In Silico and In Vitro Study of Isoquercitrin against Kidney Cancer and Inflammation by Triggering Potential Gene Targets.

Kidney cancer has emerged as a major medical problem in recent times. Multiple compounds are used to treat kidney cancer by triggering cancer-causing gene targets. For instance, isoquercitrin (quercetin-3-O-ß-d-glucopyranoside) is frequently present in fruits, vegetables, medicinal herbs, and foods and drinks made from plants. Our previous study predicted using protein-protein interaction (PPI) and molecular docking analysis that the isoquercitrin compound can control kidney cancer and inflammation by triggering potential gene targets of IGF1R, PIK3CA, IL6, and PTGS2. So, the present study is about further in silico and in vitro validation. We performed molecular dynamic (MD) simulation, gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, cytotoxicity assay, and RT-PCR and qRT-PCR validation. According to the MD simulation (250 ns), we found that IGF1R, PIK3CA, and PTGS2, except for IL6 gene targets, show stable binding energy with a stable complex with isoquercitrin. We also performed gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of the final targets to determine their regulatory functions and signaling pathways. Furthermore, we checked the cytotoxicity effect of isoquercitrin (IQ) and found that 5 µg/mL and 10 µg/mL doses showed higher cell viability in a normal kidney cell line (HEK 293) and also inversely showed an inhibition of cell growth at 35% and 45%, respectively, in the kidney cancer cell line (A498). Lastly, the RT-PCR and qRT-PCR findings showed a significant decrease in PTGS2, PIK3CA, and IGF1R gene expression, except for IL6 expression, following dose-dependent treatments with IQ. Thus, we can conclude that isoquercitrin inhibits the expression of PTGS2, PIK3CA, and IGF1R gene targets, which in turn controls kidney cancer and inflammation.

Multi-omics and imaging mass cytometry characterization of human kidneys to identify pathways and phenotypes associated with impaired kidney function.

Despite the recent advances in our understanding of the role of lipids, metabolites, and related enzymes in mediating kidney injury, there is limited integrated multi-omics data identifying potential metabolic pathways driving impaired kidney function. The limited availability of kidney biopsies from living donors with acute kidney injury has remained a major constraint. Here, we validated the use of deceased transplant donor kidneys as a good model to study acute kidney injury in humans and characterized these kidneys using imaging and multi-omics approaches. We noted consistent changes in kidney injury and inflammatory markers in donors with reduced kidney function. Neighborhood and correlation analyses of imaging mass cytometry data showed that subsets of kidney cells (proximal tubular cells and fibroblasts) are associated with the expression profile of kidney immune cells, potentially linking these cells to kidney inflammation. Integrated transcriptomic and metabolomic analysis of human kidneys showed that kidney arachidonic acid metabolism and seven other metabolic pathways were upregulated following diminished kidney function. To validate the arachidonic acid pathway in impaired kidney function we demonstrated increased levels of cytosolic phospholipase A2 protein and related lipid mediators (prostaglandin E2) in the injured kidneys. Further, inhibition of cytosolic phospholipase A2 reduced injury and inflammation in human kidney proximal tubular epithelial cells in vitro. Thus, our study identified cell types and metabolic pathways that may be critical for controlling inflammation associated with impaired kidney function in humans.

Uric acid promotes interleukin-17 expression to cause kidney injury.

Uric acid, an oxidation end-product of purine metabolism, is reportedly to be a risk factor for kidney injury. However, its underlying mechanism is still a mystery. This study aimed to reveal the detailed roles of uric acid in inducing kidney injury and the possible mechanisms. Injection of rats with uric acid significantly increased tubular injury score, and levels of blood urea nitrogen, serum creatinine, and urine kidney injury molecule-1. Uric acid increased the expression of collagen I, alpha-smooth muscle actin, tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6. Kyoto Encyclopedia of Genes and Genomes analysis result showed the IL-17 signaling pathway as the most significantly enriched pathway involved in hyperuricemia-related kidney injury. Long-term injection of uric acid induced significant production of IL-17 and recruitment of Th17 cells. Treating rats with the anti-IL-17 mAb attenuated uric acid-induced kidney injury, accompanied by the inactivation of nuclear factor-κB (NF-κB). In conclusion, uric acid was confirmed to be a risk factor for kidney injury via inducing IL-17 expression. Neutralization of IL-17 using the specific mAb relieved uric acid-induced kidney injury via inhibition of NF-κB signaling.

Autophagy and mitophagy: physiological implications in kidney inflammation and diseases.

Autophagy is a ubiquitous intracellular cytoprotective quality control program that maintains cellular homeostasis by recycling superfluous cytoplasmic components (lipid droplets, protein, or glycogen aggregates) and invading pathogens. Mitophagy is a selective form of autophagy that by recycling damaged mitochondrial material, which can extracellularly act as damage-associated molecular patterns, prevents their release. Autophagy and mitophagy are indispensable for the maintenance of kidney homeostasis and exert crucial functions during both physiological and disease conditions. Impaired autophagy and mitophagy can negatively impact the pathophysiological state and promote its progression. Autophagy helps in maintaining structural integrity of the kidney. Mitophagy-mediated mitochondrial quality control is explicitly critical for regulating cellular homeostasis in the kidney. Both autophagy and mitophagy attenuate inflammatory responses in the kidney. An accumulating body of evidence highlights that persistent kidney injury-induced oxidative stress can contribute to dysregulated autophagic and mitophagic responses and cell death. Autophagy and mitophagy also communicate with programmed cell death pathways (apoptosis and necroptosis) and play important roles in cell survival by preventing nutrient deprivation and regulating oxidative stress. Autophagy and mitophagy are activated in the kidney after acute injury. However, their aberrant hyperactivation can be deleterious and cause tissue damage. The findings on the functions of autophagy and mitophagy in various models of chronic kidney disease are heterogeneous and cell type- and context-specific dependent. In this review, we discuss the roles of autophagy and mitophagy in the kidney in regulating inflammatory responses and during various pathological manifestations.

MicroRNA-10 negatively regulates inflammation in diabetic kidney via targeting activation of the NLRP3 inflammasome.

NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome activation has emerged as a central mediator of kidney inflammation in diabetic kidney disease (DKD). However, the mechanism underlying this activation in DKD remains poorly defined. In this study, we found that kidney-enriched microRNA-10a and -10b (miR-10a/b), predominantly expressed in podocytes and tubular epithelial cells, were downregulated in kidney from diabetic mice and patients with DKD. High glucose decreased miR-10a/b expression in vitro in an osmolarity-independent manner. miR-10a/b functioned as negative regulators of the NLRP3 inflammasome through targeting the 3'untranslated region of NLRP3 mRNA, inhibiting assembly of the NLRP3 inflammasome and decreasing caspase-1-dependent release of pro-inflammatory cytokines. Delivery of miR-10a/b into kidney prevented NLRP3 inflammasome activation and renal inflammation, and it reduced albuminuria in streptozotocin (STZ)-treated mice, whereas knocking down miR-10a/b increased NLRP3 inflammasome activation. Restoration of miR-10a/b expression in established DKD ameliorated kidney inflammation and mitigated albuminuria in both db/db and STZ-treated mice. These results suggest a novel intervention strategy for inhibiting kidney inflammation in DKD by targeting the NLRP3 inflammasome.

Effects of endogenous H2S production inhibition on the homeostatic responses induced by acute high-salt diet consumption.

The gaseous modulator hydrogen sulfide (H2S) is synthesized, among other routes, by the action of cystathionine-γ-lyase (CSE) and importantly participates in body fluid homeostasis. Therefore, the present study aimed to evaluate the participation of H2S in behavioral, renal and neuroendocrine homeostatic responses triggered by the acute consumption of a high Na+ diet. After habituation, adult male Wistar rats were randomly distributed and maintained for seven days on a control [CD (0.27% of Na+)] or hypersodic diet [HD (0.81% of Na+)]. CD and HD-fed animals were treated with DL-Propargylglycine (PAG, 25 mg/kg/day, ip) or vehicle (0.9% NaCl in equivalent volume) for the same period. At the end of the experiment, animals were euthanized for blood and tissue collection. We demonstrated that a short-term increase in dietary Na+ intake, in values that mimic the variations in human consumption (two times the recommended) significantly modified hydroelectrolytic homeostasis, with repercussions in the hypothalamic-neurohypophysial system and hypothalamic-pituitary-adrenal axis function. These findings were accompanied by the development of a clear inflammatory response in renal tubular cells and microvascular components. On the other hand, the inhibition of the endogenous production of H2S by CSE provided by PAG treatment prevented the inflammation induced by HD. In the kidney, PAG treatment induced the overexpression of inducible nitric oxide synthase in animals fed with HD. Taken together, these data suggest, therefore, that HD-induced H2S production plays an important proinflammatory role in the kidney, apparently counter regulating nitric oxide actions in renal tissue.

Feed contamination with zearalenone promotes growth but affects the immune system of rainbow trout.

To investigate the effects of feed contamination with zearalenone (ZEN) at the current European Commission (EC) guidance value (2 mg⋅kg-1 feed) on the growth and health of rainbow trout, we performed a long-term feeding trial under aquaculture conditions. It started with the external feeding of the fish larvae, and continued for 96 weeks, at which point the fish had reached market size. To assess the growth of fish and their feeding efficiency throughout this period, the fish were regularly weighed and measured, and their feed consumption was monitored. Additionally, to investigate potential health effects, after 72 weeks of the exposure to ZEN, the fishes' blood was analyzed for major hematological and biochemical indices, and their head kidney, spleen, and liver were examined for morphological, histopathological, cytological, and molecular changes. Finally, to gain insight into the metabolism and distribution of ZEN in fish, the content of free and glucuronidated forms of ZEN and its major metabolites was measured in the intestine, liver, and muscles of the exposed fish. The feed-borne exposure of rainbow trout to ZEN at a dose of 2 mg⋅kg-1 feed resulted in higher feeding efficiency and growth rate, most probably due to the anabolic properties of the ZEN metabolite. Importantly for the consumers of fish, despite absorption and metabolism of ZEN in the digestive system of the fish that had been exposed for 72 weeks, the residuals of ZEN were not transferred to the fishes' muscles, which rules out a potential risk to human health related to the consumption of fish meat. However, the increased growth of fish fed with the contaminated feed may come at some cost, as the exposure to ZEN was associated with modulation of key components of the adaptive and innate immune systems. Moreover, the trunk kidney of ZEN-fed fish showed massive inflammation that was likely caused by pathogen infection. These findings raise concerns about fish health under the current recommended EC guidance values.

Arachidonic Acid Metabolism and Kidney Inflammation.

As a major component of cell membrane lipids, Arachidonic acid (AA), being a major component of the cell membrane lipid content, is mainly metabolized by three kinds of enzymes: cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP450) enzymes. Based on these three metabolic pathways, AA could be converted into various metabolites that trigger different inflammatory responses. In the kidney, prostaglandins (PG), thromboxane (Tx), leukotrienes (LTs) and hydroxyeicosatetraenoic acids (HETEs) are the major metabolites generated from AA. An increased level of prostaglandins (PGs), TxA2 and leukotriene B4 (LTB4) results in inflammatory damage to the kidney. Moreover, the LTB4-leukotriene B4 receptor 1 (BLT1) axis participates in the acute kidney injury via mediating the recruitment of renal neutrophils. In addition, AA can regulate renal ion transport through 19-hydroxystilbenetetraenoic acid (19-HETE) and 20-HETE, both of which are produced by cytochrome P450 monooxygenase. Epoxyeicosatrienoic acids (EETs) generated by the CYP450 enzyme also plays a paramount role in the kidney damage during the inflammation process. For example, 14 and 15-EET mitigated ischemia/reperfusion-caused renal tubular epithelial cell damage. Many drug candidates that target the AA metabolism pathways are being developed to treat kidney inflammation. These observations support an extraordinary interest in a wide range of studies on drug interventions aiming to control AA metabolism and kidney inflammation.

Novel Proinflammatory Function of Renal Intercalated Cells.

BACKGROUND: Serious and often fatal acute kidney injury (AKI) is frequently seen after major surgery, local and remote organ damage, and sepsis. It is associated with uncontrolled inflammation, and is usually diagnosed only after the kidneys have gone through significant and often irreversible damage. SUMMARY: During our work involving another type of kidney disease that leads to acid-base disorders of the blood, we unexpectedly found high levels of a protein called the P2Y14 "purinergic" receptor, in specialized kidney epithelial cells called intercalated cells (ICs). These cells are responsible for maintaining whole body acid-base balance by regulating the secretion of excess protons into the urine, which normalizes blood pH. However, it turns out that the P2Y14 receptor in these cells responds to a molecule called uridine diphosphate (UDP)-glucose, which is a danger signal released by damaged cells anywhere in the body. When UDP-glucose reaches the kidney, it stimulates ICs to produce chemoattractant cytokines; this results in renal inflammation and contributes to the onset of AKI. Key Message: Thus, our work now points to ICs as key mediators of renal inflammation and AKI, following surgery and/or damage to remote organs, sepsis, and also local insults to the kidney itself. The link between the proton secreting ICs of the kidney and AKI is an example of how a fundamental research project with a defined aim, in this case understanding acid-base homeostasis, can lead to a novel observation that has unexpected but major implications in another area of human health.

Cluster of differentiation-44 as a novel biomarker of lupus nephritis and its role in kidney inflammation and fibrosis.

Introduction: CD44 is a transmembrane glycoprotein implicated in tissue inflammation and fibrosis. We investigated its role in kidney inflammation and fibrosis in a murine model of lupus nephritis (LN), and the clinico-pathological association of serum CD44 level in patients with biopsy-proven Class III/IV ± V LN. Methods: NZB/W F1 mice were treated with control IgG or anti-CD44 monoclonal antibody for 4 weeks and disease parameters assessed. Serum CD44 level in LN patients was determined by ELISA. Control groups included healthy subjects and patients with non-renal SLE or non-lupus renal disease. Results: CD44 expression was absent in the normal kidney, but it was expressed in proximal and distal tubular epithelial cells and infiltrating cells in renal biopsies from patients with active proliferative LN. ScRNA-Seq datasets confirmed that CD44 was predominantly expressed in tubular cells and all immune cells identified in LN patients including tissue resident, inflammatory and phagocytic macrophages, Treg cells, effector and central memory CD4+ T cells, resident memory CD8+ T cells and naïve and activated B cells. Treatment of NZB/W F1 mice with anti-CD44 antibody preserved kidney histology and reduced proteinuria, tubulo-interstitial infiltration of CD3+, CD4+ and CD19+ immune cells, and mediators of kidney fibrosis compared to Control mice. Longitudinal studies showed that serum CD44 level increased prior to clinical renal flare by 4.5 months and the level decreased after treatment. ROC curve analysis showed that CD44 level distinguished patients with active LN from healthy subjects and patients with quiescent LN, active non-renal lupus, and non-lupus CKD (ROC AUC of 0.99, 0.96, 0.99 and 0.99 respectively). CD44 level correlated with leukocyte infiltration and interstitial inflammation scores in active LN kidney biopsies. Discussion: Our findings suggest that CD44 plays a pathogenic role in renal parenchymal inflammation and fibrosis in active LN and monitoring CD44 may facilitate early diagnosis of flare.

Marine Fish Protein Peptide Regulating Potassium Oxonate-Induced Intestinal Dysfunction in Hyperuricemia Rats Helps Alleviate Kidney Inflammation.

The metabolic disease hyperuricemia (HUA) is characterized by a disturbance in purine metabolism. Peptides, such as marine fish-derived peptides, have previously been shown to be effective in alleviating HUA. In this study, HUA rats were induced by potassium oxonate with 100 mg/kg (L), 200 mg/kg (M), and 400 mg/kg (H) of marine fish protein peptide (MFPP). The results showed that MFPP could effectively reduce the serum uric acid (SUA) levels compared with the model group rats; kidney histopathology and the levels of inflammatory factors (TNF-α, IL-6, and IL-10) indicated that MFPP attenuated HUA-induced kidney inflammation. Meanwhile, MFPP restored the abundance of beneficial bacteria, including Lactobacillus, Blautia, Colidextribacter, and Intestinimonas. MFPP further repaired the intestinal barrier by recovering the expression of gene Ildr2 encoding the tricellular tight junction protein ILDR2 and the immune-related genes Ccr7 and Nr4a3 and also regulated the expression of Entpd8 and Cyp27b1 to restore kidney function and uric acid metabolism. MFPP was proved to have potential as a therapeutic strategy to be included in dietary intervention to relieve HUA.

Lactiplantibacillus pentosus P2020 protects the hyperuricemia and renal inflammation in mice.

Introduction: Hyperuricemia (HUA) is a common metabolic disease, and its prevalence has been increasing worldwide. Pharmaceutical drugs have been used for controlling HUA but they all have certain side effects, which thus calls for discovering alternative options including using treatment of probiotics to prevent the development of HUA. Methods: We established HUA mice model induced by potassium oxonate and adenine and performed in vivo experiments to verify the ability to lower serum uric acid of Lactiplantibacillus pentosus P2020 (LPP), a probiotics stain extracted from Chinese pickle. We also tried to discussed the underlying mechanisms. Results: Oral administration with LPP significantly decreased serum uric acid and reduced renal inflammatory response by downregulating multiple inflammation pathways including NK-kB, MAPK, and TNFα. We also found that LPP administration significantly promoted uric acid excretion by regulating expression of transporters in the kidney and ileum. In addition, LPP intake improved intestinal barrier function and modulated the composition of gut microbiota. Discussion: These results suggest that probiotics LPP may have a promising potential to protect against development of HUA and HUA-related renal damage, and its working mechanisms involve regulation of inflammation pathways and expression of transporters in the kidney and ileum.

A Network Pharmacology and Molecular-Docking-Based Approach to Identify the Probable Targets of Short-Chain Fatty-Acid-Producing Microbial Metabolites against Kidney Cancer and Inflammation.

(1) Background: A large and diverse microbial population exists in the human intestinal tract, which supports gut homeostasis and the health of the host. Short-chain fatty acid (SCFA)-secreting microbes also generate several metabolites with favorable regulatory effects on various malignancies and immunological inflammations. The involvement of intestinal SCFAs in kidney diseases, such as various kidney malignancies and inflammations, has emerged as a fascinating area of study in recent years. However, the mechanisms of SCFAs and other metabolites produced by SCFA-producing bacteria against kidney cancer and inflammation have not yet been investigated. (2) Methods: We considered 177 different SCFA-producing microbial species and 114 metabolites from the gutMgene database. Further, we used different online-based database platforms to predict 1890 gene targets associated with metabolites. Moreover, DisGeNET, OMIM, and Genecard databases were used to consider 13,104 disease-related gene targets. We used a Venn diagram and various protein-protein interactions (PPIs), KEGG pathways, and GO analyses for the functional analysis of gene targets. Moreover, the subnetwork of protein-protein interactions (through string and cytoscape platforms) was used to select the top 20% of gene targets through degree centrality, betweenness centrality, and closeness centrality. To screen the possible candidate compounds, we performed an analysis of the ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties of metabolites and then found the best binding affinity using molecular docking simulation. (3) Results: Finally, we found the key gene targets that interact with suitable compounds and function against kidney cancer and inflammation, such as MTOR (with glycocholic acid), PIK3CA (with 11-methoxycurvularin, glycocholic acid, and isoquercitrin), IL6 (with isoquercitrin), PTGS2 (with isoquercitrin), and IGF1R (with 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine, isoquercitrin), showed a lower binding affinity. (4) Conclusions: This study provides evidence to support the positive effects of SCFA-producing microbial metabolites that function against kidney cancer and inflammation and makes integrative research proposals that may be used to guide future studies.

Excessive Activation of Notch Signaling in Macrophages Promote Kidney Inflammation, Fibrosis, and Necroptosis.

Diabetic nephropathy (DN) is one of the main causes of end-stage renal disease (ESRD). Existing treatments cannot control the progression of diabetic nephropathy very well. In diabetic nephropathy, Many monocytes and macrophages infiltrate kidney tissue. However, the role of these cells in the pathogenesis of diabetic nephropathy has not been fully elucidated. In this study, we analyzed patient kidney biopsy specimens, diabetic nephropathy model animals. Meanwhile, we cocultured cells and found that in diabetic nephropathy, damaged intrinsic renal cells (glomerular mesangial cells and renal tubular epithelial cells) recruited monocytes/macrophages to the area of tissue damage to defend against and clear cell damage. This process often involved the activation of different types of macrophages. Interestingly, the infiltrating macrophages were mainly M1 (CD68+iNOS+) macrophages. In diabetic nephropathy, crosstalk between the Notch pathway and NF-κB signaling in macrophages contributed to the polarization of macrophages. Hyperpolarized macrophages secreted large amounts of inflammatory cytokines and exacerbated the inflammatory response, extracellular matrix secretion, fibrosis, and necroptosis of intrinsic kidney cells. Additionally, macrophage depletion therapy with clodronate liposomes and inhibition of the Notch pathway in macrophages alleviated the pathological changes in kidney cells. This study provides new information regarding diabetic nephropathy-related renal inflammation, the causes of macrophage polarization, and therapeutic targets for diabetic nephropathy.

Innovative immunosuppression in kidney transplantation: A challenge for unmet needs.

Due to the optimal results obtained in kidney transplantation and to the lack of interest of the industries, new innovative drugs in kidney transplantation are difficult to be encountered. The best strategy to find the new drugs recently developed or under development is to search in the sections of kidney transplantation still not completely covered by the drugs on the market. These unmet needs are the prevention of delayed graft function (DGF), the protection of the graft over the long time and the desensitization of preformed anti human leukocyte antigen antibodies and the treatment of the acute antibody-mediated rejection. These needs are particularly relevant due to the expansion of some kind of kidney transplantation as transplantation from non-heart beating donor and in the case of antibody-incompatible grafts. The first are particularly exposed to DGF, the latter need a safe desensitization and a safe treatments of the antibody mediated rejections that often occur. Particular caution is needed in treating these drugs. First, they are described in very recent studies and the follow-up of their effect is of course rather short. Second, some of these drugs are still in an early phase of study, even if in well-conducted randomized controlled trials. Particular caution and a careful check need to be used in trials launched 2 or 3 years ago. Indeed, is always necessary to verify whether the study is still going on or whether and why the study itself was abandoned.

Pathogenic T-Cell Responses in Immune-Mediated Glomerulonephritis.

Glomerulonephritis (GN) comprises a group of immune-mediated kidney diseases affecting glomeruli and the tubulointerstitium. Glomerular crescent formation is a histopathological characteristic of severe forms of GN, also referred to as crescentic GN (cGN). Based on histological findings, cGN includes anti-neutrophil cytoplasmic antibody (ANCA)-associated GN, a severe form of ANCA-associated vasculitis, lupus nephritis associated with systemic lupus erythematosus, Goodpasture's disease, and IgA nephropathy. The immunopathogenesis of cGN is associated with activation of CD4+ and CD8+ T cells, which particularly accumulate in the periglomerular and tubulointerstitial space but also infiltrate glomeruli. Clinical observations and functional studies in pre-clinical animal models provide evidence for a pathogenic role of Th1 and Th17 cell-mediated immune responses in cGN. Emerging evidence further argues that CD8+ T cells have a role in disease pathology and the mechanisms of activation and function of recently identified tissue-resident CD4+ and CD8+ T cells in cGN are currently under investigation. This review summarizes the mechanisms of pathogenic T-cell responses leading to glomerular damage and renal inflammation in cGN. Advanced knowledge of the underlying immune mechanisms involved with cGN will enable the identification of novel therapeutic targets for the replacement or reduction in standard immunosuppressive therapy or the treatment of refractory disease.

First report on the prevalence of Klossiella muris in Mus musculus for S. Miguel Island - Azores (Portugal).

Klossiella is a genus of apicomplexan coccidian parasites with a global distribution, whose members typically infect the renal tissue of a wide variety of vertebrate hosts with a high level of host specificity. The presence of this parasite has been previously associated with kidney inflammatory processes. To our knowledge, this is the first report on the prevalence of Klossiella muris in the house mouse (Mus musculus) in Portugal (São Miguel Island - Azores). The prevalence of K. muris was determined through histopathological examination of renal tissue collected during necropsy of 130 mice captured between the years of 2011-2019. K. muris was diagnosed in 45.38% (CI95: 40.9-85.4) of the examined mice. Infection with this parasite was associated with mild to severe kidney inflammation, assessed by the presence of inflammatory processes in the renal cortex and medulla. CAPSULE: First record on coccidiosis caused by infection of Klossiella muris in Mus musculus in Portugal.

Hippocampal mitogen-activated protein kinase phosphatase-1 regulates behavioral and systemic effects of chronic corticosterone administration.

Clinical reports indicate a bidirectional relationship between mental illness and chronic systemic diseases. However, brain mechanisms linking chronic stress and development of mood disorders to accompanying peripheral organ dysfunction are still not well characterized in animal models. In the current study, we investigated whether activation of hippocampal mitogen-activated protein kinase phosphatase-1 (MKP-1), a key factor in depression pathophysiology, also acts as a mediator of systemic effects of stress. First, we demonstrated that treatment with the glucocorticoid receptor (GR) agonist dexamethasone or acute restraint stress (ARS) significantly increased Mkp-1 mRNA levels within the rat hippocampus. Conversely, administration of the GR antagonist mifepristone 30 min before ARS produced a partial blockade of Mkp-1 upregulation, suggesting that stress activates MKP-1, at least in part, through upstream GR signaling. Chronic corticosterone (CORT) administration evoked comparable increases in hippocampal MKP-1 protein levels and produced a robust increase in behavioral emotionality. In addition to behavioral deficits, chronic CORT treatment also produced systemic pathophysiological effects. Elevated levels of renal inflammation protein markers (NGAL and IL18) were observed suggesting tissue damage and early kidney impairment. In a rescue experiment, the effects of CORT on development of depressive-like behaviors and increased NGAL and IL18 protein levels in the kidney were blocked by CRISPR-mediated knockdown of hippocampal Mkp-1 prior to CORT exposure. In sum, these findings further demonstrate that MKP-1 is necessary for development of enhanced behavioral emotionality, while also suggesting a role in stress mechanisms linking brain dysfunction and systemic illness such as kidney disease.

An Emerging Role of TIM3 Expression on T Cells in Chronic Kidney Inflammation.

T cell immunoglobulin domain and mucin domain 3 (TIM3) was initially identified as an inhibitory molecule on IFNγ-producing T cells. Further research discovered the broad expression of TIM3 on different immune cells binding to multiple ligands. Apart from its suppressive effects on the Th1 cells, recent compelling experiments highlighted the indispensable role of TIM3 in the myeloid cell-mediated inflammatory response, supporting that TIM3 exerts pleiotropic effects on both adaptive and innate immune cells in a context-dependent manner. A large number of studies have been conducted on TIM3 biology in the disease settings of infection, cancer, and autoimmunity. However, there is a lack of clinical evidence to closely evaluate the role of T cell-expressing TIM3 in the pathogenesis of chronic kidney disease (CKD). Here, we reported an intriguing case of Mycobacterium tuberculosis (Mtb) infection that was characterized by persistent overexpression of TIM3 on circulating T cells and ongoing kidney tubulointerstitial inflammation for a period of 12 months. In this case, multiple histopathological biopsies revealed a massive accumulation of recruited T cells and macrophages in the enlarged kidney and liver. After standard anti-Mtb treatment, repeated renal biopsy identified a dramatic remission of the infiltrated immune cells in the tubulointerstitial compartment. This is the first clinical report to reveal a time-course expression of TIM3 on the T cells, which is pathologically associated with the progression of severe kidney inflammation in a non-autoimmunity setting. Based on this case, we summarize the recent findings on TIM3 biology and propose a novel model of CKD progression due to the aberrant crosstalk among immune cells.

Impact of Camellia japonica Bee Pollen Polyphenols on Hyperuricemia and Gut Microbiota in Potassium Oxonate-Induced Mice.

Camellia japonica bee pollen is one of the major types of bee pollen in China and exhibits antioxidant and anti-inflammatory activities. The aims of our study were to evaluate the effects and the possible mechanism of Camellia japonica bee pollen polyphenols on the treatment of hyperuricemia induced by potassium oxonate (PO). The results showed that Camellia japonica bee pollen ethyl acetate extract (CPE-E) owned abundant phenolic compounds and strong antioxidant capabilities. Administration with CPE-E for two weeks greatly reduced serum uric acid and improved renal function. It inhibited liver xanthine oxidase (XOD) activity and regulated the expression of urate transporter 1 (URAT1), glucose transporter 9 (GLUT9), organic anion transporter 1 (OAT1), organic cation transporter 1 (OCT1) and ATP-binding cassette superfamily gmember 2 (ABCG2) in kidneys. Moreover, CPE-E suppressed the activation of the toll-like receptor 4/myeloid differentiation factor 88/nuclear factor-κB (TLR4/MyD88/NF-κB) signaling pathway and nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome in PO-treated mice, and related inflammatory cytokines were reduced. CPE-E also modulated gut microbiota structure, showing that the abundance of Lactobacillus and Clostridiaceae increased in hyperuicemic mice. This study was conducted to explore the protective effect of CPE-E on hyperuricemia and provide new thoughts for the exploitation of Camellia japonica bee pollen.