in late pregnant rats and identified a novel role of PRR in regulation of intrarenal RAAS and α-ENaC and thus sodium and fluid retention associated with pregnancy.