Persistent chronic calcific pancreatitis with intraductal calculi associated with secondary diabetes mellitus type 3 and diabetic ketoacidosis - A case report.

Diabetes mellitus type 3 refers to diabetes secondary to an existing disease or condition of the exocrine pancreas and is an uncommon cause of diabetes occurring due to pancreatogenic pathology. It accounts for 15-20% of diabetic patients in Indian and Southeast Asian continents. This is case report of a rare case of type 3 diabetes mellitus (T3DM) presenting with diabetic ketoacidosis (DKA). The patient was admitted for DKA along with complaint of hyperglycemia, blood glucose of 405 mg/dl with HbA1c level of 13.7%. Computed tomography evidence revealed chronic calcific pancreatitis with intraductal calculi and dilated pancreatic duct.

Repetitive self-healing of Diels-Alder grafted graphene nanoplatelet reinforced carbon fiber reinforced polymer composites with outstanding mechanical properties.

The concept of using bio-inspired healing mechanisms in fiber-reinforced polymer (FRP)-based laminated composites is one of the trending areas of research for lightweight high-performance materials. To introduce self-healing in laminated composites, we developed Diels-Alder (DA) grafted graphene nanoplatelets (GNPs) and introduced them into carbon-fiber-reinforced polymer (CFRP) composites. The DA-grafted GNPs provided dual benefits, such as repetitive self-healing along with an increased mechanical performance of the modified CFRP. The GNPs were functionalized with DA adducts, i.e., bismaleimide and furfurylamine via a facile functionalization approach. The highest healing efficiency evaluated using double cantilever beam (DCB) tests was observed as ∼87% with more than 10 times repeated healing cycles. The innovative concept and strategy proposed in this work could be a gateway to a new area of research to upscale for industrialization of DA-based repetitive self-healable and durable CFRP-based composites.

From trash to treasure: review on upcycling of fruit and vegetable wastes into starch based bioplastics.

Growing public concern toward environmental sustainability is currently motivating a paradigm shift toward designing easily degradable plastics that can replace conventional synthetic plastics. The massive rise in food waste generation has led to an increased burden on landfills, thereby resulting in the higher emission of greenhouse gases. Using this food waste to produce bioplastics will benefit not only the environment but also develop a systematic food waste management system. Moreover, bioplastics are preferred due to the use of biomaterials derived from renewable resources. Furthermore, bioplastics degrade faster than conventional synthetic plastics, which take years to degrade. The biodegradation of bioplastics occurs under normal environmental conditions and disintegrates into carbon dioxide, water, biomass, and inorganic compounds without producing hazardous residues. In this review, we will discuss the synthesis of starch based bioplastics using discarded parts of various fruits and vegetables. Furthermore, we will address the importance of various components in the development of starch based bioplastics, such as fillers, plasticizers, and other additives that are essential in providing the bioplastic with different physio-mechanical properties. Therefore, bioplastic production using food waste will pave the way to achieve systematic waste management and environmental sustainability in the near future.

Depletion of cyclic-GMP levels and inhibition of cGMP-dependent protein kinase activate p21Cip1 /p27Kip1 pathways and lead to renal fibrosis and dysfunction.

Cell-cycle regulatory proteins (p21Cip1 /p27Kip1 ) inhibit cyclin and cyclin-dependent kinase (CDK) complex that promotes fibrosis and hypertrophy. The present study examined the role of CDK blockers, p21Cip1 /p27Kip1 in the progression of renal fibrosis and dysfunction using Npr1 (encoding guanylyl cyclase/natriuretic peptide receptor-A, GC-A/NPRA) gene-knockout (0-copy; Npr1-/- ), 2-copy (Npr1+/+ ), and 4-copy (Npr1++/++ ) mice treated with GC inhibitor, A71915 and cGMP-dependent protein kinase (cGK) inhibitor, (Rp-8-Br-cGMPS). A significant decrease in renal cGMP levels and cGK activity was observed in 0-copy mice and A71915- and Rp-treated 2-copy and 4-copy mice compared with controls. An increased phosphorylation of Erk1/2, p38, p21Cip1 , and p27Kip1 occurred in 0-copy and A71915-treated 2-copy and 4-copy mice, while Rp treatment caused minimal changes than controls. Pro-inflammatory (TNF-α, IL-6) and pro-fibrotic (TGF-ß1) cytokines were significantly increased in plasma and kidneys of 0-copy and A71915-treated 2-copy mice, but to lesser extent in 4-copy mice. Progressive renal pathologies, including fibrosis, mesangial matrix expansion, and tubular hypertrophy were observed in 0-copy and A71915-treated 2-copy and 4-copy mice, but minimally occurred in Rp-treated mice compared with controls. These results indicate that Npr1 has pivotal roles in inhibiting renal fibrosis and hypertrophy and exerts protective effects involving cGMP/cGK axis by repressing CDK blockers p21Cip1 and p27Kip1 .

A proposal for testing kit of corona viruses using 3D photonic structure.

Design of corona virus testing kit is proposed in this paper using silicon based 3D photonic structure through zirconium quantum dot solution at the signal of 412 nm. The principle of measurement depends on the computation of reflectance, absorbance and transmittance of virus based quantum dot solution. In this paper, the reflectance is studied through the analysis of photonic band gap and absorbance is made through its numerical treatment. Further, the numerical investigation shows that the transmitted energy through photonic structure would determine the type of corona virus. For example; if the transmitted energy lies within the visible spectrum the sample would be normal corona virus. However, the sample could be IBV (SARS COV-2) if the transmitted energy would be Infrared.

All-trans retinoic acid and sodium butyrate enhance natriuretic peptide receptor a gene transcription: role of histone modification.

The objective of the present study was to delineate the mechanisms of GC-A/natriuretic peptide receptor-A (GC-A/NPRA) gene (Npr1) expression in vivo. We used all-trans retinoic acid (ATRA) and histone deacetylase (HDAC) inhibitor, sodium butyrate (NaBu) to examine the expression and function of Npr1 using gene-disrupted heterozygous (1-copy; +/-), wild-type (2-copy; +/+), and gene-duplicated heterozygous (3-copy; ++/+) mice. Npr1(+/-) mice exhibited increased renal HDAC and reduced histone acetyltransferase (HAT) activity; on the contrary, Npr1(++/+) mice showed decreased HDAC and enhanced HAT activity compared with Npr1(+)(/+) mice. ATRA and NaBu promoted global acetylation of histones H3-K9/14 and H4-K12, reduced methylation of H3-K9 and H3-K27, and enriched accumulation of active chromatin marks at the Npr1 promoter. A combination of ATRA-NaBu promoted recruitment of activator-complex containing E26 transformation-specific 1, retinoic acid receptor α, and HATs (p300 and p300/cAMP response element-binding protein-binding protein-associated factor) at the Npr1 promoter, and significantly increased renal NPRA expression, GC activity, and cGMP levels. Untreated 1-copy mice showed significantly increased systolic blood pressure and renal expression of α-smooth muscle actin (α-SMA) and proliferating cell nuclear antigen (PCNA) compared with 2- and 3-copy mice. Treatment with ATRA and NaBu synergistically attenuated the expression of α-SMA and PCNA and reduced systolic blood pressure in Npr1(+/-) mice. Our findings demonstrate that epigenetic upregulation of Npr1 gene transcription by ATRA and NaBu leads to attenuation of renal fibrotic markers and systolic blood pressure in mice with reduced Npr1 gene copy number, which will have important implications in prevention and treatment of hypertension-related renal pathophysiological conditions.

A Cross-Sectional Study on Neuropathic Pain Associated With Quality of Sleep in Spondylosis Patients.

INTRODUCTION: Neuropathic pain (NP) is common in spondylosis patients. Cervical and lumbar spondylosis are more common in the elderly population. Spondylosis patients also suffer from poor quality of sleep (QOS). This study aims to find a correlation between NP and QOS in spondylosis patients. METHODS: We conducted a cross-sectional study and analyzed data using the chi-square test to correlate the NP with QOS. The Pittsburgh Sleep Quality Index (PSQI) and the Leeds Assessment of Neuropathic Symptoms and Signs, Self-complete (S-LANSS) questionnaires were used to assess QOS and evaluate neuropathic pain, respectively. Spondylosis was diagnosed based on the history, clinical examination, and radiological findings. RESULTS: A total of 72 spondylosis patients, with a mean age of 47.35 years, were included in this study. Out of 72 subjects, 52 (72.2%) patients had neuropathic pain (NP group), and 20 (27.8%) patients had non-neuropathic pain (non-NP group). In the NP group, 41 patients (78.8%) had poor QOS, while 11 (21.2%) had good QOS. In the non-NP group, eight (40%) had poor QOS, and 12 (60%) had good QOS. CONCLUSION: This study concludes that neuropathic pain is associated with poor quality of sleep in spondylosis patients.

GloRESatE: A dataset for global rainfall erosivity derived from multi-source data.

Numerous hydrological applications, such as soil erosion estimation, water resource management, and rain driven damage assessment, demand accurate and reliable rainfall erosivity data. However, the scarcity of gauge rainfall records and the inherent uncertainty in satellite and reanalysis-based rainfall datasets limit rainfall erosivity assessment globally. Here, we present a new global rainfall erosivity dataset (0.1° × 0.1° spatial resolution) integrating satellite (CMORPH and IMERG) and reanalysis (ERA5-Land) derived rainfall erosivity estimates with gauge rainfall erosivity observations collected from approximately 6,200 locations across the globe. We used a machine learning-based Gaussian Process Regression (GPR) model to assimilate multi-source rainfall erosivity estimates alongside geoclimatic covariates to prepare a unified high-resolution mean annual rainfall erosivity product. It has been shown that the proposed rainfall erosivity product performs well during cross-validation with gauge records and inter-comparison with the existing global rainfall erosivity datasets. Furthermore, this dataset offers a new global rainfall erosivity perspective, addressing the limitations of existing datasets and facilitating large-scale hydrological modelling and soil erosion assessments.

Scale Development for COVID-19 Vaccine Hesitancy by Integration of Socio-Demographic and Psychological Factors.

Vaccination is the most cost-effective way to maintain population health. However, it can only be effective if widespread acceptance is held. The efficacy of COVID-19 vaccines depends on their favor. When countries start to vaccinate their citizens, there is a certain level of skepticism about the effectiveness of the vaccines. The hesitancy study on vaccines has gained momentum following the pandemic. However, few studies have examined the link between the psychological and sociodemographic factors influencing the fit. This paper proposes integrating the concepts of the information systems success and stimulus-organism-response into a cognitive fit theory framework to explore the integration of psychological and sociodemographic factors in the receivers' reactions (n = 1510). This study analyses the factors that influence the hesitancy of vaccines and the public's refusal in Asia and Europe. Receivers' reactions were assessed to various stimuli and we explored the link between psychological and sociodemographic elements and the concept of fit. Two surveys were conducted following the scale development of Mackenzie. The first was to develop the fit scale, while the second was to validate the fit scale. The results of the second survey were analyzed using structural equation modelling. The results indicate that the scale's fit development is valid and reliable. The quality of the vaccine information, the psychological characteristics of the vaccine system, and vaccine receivers' satisfaction are also beneficial factors for emotional and cognitive fit. Maintaining the vaccines' quality and efficiency can help improve the fit between sociodemographic and psychological characteristics. It can also enhance receivers' satisfaction and encourage continued vaccine administration. This study is regarded as one of the first to examine and develop an emotional and cognitive fit scale for practitioners and researchers.

Activation of IKK/NF-κB provokes renal inflammatory responses in guanylyl cyclase/natriuretic peptide receptor-A gene-knockout mice.

The present study was aimed at determining the consequences of the disruption of guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) gene (Npr1) on proinflammatory responses of nuclear factor kappa B, inhibitory kappa B kinase, and inhibitory kappa B alpha (NF-κB, IKK, IκBα) in the kidneys of mutant mice. The results showed that the disruption of Npr1 enhanced the renal NF-κB binding activity by 3.8-fold in 0-copy (-/-) mice compared with 2-copy (+/+) mice. In parallel, IKK activity and IκBα protein phosphorylation were increased by 8- and 11-fold, respectively, in the kidneys of 0-copy mice compared with wild-type mice. Interestingly, IκBα was reduced by 80% and the expression of proinflammatory cytokines and renal fibrosis were significantly enhanced in 0-copy mice than 2-copy mice. Treatment of 0-copy mice with NF-κB inhibitors andrographolide, pyrrolidine dithiocarbamate, and etanercept showed a substantial reduction in renal fibrosis, attenuation of proinflammatory cytokines gene expression, and significantly reduced IKK activity and IkBα phosphorylation. These findings indicate that the systemic disruption of Npr1 activates the renal NF-κB pathways in 0-copy mice, which transactivates the expression of various proinflammatory cytokines to initiate renal remodeling; however, inhibition of NF-κB pathway repairs the abnormal renal pathology in mutant mice.

Circular bioeconomy and environmental benignness through microbial recycling of e-waste: A case study on copper and gold restoration.

This study has attempted to ascertain the linkages between circular bio-economy (CirBioeco) and recycling of electronic (e-)waste by applying microbial activities instead of the smelter and chemical technologies. To build the research hypothesis, the advances on biotechnology-driven recycling processes for metals extraction from e-waste has been analyzed briefly. Thereafter, based on the potential of microbial techniques and research hypothesis, the structural model has been tested for a significance level of 99%, which is supported by the corresponding standardization co-efficient values. A prediction model applied to determine the recycling impact on CirBioeco indicates to re-circulate 51,833 tons of copper and 58 tons of gold by 2030 for the production of virgin metals/raw-materials, while recycling rate of the accumulated e-waste remains to be 20%. This restoration volume of copper and gold through the microbial activities corresponds to mitigate 174 million kg CO2 emissions and 24 million m3 water consumption if compared with the primary production activities. The study potentially opens a new window for environmentally-friendly biotechnological recycling of e-waste under the umbrella concept of CirBioeco.

Genetic disruption of guanylyl cyclase/natriuretic peptide receptor-A upregulates renal (pro) renin receptor expression in Npr1 null mutant mice.

The objective of the present study was to determine whether targeted-disruption of Npr1 gene (encoding for guanylyl cyclase/natriuretic peptide receptor-A; GC-A/NPRA) upregulates pro(renin) receptor (P)RR expression and leads to the activation of MAPKs in Npr1 gene-knockout mice. The Npr1 homozygous (Npr1-/-; 0-copy), heterozygous (Npr1+/-; 1-copy), wild-type (Npr1+/+; 2-copy), and gene-duplicated (Npr1++/++; 4-copy) mice were utilized. To identify the canonical pathway of (P)RR, we administered ACE-1 inhibitor (captopril), AT1R blocker (losartan), and MAPKs inhibitors (U0126 and SB203580) to all Npr1 mice genotypes. The renal expression of (P)RR mRNA was increased by 3-fold in 0-copy mice and 2-fold in 1-copy mice compared with 2-copy mice, which was also associated with significantly increased expression of ACE-1 and AT1R mRNA levels. Similarly, the phosphorylation of MAPKs (Erk1/2 and p-p38) was enhanced by 3.5-fold and 3.2-fold, respectively, in 0-copy mice with significant increases in 1-copy mice compared with 2-copy mice. The kidney and plasma levels of proinflammatory cytokines were significantly elevated in 0-copy and 1-copy mice. Treatment with captopril and losartan did not alter the expression of (P)RR in any of the Npr1 mice genotypes. Interestingly, losartan significantly reduced the phosphorylation of Erk1/2 and p38 in Npr1 mice. The present results suggest that the ablation of Npr1 upregulates (P)RR, MAPKs (Erk1/2 and p38), and proinflammatory cytokines in 0-copy and 1-copy mice. In contrast, the duplication of Npr1 exhibits the anti-inflammatory and antihypertensive effects by reducing the activation of MAPKs and inhibiting the expression levels of RAAS components and proinflammatory cytokines.

Sunlight induced biosynthesis of silver nanoparticle from the bark extract of Amentotaxus assamica D.K. Ferguson and its antibacterial activity against Escherichia coli and Staphylococcus aureus.

Green synthesis of nanoparticles has gained importance due to its eco-friendly, low toxicity and cost effective nature. This study deals with the biosynthesis of silver nanoparticles (AgNPs) from the bark extract of Amentotaxus assamica. The AgNPs have been synthesised by reducing the silver ions into stable AgNPs using the bark extract of Amentotaxus assamica under the influence of sunlight irradiation. The characterisation of the biosynthesised AgNPs was carried out by UV-vis spectroscopy, X-ray diffraction analysis (XRD), Fourier transform infrared spectroscopy, scanning electron microscopy (SEM) and energy dispersive X-ray analysis. The UV-vis spectrum showed a broad peak at 472 nm. Also, the XRD confirmed the crystalline structure of the AgNPs. Moreover, the SEM analysis revealed that the biosynthesised AgNPs were spherical in shape. Also, dynamic light scattering techniques were used to evaluate the size distribution profile of the biosynthesised AgNPs. Furthermore, the biosynthesised AgNPs showed a prominent inhibitory effect against both Escherichia coli (MTCC 111) and Staphylococcus aureus (MTCC 97). Thus the biosynthesis of AgNPs from the bark extract of Amentotaxus assamica is found to eco-friendly way of producing AgNPs compared to chemical method.

DNA hypermethylation of promoter of gene p53 and p16 in arsenic-exposed people with and without malignancy.

Chronic arsenic exposure is known to produce arsenicosis and cancer. To ascertain whether perturbation of methylation plays a role in such carcinogenesis, the degree of methylation of p53 and p16 gene in DNA obtained from blood samples of people chronically exposed to arsenic and skin cancer subjects was studied. Methylation-specific restriction endonuclease digestion followed by polymerase chain reaction (PCR) of gene p53 and bisulfite treatment followed by methylation-sensitive PCR of gene p16 have been carried out to analyze the methylation status of the samples studied. Significant DNA hypermethylation of promoter region of p53 gene was observed in DNA of arsenic-exposed people compared to control subjects. This hypermethylation showed a dose-response relationship. Further, hypermethylation of p53 gene was also observed in arsenic-induced skin cancer patients compared to subjects having skin cancer unrelated to arsenic, though not at significant level. However, a small subgroup of cases showed hypomethylation with high arsenic exposure. Significant hypermethylation of gene p16 was also observed in cases of arsenicosis exposed to high level of arsenic. In man, arsenic has the ability to alter DNA methylation patterns in gene p53 and p16, which are important in carcinogenesis.

Seasonal variation of arsenic concentrations in tubewells in west Bengal, India.

This study was conducted to monitor the changes in arsenic concentration during different seasons in a one-year period during 2002-2003 in selected tubewells in an arsenic-affected area in the district of South 24 Parganas in West Bengal, India, and to map the location of the wells. Seasonal variations in concentrations of arsenic in water were measured from 74 selected tubewells, ranging in depth from 40 to 500 feet. Water samples were collected from these wells during winter, summer, monsoon, and the following winter in 2002-2003. A global positioning system was used for locating the tubewells, and a geographic information system was used for mapping. There was evidence of seasonal variation in concentrations of arsenic in water (p=0.02) with the minimum average concentration occurring in the summer season (694 microg/L) and the maximum in the monsoon season (906 microg/L). From the winter of 2002 to the winter of 2003, arsenic concentrations increased, irrespective of the depth of the tubewells, from an average of 464 microg/L to 820 microg/L (p<0.001). This extent of variation in arsenic concentration, if confirmed, has important implications for both epidemiological research and mitigation programmes.

Epoxy/Glass Fiber Laminated Composites Integrated with Amino Functionalized ZrO2 for Advanced Structural Applications.

This work demonstrates the successful silanization of ZrO2 nanoparticles (ZN) and their incorporation in glass fiber/epoxy composites. Microscopic investigation under transmission electron microscope elucidates antiaggregation and size enhancement of silanized ZrO2 nanoparticles (SZNs). FTIR spectroscopy has been used to demonstrate the chemical nature of the SZNs prepared. EDX results reveal the presence of Si onto SZNs. Incorporation of SZNs shows a strong influence on tensile and flexural properties of hybrid multiscale glass fiber composite (SZGFRP) compared to that of the neat epoxy glass fiber composite (GFRP). A significant variation of tensile strength, stiffness, and toughness of ∼27%, 62%, and 110% is observed with respect to GFRP. Strength and modulus under bending are also enhanced to ∼22% and ∼38%, respectively. Failure mechanisms obtained from macroscopic and microscopic investigation demonstrate reduced interfacial delamination for SZGFRP. Additionally, increased roughness of the fiber surface in SZGFRP laminates produces better interfacial bonding arising from SZN incorporation in laminates. This symptomatic behavior exposes the espousal of organically modified ZrO2 to enhance the interfacial bonding for their use in next generation hybrid laminates.

Genetically altered mutant mouse models of guanylyl cyclase/natriuretic peptide receptor-A exhibit the cardiac expression of proinflammatory mediators in a gene-dose-dependent manner.

The objective of this study was to examine whether genetically determined differences in the guanylyl cyclase/natriuretic peptide receptor-A gene (Npr1) affect cardiac expression of proinflammatory cytokines, hypertrophic markers, nuclear factor-κB (NF-κB), and activating protein-1 (AP-1) in am Npr1 gene-dose-dependent manner. In the present studies, adult male Npr1 gene-disrupted (Npr1(-/-)), wild-type (Npr1(+/+)), and gene-duplicated (Npr1(++/++)) mice were used. The Npr1(-/-) mice showed 41 mm Hg higher systolic blood pressure and 60% greater heart weight to body weight (HW/BW) ratio; however, Npr1(++/++) mice exhibited 15 mm Hg lower systolic blood pressure and 12% reduced HW/BW ratio compared with Npr1(+/+) mice. Significant upregulation of gene expression of proinflammatory cytokines and hypertrophic markers along with enhanced NF-κB/AP-1 binding activities were observed in the Npr1(-/-) mouse hearts. Conversely, hypertrophic markers and proinflammatory cytokines gene expression as well as NF-κB/AP-1 binding activities were markedly decreased in Npr1(++/++) mouse hearts compared with wild-type mice. The ventricular guanylyl cyclase activity and cGMP levels were reduced by 96% and 87%, respectively, in Npr1(-/-) mice; however, these parameters were amplified by 2.8-fold and 3.8-fold, respectively, in Npr1(++/++) mice. Echocardiographic analysis revealed significantly increased fractional shortening in Npr1(++/++) mice (P < .05) but greatly decreased in Npr1(-/-) mice (P < .01) hearts compared with Npr1(+/+) mice. The present findings suggest that Npr1 represses the expression of cardiac proinflammatory mediators, hypertrophic markers, and NF-κB/AP-1-mediated mechanisms, which seem to be associated in an Npr1 gene-dose-dependent manner.

Interactive roles of NPR1 gene-dosage and salt diets on cardiac angiotensin II, aldosterone and pro-inflammatory cytokines levels in mutant mice.

OBJECTIVE: The objective of the present study was to elucidate the interactive roles of guanylyl cyclase/natriuretic peptide receptor-A (NPRA) gene (Npr1) and salt diets on cardiac angiotensin II (ANG II), aldosterone and pro-inflammatory cytokines levels in Npr1 gene-targeted (1-copy, 2-copy, 3-copy, 4-copy) mice. METHODS: Npr1 genotypes included 1-copy gene-disrupted heterozygous (+/-), 2-copy wild-type (+/+), 3-copy gene-duplicated heterozygous (++/+) and 4-copy gene-duplicated homozygous (++/++) mice. Animals were fed low, normal and high-salt diets. Plasma and cardiac levels of ANG II, aldosterone and pro-inflammatory cytokines were determined. RESULTS: With a high-salt diet, cardiac ANG II levels were increased (+) in 1-copy mice (13.7 ±â€Š2.8 fmol/mg protein, 111%) compared with 2-copy mice (6.5 ±â€Š0.6), but decreased (-) in 4-copy (4.0 ±â€Š0.5, 38%) mice. Cardiac aldosterone levels were increased (+) in 1-copy mice (80 ±â€Š4 fmol/mg protein, 79%) compared with 2-copy mice (38 ±â€Š3). Plasma tumour necrosis factor alpha was increased (+) in 1-copy mice (30.27 ±â€Š2.32 pg/ml, 38%), compared with 2-copy mice (19.36 ±â€Š2.49, 24%), but decreased (-) in 3-copy (11.59 ±â€Š1.51, 12%) and 4-copy (7.13 ±â€Š0.52, 22%) mice. Plasma interleukin (IL)-6 and IL-1α levels were also significantly increased (+) in 1-copy compared with 2-copy mice but decreased (-) in 3-copy and 4-copy mice. CONCLUSION: These results demonstrate that a high-salt diet aggravates cardiac ANG II, aldosterone and pro-inflammatory cytokine levels in Npr1 gene-disrupted 1-copy mice, whereas, in Npr1 gene-duplicated (3-copy and 4-copy) mice, high salt did not render such elevation, suggesting the potential roles of Npr1 against salt loading.

Disruption of Npr1 gene differentially regulates the juxtaglomerular and distal tubular renin levels in null mutant mice.

Atrial natriuretic peptide (ANP) exerts an inhibitory effect on juxtaglomerular (JG) renin synthesis and release by activating guanylyl cyclase/ natriuretic peptide receptor-A (GC-A/NPRA). Renin has also been localized in connecting tubule cells; however, the effect of ANP/NPRA signaling on tubular renin has not been determined. In the present study, we determined the role of NPRA in regulating both JG and tubular renin using Npr1 (coding for NPRA) gene-disrupted mice, which exhibit a hypertensive phenotype. Renin-positive immunoreactivity in Npr1(-/-) homozygous null mutant mice was significantly reduced compared with Npr1(+/+) wild-type mice (23% vs 69% renin-positive glomeruli). However, after chronic diuretic treatment, Npr1(-/-) mice showed an increment of JG renin immunoreactivity compared with Npr1(+/+) mice (70% vs 81% renin-positive glomeruli). There were no significant differences in the distal tubule renin between Npr1(+/+) and Npr1(-/-) mice. However, after diuretic treatment, Npr1(-/-) mice showed a significant decrease in renin immunoreactivity in principal cells of cortical collecting ducts (p<0.05). The increased JG renin immunoreactivity after reduction in blood pressure in diuretic-treated Npr1(-/-) mice, demonstrates an inhibitory action of ANP/NPRA system on JG renin; however, a decreased expression of distal tubular renin suggests a differential effect of ANP/NPRA signaling on JG and distal tubular renin.

Targeted disruption of guanylyl cyclase-A/natriuretic peptide receptor-A gene provokes renal fibrosis and remodeling in null mutant mice: role of proinflammatory cytokines.

Binding of atrial and brain natriuretic peptides to guanylyl cyclase-A/natriuretic peptide receptor-A produces second messenger cGMP, which plays an important role in maintaining renal and cardiovascular homeostasis. Mice carrying a targeted disruption of the Npr1 gene coding for guanylyl cyclase-A/natriuretic peptide receptor-A exhibit changes that are similar to those that occur in untreated human hypertension, including elevated blood pressure, cardiac hypertrophy, and congestive heart failure. The objective of this study was to determine whether disruption of the Npr1 gene in mice provokes kidney fibrosis, remodeling, and derangement. We found that systemic disruption of the Npr1 gene causes increased renal tubular damage characterized by dilation, flattening of epithelium, and expansion of interstitial spaces in Npr1(-/-) (0-copy) mice. Significant increases occurred in the expression levels of TNF-α (4-fold), IL-6 (4.5-fold), and TGF-ß1 (2-fold) in 0-copy null mutant mice compared with 2-copy wild-type mice. An increased epithelial-to-mesenchymal transition indicated by increased expression of α-smooth muscle actin, was observed in Npr1(-/-) mouse kidneys. Treatment with captopril and losartan showed a 38 and 46% attenuation in fibrosis and 30 and 42% reduction in α-smooth muscle actin immunoexpression, respectively, in 1-copy and 0-copy mice compared with 2-copy mice. Although bendroflumethiazide treatment did not show any effect. The present results demonstrate that the disruption of Npr1 gene activates proinflammatory cytokines leading to fibrosis, hypertrophic growth, and remodeling of the kidneys of mutant mice.