Transcriptomic profiling of human granulosa cells between women with advanced maternal age with different ovarian reserve.

BACKGROUND: Age-related diminished ovarian reserve (DOR) is not absolute. Some advanced maternal age (AMA) still have normal ovarian reserve (NOR) and often show better pregnancy outcomes. Exploring the transcriptomic profile of granulosa cells (GCs) in AMA could lead to new ideas for mitigating age-related diminished ovarian reserve. AIM: This study aimed to analyze the transcriptomic profile of GCs in AMA with different ovarian reserve. RESULTS: In total, 6273 statistically significant differential expression genes (DEGs) (|log2fc|> 1, q < 0.05) were screened from the two groups, among which 3436 genes were upregulated, and 2837 genes were downregulated in the DOR group. Through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, the potential functions of dysregulated genes in AMA with DOR or NOR were predicted. The GO enrichment analysis revealed that the DEGs were mainly enriched in obsolete oxidation-reduction process, mitochondrion, metal ion binding, ATP binding, etc. The KEGG pathway enrichment analysis revealed that the above-mentioned DEGs were mainly enriched in ferroptosis, regulation of actin cytoskeleton, oxidative phosphorylation, etc. Meanwhile, verification of the mRNA expression levels of DEGs revealed the possible involvement of "ferroptosis" in age-related diminished ovarian reserve. CONCLUSIONS: From a new clinical perspective, we presented the first data showing the transcriptomic profile in GCs between AMA with different ovarian reserve. At the same time, we identified the role of ferroptosis in the GCs of AMA, providing a new biological basis for studying ovarian aging and improving pregnancy outcomes of AMA.

Evaluation of new IPSS-Molecular model and comparison of different prognostic systems in patients with myelodysplastic syndrome.

A risk-adapted treatment strategy is of crucial importance in patients with myelodysplastic syndromes (MDS). Previous risk prognostic scoring systems did not integrate molecular abnormalities. The new IPSS-Molecular (IPSS-M) model, combing genomic profiling with hematologic and cytogenetic parameters, was recently developed to evaluate the associations with leukemia-free survival (LFS), leukemic transformation, and overall survival (OS). However, it has not yet been widely validated in clinics. This study aims to further validate the prognostic power of IPSS-M based on real-world data and to compare the prognostic value of different scoring systems in patients with MDS. IPSS-M Web calculator was used to calculate a tailored IPSS-M score of the enrolled patient (N = 255), and the risk category was defined correspondingly. We next compared the IPSS-M prognostic power to that of IPSS, IPSS-R, and WPSS. We found that IPSS-M risk classification was statistically significant for 3-year OS and LFS. Compared with other tools, IPSS-M was superior in sensitivity and accuracy for 3-year OS and LFS. The mapping C-index between IPSS-R and IPSS-M categories resulted in improved discrimination across the OS, but not LFS and leukemic transformation. The result of different treatment options indicated that allogeneic hematopoietic stem cell transplantation (allo-HSCT) can result in a better OS than those without allo-HSCT. In conclusion, IPSS-M was a valuable tool for risk stratification compared with other risk prognostic scoring systems. However, more studies should be conducted to explore the appropriate treatment options for different groups stratified by IPSS-M.

Comparison of two different starting dose of rhFSH in GnRH antagonist protocol for patients with normal ovarian reserve.

Objective: To evaluate different starting doses of recombinant human follicle-stimulating hormone (rhFSH) on pregnancy outcomes for patients with normal ovarian reserve during gonadotropin- releasing hormone antagonist (GnRH-ant) protocol-controlled ovarian stimulation of in vitro fertilization (IVF) cycles. Methods: In this retrospective study, a total of 1138 patients undergoing IVF cycles following the GnRH-ant protocol were enrolled. Patients were divided into two groups according to the starting dose of rhFSH. 617 patients received a starting dose of rhFSH of 150 IU, and 521 patients received a starting dose of rhFSH of 225 IU. We compared demographic characteristics, ovarian stimulation and embryological characteristics, and pregnancy and birth outcomes between the two groups. Multivariate logistic regression analysis was performed to examine the possible effects of the known potential confounding factors on pregnancy outcomes. Results: The number of oocytes retrieved in the 150 IU rhFSH group was significantly lower than those in the 225 IU rhFSH group. There was no significant difference between the two groups referring to embryological characteristics. The proportion of fresh embryo transfer in the 150 IU rhFSH group was significantly higher than that in the 225 IU rhFSH group (48.30% vs. 40.90%), and there was no difference in the risk of ovarian hyperstimulation syndrome and pregnancy outcomes between the two groups. Conclusions: In conclusion, the starting dose of rhFSH of 150 IU for ovarian stimulation has a similar pregnancy outcome as starting dose of rhFSH of 225 IU in GnRH-ant protocol for patients with normal ovarian reserve. Considering the potential cost-effectiveness and shorter time to live birth, the starting dose of rhFSH of 150 IU may be more suitable than 225 IU.

Role of signal transduction pathways in IL-1ß-induced apoptosis: Pathological and therapeutic aspects.

BACKGROUND: Interleukin-1ß (IL-1ß) is a pro-inflammatory cytokine mainly produced by monocytes and macrophages with a wide range of biological effects. Evidence has shown that IL-1ß plays a vital role in the process of apoptosis; however, the specific mechanisms, by which IL-1ß induces apoptosis, vary due to different cellular and experimental conditions. Therefore, this present reviewstudy aimed to systematically review the association between the molecular mechanisms of IL-1ß-induced apoptosis in pathological processes and the role of signaling pathways. This article also sought to briefly investigate the potential of signaling pathway-targeted therapy in the prevention and treatment of disease. METHODS: This is a literature review article. The present discourse aim is first to scrutinize and assess the available literature on IL-1ß and apoptosis. The relevant studies using the keywords of "IL-1ß-induced apoptosis" and "signaling pathways" were searched in the databases of PubMed, Scopus, Google Scholar, and Web of Science. Gathered relevant material, and extracted information was then assessed. RESULTS: IL-1ß can induce apoptosis in various types of cells under different external stimuli via the mitochondrial pathway, death receptor pathway and endoplasmic reticulum pathway, and that the different pathways are often interconnected. The NF-kB signaling pathway, p38MAPK, and JNK signaling pathways mainly play a proapoptotic part, and the ERK1/2 pathway has a bidirectional role in regulating apoptosis, while activation of the PI3K-Akt signaling pathway can inhibit apoptosis. CONCLUSION: This review indicates that IL-1ß-induced apoptosis plays an important role in pathogenesis and development of pathology of many inflammatory diseases. Elucidating the role of the signaling pathways will aid the development of targeted therapeutic treatments.

A highly-sensitive sensor based on carbon nanohorns@reduced graphene oxide coated by gold platinum core-shell nanoparticles for electrochemical detection of carbendazim in fruit and vegetable juice.

Carbendazim (CBZ) is beneficial to fruit and vegetable cultivation, but its residue will cause fruit and vegetable juice pollution. In this work, an electrochemical sensor based on carbon nanohorns@reduced graphene oxide coated by gold platinum core-shell nanoparticles (Au@Pt/CNHs@RGO/GCE) was prepared for CBZ detection. The results showed that the assembly of CNHs and RGO assisted by ultrasound improved the electron transfer ability and electrochemical active surface area of CNHs@RGO. Moreover, the coating of Au@Pt nanoparticles further enhanced the sensitivity of the sensor. With the synergistic effect of the three materials, the sensor had a wider linear range (0.05 µmol/L-50 µmol/L), a lower limit of detection (1.64 nmol/L), and satisfactory recovery rates (90.60 % ∼ 97.60 %, carrot juice; 94.00-114.43 %, orange juice). Additionally, the sensor presented good anti-interference and repeatability. This work provides a simple, rapid, economical, sensitive, and accurate sensor for CBZ quantification in fruit and vegetable juice.

Highly sensitive electrochemical detection of carbendazim residues in water by synergistic enhancement of nitrogen-doped carbon nanohorns and polyethyleneimine modified carbon nanotubes.

Carbendazim (CBZ) can protect crops from pathogens, but it is also easy to cause pesticide residues, threatening human health. In our work, an electrochemical sensor based on nitrogen-doped carbon nanohorns (N-CNHs) and polyethyleneimine-modified carbon nanotubes (PEI-CNTs) was developed for the detection of CBZ content in water. The results showed that N-doping provided the CN bonds for CNHs and improved the electrochemical reaction performance of N-CNHs surface. With the participation of PEI, the surface of CNTs was positively charged and contained a large number of NH bonds, which not only promoted the electrostatic assembly of N-CNHs and PEI-CNTs but also was beneficial to further enriching CBZ. After further ultrasound-assisted assembly of N-CNHs and PEI-CNTs, the electron transfer capacity, electrochemical active surface area, and catalytic activity of N-CNHs/PEI-CNTs were significantly improved. The sensor performed a wider linear range (15 nmol/L ~ 70 µmol/L), low detection limit (4 nmol/L) and satisfactory recovery (87.33 % ~ 117.67 %) under the optimal conditions. In addition, the sensor had good anti-interference, reproducibility, and stability. Our work provided a new strategy for quantification of CBZ in environment.

Advances in the Study of the Mechanisms of Physiological Root Resorption in Deciduous Teeth.

Physiological root resorption of deciduous teeth is a complex physiological process that is essential for the normal replacement of deciduous teeth and permanent teeth in clinical practice, but its importance is often overlooked due to the presence of permanent teeth. This physiological process includes not only the resorption of hard tissues of deciduous teeth, such as dentin and cementum, but also the elimination of soft tissues, such as pulp and periodontal ligament (PDL). However, the mechanisms of physiological root resorption are not yet clear. In this article, the advances of research on the mechanisms related to physiological root resorption will be reviewed in two main aspects: hard tissues and soft tissues of deciduous teeth, specifically in relation to the effects of inflammatory microenvironment and mechanical stress on the resorption of hard tissues, the repair of hard tissues, and the elimination and the histological events of soft tissues.

Elevated pCO2 changes community structure and function by affecting phytoplankton group-specific mortality.

The rise of atmospheric pCO2 has created a number of problems for marine ecosystem. In this study, we initially quantified the effects of elevated pCO2 on the group-specific mortality of phytoplankton in a natural community based on the results of mesocosm experiments. Diatoms dominated the phytoplankton community, and the concentration of chlorophyll a was significantly higher in the high-pCO2 treatment than the low-pCO2 treatment. Phytoplankton mortality (percentage of dead cells) decreased during the exponential growth phase. Although the mortality of dinoflagellates did not differ significantly between the two pCO2 treatments, that of diatoms was lower in the high-pCO2 treatment. Small diatoms dominated the diatom community. Although the mortality of large diatoms did not differ significantly between the two treatments, that of small diatoms was lower in the high-pCO2 treatment. These results suggested that elevated pCO2 might enhance dominance by small diatoms and thereby change the community structure of coastal ecosystems.

The sbv IMPROVER Systems Toxicology Computational Challenge: Identification of Human and Species-Independent Blood Response Markers as Predictors of Smoking Exposure and Cessation Status.

Cigarette smoking entails chronic exposure to a mixture of harmful chemicals that trigger molecular changes over time, and is known to increase the risk of developing diseases. Risk assessment in the context of 21st century toxicology relies on the elucidation of mechanisms of toxicity and the identification of exposure response markers, usually from high-throughput data, using advanced computational methodologies. The sbv IMPROVER Systems Toxicology computational challenge (Fall 2015-Spring 2016) aimed to evaluate whether robust and sparse (≤40 genes) human (sub-challenge 1, SC1) and species-independent (sub-challenge 2, SC2) exposure response markers (so called gene signatures) could be extracted from human and mouse blood transcriptomics data of current (S), former (FS) and never (NS) smoke-exposed subjects as predictors of smoking and cessation status. Best-performing computational methods were identified by scoring anonymized participants' predictions. Worldwide participation resulted in 12 (SC1) and six (SC2) final submissions qualified for scoring. The results showed that blood gene expression data were informative to predict smoking exposure (i.e. discriminating smoker versus never or former smokers) status in human and across species with a high level of accuracy. By contrast, the prediction of cessation status (i.e. distinguishing FS from NS) remained challenging, as reflected by lower classification performances. Participants successfully developed inductive predictive models and extracted human and species-independent gene signatures, including genes with high consensus across teams. Post-challenge analyses highlighted "feature selection" as a key step in the process of building a classifier and confirmed the importance of testing a gene signature in independent cohorts to ensure the generalized applicability of a predictive model at a population-based level. In conclusion, the Systems Toxicology challenge demonstrated the feasibility of extracting a consistent blood-based smoke exposure response gene signature and further stressed the importance of independent and unbiased data and method evaluations to provide confidence in systems toxicology-based scientific conclusions.

Human blood gene signature as a marker for smoking exposure: computational approaches of the top ranked teams in the sbv IMPROVER Systems Toxicology challenge.

Crowdsourcing has emerged as a framework to address methodological challenges in omics data analysis and assess the extent to which omics data are predictive of phenotypes of interest. The sbv IMPROVER Systems Toxicology Challenge was designed to leverage crowdsourcing to determine whether human blood gene expression levels are informative of current and past smoking. Participating teams were invited to use a training gene expression dataset to derive parsimonious models (up to 40 genes) that can accurately classify subjects into exposure groups: smokers, former smokers that quit for at least one year, and never-smokers. Teams were ranked based on two classification performance metrics evaluated on a blinded test dataset. The analytical approaches of the first- and third-ranked teams, that are presented in detail in this article, involved feature selection by moderated t-test or LASSO regression and linear discriminant analysis (LDA) and logistic regression classifiers, respectively. While the 12-gene signature of the top team allowed the classification of current smokers with 100% sensitivity at 93% specificity, discriminating former smokers from never-smokers was much more challenging (65% sensitivity at 57% specificity). Gene ontology molecular functions and KEGG pathways associated with current smoking included G protein-coupled receptor activity, signaling receptor activity, calcium ion binding, and the Neuroactive ligand-receptor interaction pathway. Selection of marker genes by either moderated t-test or multivariate LASSO regression followed by LDA or logistic regression, are robust approaches to classification with omics data, confirming in part findings of previous sbv IMPROVER challenges. While current smoking is accurately identified based on blood mRNA levels, smoking cessation for more than one year is accompanied by a "normalization" of the expression of certain mRNAs, making it difficult to distinguish former smokers from never-smokers.

Development and characterization of EST-SSR markers in Stipa breviflora (Poaceae).

PREMISE OF THE STUDY: Stipa breviflora (Poaceae) is one of the dominant species of the desert steppe in the eastern Eurasian grasslands. Simple sequence repeat (SSR) markers were developed for use in genetic diversity studies of this species. METHODS AND RESULTS: A total of 1954 potentially polymorphic loci were obtained by comparing transcriptome data of eight different S. breviflora individuals. We selected 81 loci to verify polymorphism and 63 loci amplified, of which 21 loci exhibited polymorphism. The number of alleles per locus varied from two to 24, the observed heterozygosity ranged from 0.083 to 0.958, and the expected heterozygosity ranged from 0.396 to 0.738. CONCLUSIONS: These newly identified SSR loci can be used for population genetic and landscape genetic studies of S. breviflora. In addition, 14 loci also amplified in six related Stipa species (S. grandis, S. krylovii, S. bungeana, S. aliena, S. gobica, and S. purpurea).

Distinct populations of label-retaining cells in the adult kidney are defined temporally and exhibit divergent regional distributions.

DNA label-retention, or retention of a thymidine analog, is a characteristic of slow cycling cells and has been used to identify stem cells in several organ systems. Recent findings have demonstrated inconsistent localization of label-retaining cells (LRCs) in the kidney. Differences in the dose and timing of administration of deoxyuridine, the length of the chase period, and the species of animal used have made understanding the distinctions between these findings difficult. In the present studies, we utilized a dual loading scheme in the same animal to demonstrate that the cells labeled at different ages identified independent populations of LRC that distributed globally in an anti-parallel manner in the kidney. Loading with a DNA label in neonates identified LRC more often in the papilla, while administering the DNA label in adult mice identified LRC prominently in the cortex and the outer medulla. Furthermore, the tissue compartment distribution (epithelial-endothelial-interstitial) as well as the specific distribution within the nephron epithelia differed for these populations. These findings highlighted the complexity of the dynamics of cell proliferation in the kidney throughout the postnatal and adult period and call attention to the confusion associated with the term "label-retaining cells" for different timings of the loading and chase periods. This study indicated that the results of previous studies should be viewed as nonoverlapping and that further studies are needed to ascertain the role of each of these populations in the steady-state maintenance and injury recovery of the kidney.

Pivotal role of apoptosis signal-regulating kinase 1 in monoclonal free light chain-mediated apoptosis.

Renal failure, a major complication associated with multiple myeloma, is usually related to deposition of monoclonal immunoglobulin free light chains (FLCs) and directly contributes to morbidity and mortality in this disease. The present study focused on the cytotoxic effects of monoclonal FLCs. Human proximal tubular epithelial cells (HK-2) were examined after incubation with two human monoclonal FLCs (termed κ2 and λ3). Incubation of HK-2 cells for 24 and 48 hours with either FLCs at 1 mg/mL promoted activation of caspase-9 and caspase-3 and increased the rate of apoptosis. Because prior studies demonstrated that FLCs generated intracellular oxidative stress, our studies focused on the redox-sensitive mitogen-activated protein kinase kinase kinase known as apoptosis signal-regulating kinase 1 (ASK1). A time-dependent increase in phosphorylation of ASK1 at T845, indicating activation of this enzyme, was observed. Small interfering RNA designed to reduce ASK1 expression in HK-2 cells successfully decreased ASK1, which was confirmed by Western blot analysis. Incubation of ASK1-depleted HK-2 cells with the two FLCs prevented the increase in apoptosis while pretreating HK-2 cell with nontargeting small interfering RNA did not prevent FLCs-mediated apoptosis. The combined data demonstrate that monoclonal FLCs activated the intrinsic apoptotic pathway in renal epithelial cells by activation of ASK1.

Immunoglobulin light chains activate nuclear factor-κB in renal epithelial cells through a Src-dependent mechanism.

One of the major attendant complications of multiple myeloma is renal injury, which contributes significantly to morbidity and mortality in this disease. Monoclonal immunoglobulin free light chains (FLCs) are usually directly involved, and tubulointerstitial renal injury and fibrosis are prominent histologic features observed in myeloma. The present study examined the role of monoclonal FLCs in altering the nuclear factor κ light chain enhancer of activated B cells (NF-κB) activity of renal epithelial cells. Human proximal tubule epithelial cells exposed to 3 different human monoclonal FLCs demonstrated Src kinase-dependent activation of the NF-κB pathway, which increased production of monocyte chemoattractant protein-1 (MCP-1). Tyrosine phosphorylation of inhibitor of κB kinases (IKKs) IKKα and IKKß and a concomitant increase in inhibitor of κB (IκB) kinase activity in cell lysates were observed. Time-dependent, Src kinase-dependent increases in serine and tyrosine phosphorylation of IκBα and NF-κB activity were also demonstrated. Proteasome inhibition partially blocked FLC-induced MCP-1 production. These findings fit into a paradigm characterized by FLC-induced redox-signaling events that activated the canonical and atypical (IKK-independent) NF-κB pathways to promote a proinflammatory, profibrotic renal environment.

Immunoglobulin light chains activate tubular epithelial cells through redox signaling.

The renal proximal tubule metabolizes circulating low-molecular-weight proteins such as Ig free light chains. In the setting of plasma cell dyscrasias, the burden of filtered protein can be very high. Endocytosis of certain nephrotoxic light chains induces H(2)O(2) production and monocyte chemoattractant protein-1 (MCP-1) release, leading to recruitment of inflammatory cells and interstitial fibrosis, but how these processes are linked mechanistically is not well understood. This study investigated the relationship between H(2)O(2) generated after light chain endocytosis by human proximal tubular (HK-2) cells and activation of c-Src, a redox-sensitive tyrosine kinase. HK-2 cells exposed to two different light chains upregulated c-Src activity, which increased the production of MCP-1. In parallel, we observed a time-dependent oxidation of c-Src. Inhibition of c-Src activity and silencing c-Src expression abrogated the light chain-induced MCP-1 response, but had no effect on H(2)O(2), indicating that production of H(2)O(2) is upstream of c-Src in the signaling cascade. Silencing megalin and cubilin expression inhibited the MCP-1 response, whereas extracellular catalase did not, indicating that endocytosis is required and that intracellular generation of reactive oxygen species activates c-Src. These data show that intracellular H(2)O(2) induced by endocytosis of monoclonal free light chains oxidizes and activates c-Src, which promotes release of MCP-1.

Potassium inhibits dietary salt-induced transforming growth factor-beta production.

Human and animal studies demonstrate an untoward effect of excess dietary NaCl (salt) intake on cardiovascular function and life span. The endothelium in particular augments the production of transforming growth factor (TGF)-beta, a fibrogenic growth factor, in response to excess dietary salt intake. This study explored the initiating mechanism that regulates salt-induced endothelial cell production of TGF-beta. Male Sprague-Dawley rats were given diets containing different amounts of NaCl and potassium for 4 days. A bioassay for TGF-beta demonstrated increased (35.2%) amounts of active TGF-beta in the medium of aortic ring segments from rats on the high-salt diet compared with rats maintained on a 0.3% NaCl diet. Inhibition of the large-conductance, calcium-activated potassium channel inhibited dietary salt-induced vascular production of TGF-beta but did not affect production of TGF-beta by ring segments from rats on the low-salt diet. Immunohistochemical and Western analyses demonstrated the alpha subunit of the calcium-activated potassium channel in endothelial cells. Increasing medium [K+] inhibited production of dietary salt-induced vascular production levels of total and active TGF-beta but did not alter TGF-beta production by aortic rings from rats on the 0.3% NaCl diet. Increasing dietary potassium content decreased urinary active TGF-beta in animals receiving the high-salt diet but did not change urinary active TGF-beta in animals receiving the low-salt diet. The findings demonstrated an interesting interaction between the dietary intake of potassium and excess NaCl and further showed the fundamental role of the endothelial calcium-activated potassium channel in the vascular response to excess salt intake.

Immunoglobulin light chains generate hydrogen peroxide.

As low molecular weight proteins, restriction from glomerular filtration is minimized, permitting significant amounts of Ig light chains to be endocytosed into the proximal tubule epithelium, particularly in plasma cell dyscrasias. Recent studies have shown that this effect of concentrating light chains within the proximal tubule alters cell function. This study demonstrated that light chains belonged to a class of proteins that are capable of catalyzing the formation of hydrogen peroxide. Sufficient amounts of hydrogen peroxide were produced in HK-2 cells to stimulate the production of monocyte chemoattractant protein-1 (MCP-1), a key chemokine involved in monocyte/macrophage migration and activation of the proximal tubule, and to increase lactate dehydrogenase release into the medium. The light chain-mediated effect on MCP-1 production was inhibited by co-incubation with 1,3-dimethyl-2-thiourea, which also inhibited lactate dehydrogenase release, and by pyrrolidine dithiocarbamate, an inhibitor of NF-kappaB. The amount of light chain that stimulated an intracellular redox-signaling pathway in the proximal tubule cells was well within levels that are seen in patients who have plasma cell dyscrasias. The conclusion is that light chains possess a unique property that permits the development of intracellular oxidative stress that in turn promotes activation of the proximal tubule and elaboration of MCP-1.

Mechanism of hypertensive nephropathy in the Dahl/Rapp rat: a primary disorder of vascular smooth muscle.

The Dahl/Rapp salt-sensitive (S) rat is a model of salt-sensitive hypertension and hypertensive renal disease. This study explored the role of vascular remodeling in the development of renal failure in S rats. Groups of S and Sprague-Dawley rats were given 0.3 and 8.0% NaCl diets for up to 21 days and evidence of smooth muscle proliferation identified using immunohistochemistry that showed nuclear accumulation of proliferating cell nuclear antigen and 5-bromo-2'-deoxy-uridine. Compared with the other three groups, S rats on 8.0% NaCl diet showed increased nuclear labeling of cells of the aorta and arteries and arterioles of the kidney by the end of the first week of study. Progressive luminal narrowing of the interlobular arteries and preglomerular arterioles occurred in S rats over the 3 wk on the 8.0% NaCl diet. Accumulation of pimonidazole adducts and nuclear accumulation of hypoxia-inducible factor-1alpha (HIF-1alpha) were used as markers of tissue hypoxia. By the end of the second week of study, pimonidazole levels increased in S rats on 8.0% NaCl diet and deposition was apparent in tubular cells in the cortex and medulla. At the completion of the experiment, HIF-1alpha levels were increased in nuclear extracts from the cortex and medulla of S rats on this diet, compared with the other three groups of rats. The data demonstrated a disorder of the vascular remodeling process with proliferation of vascular smooth muscle cells temporally followed by development of tissue hypoxia in the hypertensive nephropathy of S rats on 8.0% NaCl diet.

Activation of the Fas/Fas ligand pathway in hypertensive renal disease in Dahl/Rapp rats.

BACKGROUND: Hypertensive nephrosclerosis is the second most common cause of end-stage renal failure in the United States. The mechanism by which hypertension produces renal failure is incompletely understood. Recent evidence demonstrated that an unscheduled and inappropriate increase in apoptosis occurred in the Dahl/Rapp rat, an inbred strain of rat that uniformly develops hypertension and hypertensive nephrosclerosis; early correction of the hypertension prevents the renal injury. The present study examined the role of the Fas/FasL pathway in this process. METHODS: Young male Dahl/Rapp salt-sensitive (S) and Sprague-Dawley rats were fed diets that contained 0.3% or 8.0% NaCl diets. Kidneys were examined at days 7 and 21 of the study. RESULTS: An increase in Fas and FasL expression was observed in glomerular and tubular compartments of kidneys of hypertensive S rats, whereas dietary salt did not change expression of either of these molecules in normotensive Sprague-Dawley rats. Associated with this increase was cleavage of Bid and activation of caspase-8, the initiator caspase in this apoptotic pathway, by day 21 of the study. CONCLUSIONS: Augmented expression of apoptotic signaling by the Fas/FasL pathway occurred during development of end-stage renal failure in this model of hypertensive nephrosclerosis.