Immunology of Kidney Disease.

The immune system and the kidneys are closely related. Immune components mediate acute kidney disease and are crucial to the progression of chronic kidney disease. Beyond its pathogenic functions, the immune system supports immunological homeostasis in healthy kidneys. The kidneys help maintain immune equilibrium by removing metabolic waste products and toxins, thereby limiting local and systemic inflammation. In this review, we describe the close relationship between the immune system and the kidneys. We discuss how the imbalance in the immune response can be deleterious to the kidneys and how immunomodulation can be important in preventing end-stage renal disease. In addition, recent tools such as in silico platforms and kidney organoids can help unveil the relationship between immune cells and kidney homeostasis. Expected final online publication date for the Annual Review of Immunology, Volume 42 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Vitamin D and chronic kidney disease: Insights on lipid metabolism of tubular epithelial cell and macrophages in tubulointerstitial fibrosis.

Chronic kidney disease (CKD) has been recognized as a significant global health problem due to being an important contributor to morbidity and mortality. Inflammation is the critical event that leads to CKD development orchestrated by a complex interaction between renal parenchyma and immune cells. Particularly, the crosstalk between tubular epithelial cells (TECs) and macrophages is an example of the critical cell communication in the kidney that drives kidney fibrosis, a pathological feature in CKD. Metabolism dysregulation of TECs and macrophages can be a bridge that connects inflammation and fibrogenesis. Currently, some evidence has reported how cellular lipid disturbances can affect kidney disease and cause tubulointerstitial fibrosis highlighting the importance of investigating potential molecules that can restore metabolic parameters. Vitamin D (VitD) is a hormone naturally produced by mammalian cells in a coordinated manner by the skin, liver, and kidneys. VitD deficiency or insufficiency is prevalent in patients with CKD, and serum levels of VitD are inversely correlated with the degree of kidney inflammation and renal function. Proximal TECs and macrophages produce the active form of VitD, and both express the VitD receptor (VDR) that evidence the importance of this nutrient in regulating their functions. However, whether VitD signaling drives physiological and metabolism improvement of TECs and macrophages during kidney injury is an open issue to be debated. In this review, we brought to light VitD as an important metabolic modulator of lipid metabolism in TECs and macrophages. New scientific approaches targeting VitD e VDR signaling at the cellular metabolic level can provide a better comprehension of its role in renal physiology and CKD progression.

Photobiomodulation Reduces the Cytokine Storm Syndrome Associated with COVID-19 in the Zebrafish Model.

Although the exact mechanism of the pathogenesis of coronavirus SARS-CoV-2 (COVID-19) is not fully understood, oxidative stress and the release of pro-inflammatory cytokines have been highlighted as playing a vital role in the pathogenesis of the disease. In this sense, alternative treatments are needed to reduce the level of inflammation caused by COVID-19. Therefore, this study aimed to investigate the potential effect of red photobiomodulation (PBM) as an attractive therapy to downregulate the cytokine storm caused by COVID-19 in a zebrafish model. RT-qPCR analyses and protein-protein interaction prediction among SARS-CoV-2 and Danio rerio proteins showed that recombinant Spike protein (rSpike) was responsible for generating systemic inflammatory processes with significantly increased levels of pro-inflammatory (il1b, il6, tnfa, and nfkbiab), oxidative stress (romo1) and energy metabolism (slc2a1a and coa1) mRNA markers, with a pattern similar to those observed in COVID-19 cases in humans. On the other hand, PBM treatment was able to decrease the mRNA levels of these pro-inflammatory and oxidative stress markers compared with rSpike in various tissues, promoting an anti-inflammatory response. Conversely, PBM promotes cellular and tissue repair of injured tissues and significantly increases the survival rate of rSpike-inoculated individuals. Additionally, metabolomics analysis showed that the most-impacted metabolic pathways between PBM and the rSpike treated groups were related to steroid metabolism, immune system, and lipid metabolism. Together, our findings suggest that the inflammatory process is an incisive feature of COVID-19 and red PBM can be used as a novel therapeutic agent for COVID-19 by regulating the inflammatory response. Nevertheless, the need for more clinical trials remains, and there is a significant gap to overcome before clinical trials can commence.

Metabolic Alterations in SARS-CoV-2 Infection and Its Implication in Kidney Dysfunction.

Clinical strategies focusing on pathogen elimination are expected in an infectious-disease outbreak, such as the severe coronavirus disease 2019 (COVID-19), to avoid organ dysfunction. However, understanding the host response to viral infection is crucial to develop an effective treatment to optimize the patient's conditions. The pathogenic viruses can promote metabolic changes during viral infection, favoring its survival, altering cell phenotype and function, and causing sustained inflammation and tissue injury. Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), the etiological agent of COVID-19, provokes systemic and cell metabolic changes and possibly altering lipid and glucose metabolism. Besides severe acute respiratory syndrome (SARS), SARS-CoV-2 can cause acute kidney injury, which has been associated with the severity of the disease. Although it is not clear the mechanisms whereby SARS-CoV-2 induces kidney dysfunction, it is known that the virus presents kidney tropism, namely, podocytes and proximal tubular epithelial cells. Changes in renal cell metabolism and systemic metabolic disorders are important events in kidney injury progression. Here, we explored the metabolism and its interface with SARS-CoV-2 infection and raised the perspective on metabolism disturbances as a critical event to kidney dysfunction in COVID-19.

Gut Microbiota and Intestinal Epithelial Myd88 Signaling Are Crucial for Renal Injury in UUO Mice.

Increasing evidence shows the essential participation of gut microbiota in human health and diseases by shaping local and systemic immunity. Despite an accumulating body of studies showing that chronic kidney disease (CKD) is closely associated with disturbances in the composition of gut microbiota, it remains unclear the importance of gut microbiota in the onset and development of CKD. For the purpose of untangling the role of gut microbiota in CKD, gut microbiota was depleted with a pool of broad-spectrum antibiotics in mice submitted to unilateral ureteral obstruction (UUO). Depletion of gut microbiota significantly decreased levels of proinflammatory cytokines and fibrosis markers, attenuating renal injury. Additionally, to study whether the pathogenic role of gut microbiota is dependent of microbial-host crosstalk, we generated mice lacking Myd88 (myeloid differentiation primary response gene 8) expression in intestinal epithelial cells (IECs) and performed UUO. The absence of Myd88 in IECs prevented a bacterial burden in mesenteric lymph nodes as observed in WT mice after UUO and led to lower expression of proinflammatory cytokines and chemokines, reducing deposition of type I collagen and, ultimately, attenuating renal damage. Therefore, our results suggest that the presence of gut microbiota is crucial for the development of CKD and may be dependent of Myd88 signaling in IECs, which appears to be essential to maturation of immune cells intimately involved in aggravation of inflammatory scenarios.

TLR2 and TLR4 play opposite role in autophagy associated with cisplatin-induced acute kidney injury.

Acute kidney injury (AKI) is considered an inflammatory disease in which toll-like receptors (TLRs) signaling pathways play an important role. The activation of TLRs results in production of several inflammatory cytokines leading to further renal damage. In contrast, TLRs are key players on autophagy induction, which is associated with a protective function on cisplatin-induced AKI. Hence, the present study aimed to evaluate the specific participation of TLR2 and TLR4 molecules on the development of cisplatin-induced AKI. Complementarily, we also investigated the link between TLRs and heme oxygenase-1 (HO-1), a promisor cytoprotective molecule. First, we observed that only the absence of TLR2 but not TLR4 in mice exacerbated the renal dysfunction, tissue injury and mortality rate, even under an immunologically privileged microenvironment. Second, we demonstrated that TLR2 knockout (KO) mice presented lower expression of autophagy-associated markers when compared with TLR4 KO animals. Similar parameter was confirmed in vitro, using tubular epithelial cells derived from both KO mice. To test the cross-talking between HO-1 and TLRs, hemin (an HO-1 internal inducer) was administrated in cisplatin-treated TLR2 and TLR4 KO mice and it was detected an improvement in the global renal tissue parameters. However, this protection was less evident at TLR2 KO mice. In summary, we documented that TLR2 plays a protective role in cisplatin-induced AKI progression, in part, by a mechanism associated with autophagy up-regulation, considering that its interplay with HO-1 can promote renal tissue recover.

Antioxidant, anti-rheumatic and anti-inflammatory investigation of extract and dicentrinone from Duguetia furfuracea (A. St.-Hil.) Benth. & Hook. f.

ETHNOPHARMACOLOGICAL RELEVANCE: The preparations of teas and syrups using Duguetia furfuracea have been used in folk medicine to treat rheumatism and back pain. Several rheumatic diseases are anti-inflammatory and are treated with several anti-inflammatories. AIM OF THE STUDY: The objective of this work were to evaluate the chemical investigation of methanolic extract obtained from leaves of D. furfuracea (MEDF) and test the MEDF, such as chloroform (CF), ethyl acetate (EAF) and hydromethanol (HMF) fractions and the alkaloid dicentrinone (DF-1) in vitro antioxidant effects and in vivo models of inflammation. MATERIAL AND METHODS: MEDF and CF were analyzed by LC-PDA and the results revealed the presence of alkaloid aporphine and oxoaporphine. The concentrations of total phenols, flavonoids and flavonols were determined. Additionally, MEDF, fractions and dicentrinone were evaluated free radical scavenging activity 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and peroxidation ß-carotene/linoleic acid and malondialdehyde (MDA) assays. The anti-inflammatory effects of MEDF, fractions and dicentrinone were studied in carrageenan-induced paw edema. The anti-rheumatic potential was studied in air pouch model and zymosan-induced arthritis. RESULTS: CF fractionation resulted in the isolation of the oxaporphine alkaloid dicentrinone (DF-1). The highest phenols (624.37mg GAE/g extract), flavonoids (580.51mg QE/g extract) and flavonols (254.44mg QE/g extract), concentration was found in extract. In antioxidant tests, MEDF exhibited the highest scavenging activity and lipoperoxidation. The extract (30-300mg/kg) and all tested fractions inhibited the edema induced by carrageenan. The oral administration of DF-1 inhibited both edema associated with carrageenan-induced inflammation in mice. In air pouch model of inflammation, MEDF (30-300mg/kg) and DF-1 (100mg/kg) inhibited leukocyte migration and plasmatic leakage induced by carrageenan in mice. Finally, MEDF (100mg/kg) did not alter zymozan-induced arthritis in mice. CONCLUSION: The results showed that D. furfuracea exhibits antioxidant, anti-rheumatic potential and anti-inflammatory activity. The presence of the alkaloid dicentrinone in extract and CF fraction could be responsible, at least in part, for the observed effects.

The cannabinoid 2 receptor agonist ß-caryophyllene modulates the inflammatory reaction induced by Mycobacterium bovis BCG by inhibiting neutrophil migration.

OBJECTIVE AND DESIGN: ß-Caryophyllene (BCP) is a sesquiterpene that binds to the cannabinoid 2 (CB2) receptor and exerts anti-inflammatory effects. In this study, we investigated the anti-inflammatory effect of BCP and another CB2 agonist, GP1a in inflammatory experimental model induced by Mycobacterium bovis (BCG). METHODS: C57Bl/6 mice were pretreated orally with BCP (0.5-50 mg/kg) or intraperitonealy with GP1a (10 mg/kg) 1 h before the induction of pleurisy or pulmonary inflammation by BCG. The direct action of CB2 agonists on neutrophils function was evaluated in vitro. RESULTS: ß-Caryophyllene (50 mg/kg) impaired BCG-induced neutrophil accumulation in pleurisy without affecting mononuclear cells or the production of TNF-α and CCL2/MCP-1. However, BCP inhibited CXCL1/KC, leukotriene B4 (LTB4), IL-12, and nitric oxide production. GP1a had a similar effect to BCP. Preincubation of neutrophils with BCP (10 µM) impaired chemotaxis toward LTB4 and adhesion to endothelial cells stimulated with TNF-α, and both, BCP and GP1a, impaired LTB4-induced actin polymerization. CONCLUSION: These results suggest that the CB2 receptor may represent a new target for modulating the inflammatory reaction induced by mycobacteria.

Analysis of the anti-inflammatory and chemopreventive potential and description of the antimutagenic mode of action of the Annona crassiflora methanolic extract.

CONTEXT: Annona crassiflora Mart. (Annonaceae) is a medicinal plant that is widely used in folk medicine, which leads to its investigation as a potential source of new pharmacological principles. OBJECTIVE: This study describes the anti-inflammatory, antiallodynic, and antimutagenic/chemopreventive activities of the leaves A. crassiflora methanolic extract. Its antimutagenic mode of action was analyzed in a plant or animal experimental model. MATERIALS AND METHODS: Total flavonoids were quantified by spectrophotometry at 415 nm and its composition was analyzed by (1)H NMR spectra. Animals received orally, 30, 100, and 300 mg/kg of extract in both tests, carrageenan-induced paw edema and myeloperoxidase activity. Animals were treated with 100 and 300 mg/kg, in all the analyzed tests, pleural cell migration and protein exudation, carrageenan-induced cell migration into the pouch, induction of joint inflammation and carrageenan-induced allodynia response in the mouse paw. To evaluate the antimutagenic/chemopreventive activity through the Allium cepa test, we used 5, 10, and 15 mg/L of extract, and for the micronucleus test in the peripheral blood, we used the dose of 15 mg/kg. RESULTS: The fractionation of the ethyl acetate (EA) fraction, resulting from the partition of the methanol extract of the A. crassiflora, afforded through chromatographic methods resulted in the isolation of kaempferol 3-O-ß-glucoside and kaempferol 3-O-ß-diglucoside. Oral treatment with 100 and 300 mg/kg of extract significantly inhibited the carrageenan-induced edema formation, with inhibitions of 53 ± 7% and 47 ± 10%; in MPO activity, the observed inhibitions were 60 ± 7% for 100 mg/kg treatment and 63 ± 7% for 300 mg/kg. The ACME reduced significantly the total leukocytes (an inhibition of 78 ± 9% with 100 mg/kg and 90 ± 7% with 300 mg/kg) and protein levels (approximately 100% inhibition with both doses) in the pleurisy model. In carrageenan-induced leukocyte migration into the pouch, the extract inhibited leukocyte migration only when administered 300 mg/kg per dose (the reduction was 43 ± 5%). Pretreatment with extract failed to reduce the zymosan-induced edema formation and did not inhibit the carrageenan-induced mechanical allodynia. Damage reduction in Allium cepa tested with different concentrations (5, 10, and 15 mg/L) was 66.17, 75.75, and 69.19% for the pre-treatment; 72.72, 33.33, and 22.22% for the simple simultaneous treatment; 100.50, 93.93, and 102.52% for the simultaneous treatment with pre-incubation; 89.39, 79.79, and 84.34%; for the post-treatment, and 86.36, 81.31, and 93.43% for the continuous treatment. The antimutagenic evaluation in the micronucleous test showed a damage reduction of 75.00 and 64.58% for the pre-treatment and simultaneous protocols, respectively. The post-treatment protocol increased the cyclophosphamide effects in 45.83%. CONCLUSION: These results suggest that this medicinal plant has chemopreventive and anti-inflammatory therapeutic potential.

Composition and evaluation of the anti-inflammatory and anticancer activities of the essential oil from Annona sylvatica A. St.-Hil.

The essential oil from the leaves of Annona sylvatica (EOAS) was extracted by hydrodistillation, and the analysis was performed by gas chromatography-mass spectrometry. The main compounds identified in the EOAS were sesquiterpenes, such as hinesol, z-caryophyllene, ß-maaliene, γ-gurjunene, silphiperfol-5-en-3-ol, ledol, cubecol-1-epi, and muurola-3,5-diene. Oral administration of the EOAS (20 and 200 mg/kg) and subcutaneous injection of dexamethasone (0.5 mg/kg, reference drug) significantly inhibited carrageenan- and complete Freund's adjuvant-induced mouse paw edema. The anticancer activity the EOAS showed growth inhibitory activity on all cell lines when administered in a high concentration. The EOAS inhibited the growth of human cancer cell lines with GI(50) values in the range of 36.04-45.37 µg/mL on all of the cell lines tested. This work describes for the first time the anti-inflammatory and anticancer effects of the essential oil of A. sylvatica and its composition. Considering that drugs currently available for the treatment of inflammatory and cancer conditions show undesirable side-effects, the present results may have clinical relevance and open new possibilities for the development of novel anti-inflammatory and anticancer drugs.