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Recent studies suggest that disruptions in intestinal homeostasis, such as changes in gut microbiota composition, infection, and inflammatory-related gut diseases, can be associated with kidney diseases. For instance, genomic investigations highlight how susceptibility genes linked to IgA nephropathy are also correlated with the risk of inflammatory bowel disease. Conversely, investigations demonstrate that the use of short-chain fatty acids, produced through fermentation by intestinal bacteria, protects kidney function in models of acute and chronic kidney diseases. Thus, the dialogue between the gut and kidney seems to be crucial in maintaining their proper function, although the factors governing this crosstalk are still emerging as the field evolves. In recent years, a series of studies have highlighted the significance of enteroendocrine cells (EECs) which are part of the secretory lineage of the gut epithelial cells, as important components in gut-kidney crosstalk. EECs are distributed throughout the epithelial layer and release more than 20 hormones in response to microenvironment stimuli. Interestingly, some of these hormones and/or their pathways such as Glucagon-Like Peptide 1 (GLP-1), GLP-2, gastrin, and somatostatin have been shown to exert renoprotective effects. Therefore, the present review explores the role of EECs and their hormones as regulators of gut-kidney crosstalk and their potential impact on kidney diseases. This comprehensive exploration underscores the substantial contribution of EEC hormones in mediating gut-kidney communication and their promising potential for the treatment of kidney diseases. [ABSTRACT FROM AUTHOR]

Cardiorenal syndrome type 3 (CRS 3) occurs when there is an acute kidney injury (AKI) leading to the development of an acute cardiac injury. The immune system is involved in modulating the severity of kidney injury, and the role of immune system cells in the development of CRS 3 is not well established. The present work aims to characterize the macrophage and T and B lymphocyte populations in kidney and heart tissue after AKI induced by renal I/R. Thus, C57BL/6 mice were subjected to a renal I/R protocol by occlusion of the left renal pedicle (unilateral) for 60 min, followed by reperfusion for 3, 8 and 15 days. The immune cell populations of interest were identified using flow cytometry, and RT-qPCR was used to evaluate gene expression. As a result, a significant increase in TCD4+, TCD8+ lymphocytes and M1 macrophages to the renal tissue was observed, while B cells in the heart decreased. A renal tissue repair response characterized by Foxp3 activation predominated. However, a more inflammatory profile was shown in the heart tissue influenced by IL-17RA and IL-1β. In conclusion, the AKI generated by renal I/R was able to activate and recruit T and B lymphocytes and macrophages, as well as pro-inflammatory mediators to renal and cardiac tissue, showing the role of the immune system as a bridge between both organs in the context of CRS 3. [ABSTRACT FROM AUTHOR]

Inflammation, a process intimately linked to renal disease, can be defined as a complex network of interactions between renal parenchymal cells and resident immune cells, such as macrophages and dendritic cells, coupled with recruitment of circulating monocytes, lymphocytes, and neutrophils. Once stimulated, these cells activate specialized structures such as Toll-like receptor and Nod-like receptor (NLR). By detecting danger-associated molecules, these receptors can set in motion major innate immunity pathways such as nuclear factor ĸB (NF-ĸB) and NLRP3 inflammasome, causing metabolic reprogramming and phenotype changes of immune and parenchymal cells and triggering the secretion of a number of inflammatory mediators that can cause irreversible tissue damage and functional loss. Growing evidence suggests that this response can be deeply impacted by the crosstalk between the kidneys and other organs, such as the gut. Changes in the composition and/or metabolite production of the gut microbiota can influence inflammation, oxidative stress, and fibrosis, thus offering opportunities to positively manipulate the composition and/or functionality of gut microbiota and, consequentially, ameliorate deleterious consequences of renal diseases. In this review, we summarize the most recent evidence that renal inflammation can be ameliorated by interfering with the gut microbiota through the administration of probiotics, prebiotics, and postbiotics. In addition to these innovative approaches, we address the recent discovery of new targets for drugs long in use in clinical practice. Angiotensin II receptor antagonists, NF-ĸB inhibitors, thiazide diuretics, and antimetabolic drugs can reduce renal macrophage infiltration and slow down the progression of renal disease by mechanisms independent of those usually attributed to these compounds. Allopurinol, an inhibitor of uric acid production, has been shown to decrease renal inflammation by limiting activation of the NLRP3 inflammasome. So far, these protective effects have been shown in experimental studies only. Clinical studies will establish whether these novel strategies can be incorporated into the arsenal of treatments intended to prevent the progression of human disease. [ABSTRACT FROM AUTHOR]

Mesenchymal stromal cells (MSCs) orchestrate tissue repair by releasing cell-derived microvesicles (MVs), which, presumably by small RNA species, modulate global gene expression. The knowledge of miRNA/mRNA signatures linked to a reparative status may elucidate some of the molecular events associated with MSC protection. Here, we used a model of cisplatin-induced kidney injury (acute kidney injury) to assess how MSCs or MVs could restore tissue function. MSCs and MVs presented similar protective effects, which were evidenced in vivo and in vitro by modulating apoptosis, inflammation, oxidative stress, and a set of prosurvival molecules. In addition, we observed that miRNAs (i.e., miR-880, miR-141, miR-377, and miR-21) were modulated, thereby showing active participation on regenerative process. Subsequently, we identified that MSC regulates a particular miRNA subset which mRNA targets are associated with Wnt/TGF-β, fibrosis, and epithelial-mesenchymal transition signaling pathways. Our results suggest that MSCs release MVs that transcriptionally reprogram injured cells, thereby modulating a specific miRNA-mRNA network. [ABSTRACT FROM AUTHOR]

Inflammatory bowel diseases (IBD) is the result of dysregulation of mucosal innate and adaptive immune responses. Factors such as genetic, microbial and environmental are involved in the development of these disorders. Accordingly, animal models that mimic human diseases are tools for the understanding the immunological processes of the IBD as well as to evaluate new therapeutic strategies. Crotoxin (CTX) is the main component of Crotalus durissus terrificus snake venom and has an immunomodulatory effect. Thus, we aimed to evaluate the modulatory effect of CTX in a murine model of colitis induced by 2,4,6- trinitrobenzene sulfonic acid (TNBS). The CTX was administered intraperitoneally 18 hours after the TNBS intrarectal instillation in BALB/c mice. The CTX administration resulted in decreased weight loss, disease activity index (DAI), macroscopic tissue damage, histopathological score and myeloperoxidase (MPO) activity analyzed after 4 days of acute TNBS colitis. Furthermore, the levels of TNF-α, IL-1β and IL-6 were lower in colon tissue homogenates of TNBS-mice that received the CTX when compared with untreated TNBS mice. The analysis of distinct cell populations obtained from the intestinal lamina propria showed that CTX reduced the number of group 3 innate lymphoid cells (ILC3) and Th17 population; CTX decreased IL-17 secretion but did not alter the frequency of CD4+Tbet+ T cells induced by TNBS instillation in mice. In contrast, increased CD4+FoxP3+ cell population as well as secretion of TGF-β, prostaglandin E2 (PGE2) and lipoxin A4 (LXA4) was observed in TNBS-colitis mice treated with CTX compared with untreated TNBS-colitis mice. In conclusion, the CTX is able to modulate the intestinal acute inflammatory response induced by TNBS, resulting in the improvement of clinical status of the mice. This effect of CTX is complex and involves the suppression of the pro-inflammatory environment elicited by intrarectal instillation of TNBS due to the induction of a local anti-inflammatory profile in mice. [ABSTRACT FROM AUTHOR]

Nephrotoxicity is substantial side effect for 30% of patients undergoing cancer therapy with cisplatin and may force them to change or even abandon the treatment. Studies regarding aerobic exercise have shown its efficacy for the treatment of many types of diseases and its capacity to reduce tumors. However, little is known about the impact of physical exercise on cisplatin-induced acute kidney injury (AKI). In the present study, our aim was to investigate the role of physical exercise in AKI induced by cisplatin. We submitted C57Bl6 male mice to seven weeks of chronic exercise on a training treadmill and treated them with single i.p. injection of cisplatin (20 mg/kg) in the last week. Exercise efficacy was confirmed by an increased capillary-to-fiber ratio in the gastrocnemius muscle of exercised groups (EX and CIS-EX). The group submitted to exercise before cisplatin administration (CIS-EX) exhibited less weight loss and decreased serum urea levels compared to the cisplatin group (CIS). Exercise also showed a protective role against cisplatin-induced cell death in the kidney. The CIS-EX group showed a lower inflammatory response, with less TNF and IL-10 expression in the kidney and serum. In the same group, we observed an increase of IL-6 and HO-1 expression in the kidney. Taken together, our results indicate that chronic aerobic exercise is able to attenuate AKI by inducing IL-6 and HO-1 production, which results in lower inflammatory and apoptotic profiles in the kidney. [ABSTRACT FROM AUTHOR]

Diabetes and obesity are worldwide health problems. White fat dynamically participates in hormonal and inflammatory regulation. White adipose tissue is recognized as a multifactorial organ that secretes several adipose-derived factors that have been collectively termed “adipokines.” Adipokines are pleiotropic molecules that gather factors such as leptin, adiponectin, visfatin, apelin, vaspin, hepcidin, RBP4, and inflammatory cytokines, including TNF and IL-1β, among others. Multiple roles in metabolic and inflammatory responses have been assigned to these molecules. Several adipokines contribute to the self-styled “low-grade inflammatory state” of obese and insulin-resistant subjects, inducing the accumulation of metabolic anomalies within these individuals, including autoimmune and inflammatory diseases. Thus, adipokines are an interesting drug target to treat autoimmune diseases, obesity, insulin resistance, and adipose tissue inflammation. The aim of this review is to present an overview of the roles of adipokines in different immune and nonimmune cells, which will contribute to diabetes as well as to adipose tissue inflammation and insulin resistance development. We describe how adipokines regulate inflammation in these diseases and their therapeutic implications. We also survey current attempts to exploit adipokines for clinical applications, which hold potential as novel approaches to drug development in several immune-mediated diseases.

The microbiota shields the host against infections in a process known as colonization resistance. How infections themselves shape this fundamental process remains largely unknown. Here, we show that gut microbiota from previously infected hosts display enhanced resistance to infection. This long-term functional remodeling is associated with altered bile acid metabolism leading to the expansion of taxa that utilize the sulfonic acid taurine. Notably, supplying exogenous taurine alone is sufficient to induce this alteration in microbiota function and enhance resistance. Mechanistically, taurine potentiates the microbiota's production of sulfide, an inhibitor of cellular respiration, which is key to host invasion by numerous pathogens. As such, pharmaceutical sequestration of sulfide perturbs the microbiota's composition and promotes pathogen invasion. Together, this work reveals a process by which the host, triggered by infection, can deploy taurine as a nutrient to nourish and train the microbiota, promoting its resistance to subsequent infection. • Prior gut infection increases the microbiota's resistance to subsequent infection • Infection induces host taurine production and the expansion of taurine utilizers • The gut microbiota converts taurine to sulfide, inhibiting pathogen respiration • Sulfide sequestration unleashes endogenous respirers in the gut microbiota Previous intestinal infection increases the gut microbiota's resistance to subsequent infection by inhibiting the ability of pathogens to respire. [ABSTRACT FROM AUTHOR]

Mesenchymal stromal cells (MSCs) can generate immunological tolerance due to their regulatory activity in many immune cells. Extracellular vesicles (EVs) release is a pivotal mechanism by which MSCs exert their actions. In this study, we evaluate whether mesenchymal stromal cell extracellular vesicles (MSC-EVs) can modulate T cell response. MSCs were expanded and EVs were obtained by differential ultracentrifugation of the supernatant. The incorporation of MSC-EVs by T cells was detected by confocal microscopy. Expression of surface markers was detected by flow cytometry or CytoFLEX and cytokines were detected by RT-PCR, FACS and confocal microscopy and a miRNA PCR array was performed. We demonstrated that MSC-EVs were incorporated by lymphocytes in vitro and decreased T cell proliferation and Th1 differentiation. Interestingly, in Th1 polarization, MSC-EVs increased Foxp3 expression and generated a subpopulation of IFN-γ+/Foxp3+T cells with suppressive capacity. A differential expression profile of miRNAs in MSC-EVs-treated Th1 cells was seen, and also a modulation of one of their target genes, TGFbR2. MSC-EVs altered the metabolism of Th1-differentiated T cells, suggesting the involvement of the TGF-β pathway in this metabolic modulation. The addition of MSC-EVs in vivo, in an OVA immunization model, generated cells Foxp3+. Thus, our findings suggest that MSC-EVs are able to specifically modulate activated T cells at an alternative regulatory profile by miRNAs and metabolism shifting. [ABSTRACT FROM AUTHOR]