We aimed to investigate the mechanism by which spironolactone protects against hypertensive renal fibrosis.

For in-vivo experiments, we established Control, SHR, and SHR+spironolactone (20 mg/kg/day) groups. For in-vitro experiments, we established Control, TGF-β1-induced (10 ng/ml), and spironolactone (1 μmol/l) intervention groups. Renal function and serum potassium, estradiol, testosterone, and plasma aldosterone levels were assessed, along with autophagy indicators LC3 and p62, and NLRP3 inflammasome-related proteins (NLRP3, caspase-1, IL-1β and IL-18). Additionally, changes in macrophage polarization and T cell and dendritic cell populations were determined.

20 mg/kg/day of spironolactone effectively maintained systolic pressure and renal function by lowering aldosterone levels and significantly reducing testosterone levels. Hypertensive renal fibrosis was predominant in the glomeruli, tubules, and interstitium, and was associated with autophagy inhibition in renal tubules, NLRP3 inflammasome activation, both M1 and M2 macrophage polarization, with a predominant effect on M1 polarization, decreased CD4+ T cell population and CD4/CD8 ratio, and increased CD8+ T cell and dendritic cell population. Autophagy negatively regulated the NLRP3 inflammasome. Spironolactone inhibited both M1 and M2 macrophages polarization, mainly M1 macrophage polarization, reduced CD8+ T and dendritic cell population, increased CD4+ T cell population, negatively regulated the release of NLRP3 inflammasome-related proteins in macrophages, and restored autophagy in the glomeruli and renal tubules.

Spironolactone acts on sites where the mineralocorticoid receptor is present. A dose of 20 mg/kg/day spironolactone is well tolerated and protects against hypertension-induced renal fibrosis by restoring autophagy and suppressing NLRP3 inflammasome activation.

The kidneys are crucial for filtering blood, managing overall body water, electrolyte, and acid-base balance, and regulating blood pressure. They remove metabolic waste products, toxins, and drugs. In addition, they limit inflammation by clearing cytokines and reduce immune cell activation by removing bacterial components. Dendritic cells (DCs) in the kidney maintain peripheral tolerance. About 85% of filtered water is reabsorbed by the proximal tubule, exposing distal nephron cells to high concentrations of low molecular weight antigens. These antigens are captured by DCs, helping to inactivate potentially autoreactive T cells and maintain tolerance to circulating antigens. In kidney failure, immune function is severely compromised due to the retention of toxins and cytokines, which activate immune cells and increase systemic inflammation. The kidneys are also vulnerable to immune-mediated diseases. Loss of immune homeostasis, characterized by over- or under-activity of the immune response, can adversely affect kidney function. With advances in immunology and cellular biology, biologic therapies targeting various pathways involved in the pathophysiology of kidney diseases are being developed. In this review, the immunologic aspects of kidney diseases and focus on cytokine-based therapies that may hold promise for the treatment of kidney diseases in the future will be presented.

The NOD-like receptor family, particularly the protein 3 that contains the pyrin domain (NLRP3), is an intracellular sensing protein complex responsible for detecting patterns associated with pathogens and injuries. NLRP3 plays a crucial role in the innate immune response. Currently, a wide range of research has indicated the crucial importance of NLRP3 in various inflammatory conditions. Similarly, the NLRP3 inflammasome plays a significant role in preserving intestinal balance and impacting the advancement of diseases. In addition, several randomized trials have demonstrated the safety and efficacy of targeting NLRP3 in the treatment of colitis, colorectal cancer, and related diseases. This review explores the mechanisms of NLRP3 assembly and activation in the gut. We describe its pathological significance in intestinal diseases. Finally, we summarize current and future therapeutic approaches targeting NLRP3 for intestinal diseases.

Autoinflammation and autoimmunity are almost "opposite" phenomena characterized by chronic activation of the immune system, 'innate' in the first and 'adaptive' in the second, leading to inflammation of several tissues with specific protean effectors of tissue damage. The mechanism of involvement of multiprotein complexes called 'inflammasomes' within autoimmune pictures, differently from autoinflammatory conditions, is yet undeciphered. In this review we provide a comprehensive overview on NLRP3 inflammasome contribution into the pathogenesis of some autoimmune diseases. In response to autoantibodies against nucleic acids or tissue-specific antigens the NLRP3 inflammasome is activated within dendritic cells and macrophages of patients with systemic lupus erythematosus. Crucial is NLRP3 inflammasome to amplify tissue inflammation with interleukin-1 overexpression and matrix metalloproteinase production at the joint level in rheumatoid arthritis. A deregulated NLRP3 inflammasome activation occurs in the serous acini of salivary and lacrimal glands prone to Sjogren's syndrome, but also in the inflammatory process involving endothelial cells, leucocyte recruitment, and platelet plugging of vasculitides. Furthermore, organ-specific autoimmune diseases such as thyroiditis and hepatitis may display hyperactive NLRP3 inflammasomes at the level of resident immune cells within thyroid or liver, respectively. Therefore, it is not unexpected that preclinical studies have shown how specific inflammasome inhibitors may significantly overthrow the severity of different autoimmune diseases and slow down their trend towards an ominous progression. Specific markers of inflammasome activation could also reveal subclinical inflammatory components escaping conventional diagnostic approaches or improve monitoring of autoimmune diseases and personalizing their treatment.

Pyroptosis, the most inflammatory form of cell death, is dependent on membrane pore formation governed by the assembly of cleaved Gasdermin D (GSDMD). We hypothesized that regulated necrosis pathways are crucial in the pathophysiology of acute kidney injury (AKI). Mice with an isoleucine-to-asparagine loss-of-function mutation in the Gasdermin D gene (GSDMDI105N/I105N) generated by ethylnitrosourea-mutagenesis were subjected to bilateral renal ischemia-reperfusion injury (IRI) with bio-molecular readouts performed at 24 h. IRI was also performed in mice pretreated with disulfiram. Whole-body irradiation followed by syngeneic bone marrow transplantation generated chimeric mice prior to IRI. Mice homozygous for the GSDMD I105N mutation were protected from IRI, demonstrating lower serum creatinine and reduced histological injury, as well as decreased pro-inflammatory cytokine expression and oxidative stress. Chimeric mice showed that this protection was predominantly governed by mutations in the parenchymal tissue, with a potential contribution from the hematopoietic compartment. Pharmacological inhibition of GSDMD pore formation using disulfiram protected against IRI. Manipulation of GSDMD is an attractive target to mitigate inflammation and cellular death following AKI.

Chronic kidney disease (CKD) is a condition caused by the gradual decline of renal function that approximatively affects 10-12% of the world population, thus representing a public health priority. In CKD patients, chronic and systemic low-grade inflammation is observed, and it significantly contributes to disease development and progression, especially for patients with advanced disease. It also results in CKD-associated complications and increased mortality. The low-grade inflammation is due to different factors, such as the decline of glomerular filtration rate, increased immune system activation, reactive oxygen species release, and intestinal homeostasis. Therefore, the possibility to control chronic low-grade inflammation in CKD deserves great attention. In this review, we will examine the current possible pharmacological approaches to counteract the inflammatory state in CKD, focusing our attention both on the pro-inflammatory factors and the pro-resolving mediators involved in CKD inflammatory state.

Recent research has uncovered new mechanisms that disrupt the balance between the host and microbes in the middle ear, potentially leading to dysbiosis and chronic suppurative otitis media (CSOM). Dysbiotic microbial communities, including core pathogens such as persister cells, are recognized for displaying cooperative virulence. These microbial communities not only evade the host's immune defenses but also promote inflammation that leads to tissue damage. This leads to uncontrolled disorder and pathogen proliferation, potentially causing hearing loss and systemic complications. In this discussion, we examine emerging paradigms in the study of CSOM that could provide insights into other polymicrobial inflammatory diseases. Additionally, we underscore critical knowledge gaps essential for developing a comprehensive understanding of how microbes interact with both the innate and adaptive immune systems to trigger and maintain CSOM.

Diabetes mellitus is associated with systemic damage across multiple organ systems, and an increasing number of patients are presenting with diabetic kidney disease as its initial manifestation. The onset and progression of diabetic nephropathy is closely associated with podocyte injury.

Sodium-glucose cotransporter type 2 (SGLT2) inhibitors, which can significantly reduce glucose levels as well as protecting against kidney damage, are therefore widely used for the clinical treatment of patients with diabetic kidney disease. An increasing body of research has revealed that the renal protective effect of SGLT2 inhibitors is primarily derived from their enhancement of podocyte autophagy and their inhibition of inflammation and podocyte apoptosis. Multiple signaling pathways are involved in these processes.

A deeper exploration of the renal protective effects of SGLT2 inhibitors and the underlying mechanisms will provide more solid theoretical support for their application in the prevention and treatment of diabetic kidney disease.

Acute kidney injury, a rapid decline in kidney function coupled with physiological and homeostatic perturbations, is an independent risk factor for both short-term and long-term health outcomes. As incidence of acute kidney injury continues to rise globally, the significant clinical and economic challenge of acute kidney injury underscores the need for its prompt recognition and application of novel and germane strategies to reduce its severity and facilitate recovery. Understanding the multifaceted cascade of events engaged in pathogenesis of acute kidney injury is pivotal for the development of effective preventive and therapeutic strategies. To facilitate an in-depth discussion on emerging therapeutic targets, this review will examine the role of macrophages in kidney injury and repair, explore the alterations in mitochondrial biogenesis dynamics induced by acute kidney injury, and provide insights into the molecular mechanisms underlying the contribution of ferroptosis to kidney injury.

Cognitive impairments are common clinical manifestation of Alzheimer's disease, vascular dementia, type 2 diabetes mellitus, and autoimmune diseases. Emerging evidence has suggested a strong correlation between peripheral chronic inflammation and cognitive impairments. For example, nearly 40% of individuals with inflammatory bowel disease also suffer from cognitive impairments. In this condition, NLRP3 inflammasome (NLRP3-I) generating pro-inflammatory cytokines like IL-1β serves as a significant effector, and its persistence exerts adverse effects to both periphery and the brain. Moreover, investigations on serum biomarkers of mild cognitive impairments have shown NLRP3-I components' upregulation, suggesting the involvement of peripheral inflammasome pathway in this disorder. Here, we systematically reviewed the current knowledge of NLRP3-I in inflammatory disease to uncover its potential role in bridging peripheral chronic inflammation and cognitive impairments. This review summarizes the molecular features and ignition process of NLRP3-I in inflammatory response. Meanwhile, various effects of NLRP3-I involved in peripheral inflammation-associated disease are also reviewed, especially its chronic disturbances to brain homeostasis and cognitive function through routes including gut-brain, liver-brain, and kidney-brain axes. In addition, current promising compounds and their targets relative to NLRP3-I are discussed in the context of cognitive impairments. Through the detailed investigation, this review highlights the critical role of peripheral NLRP3-I in the pathogenesis of cognitive disorders, and offers novel perspectives for developing effective therapeutic interventions for diseases associated with cognitive impairments. The present review outlines the current knowledge on the ignition of NLRP3-I in inflammatory disease and more importantly, emphasizes the role of peripheral NLRP3-I as a causal pathway in the development of cognitive disorders. Although major efforts to restrain cognitive decline are mainly focused on the central nervous system, it has become clear that disturbances from peripheral immune are closely associated with the dysfunctional brain. Therefore, attenuation of these inflammatory changes through inhibiting the NLRP3-I pathway in early inflammatory disease may reduce future risk of cognitive impairments, and in the meantime, considerations on such pathogenesis for combined drug therapy will be required in the clinical evaluation of cognitive disorders.

This study aims to investigate the role of hypercalciuria and pyroptosis in the formation of calcium oxalate kidney stones. Bioinformatics analysis was performed to compare the correlation of pyroptosis scores and cell adhesion scores between Randall's plaques and normal tissues from kidney stone patients. For the in vitro experiments, we investigated the effects of high concentrations of Ca2+ on the pyroptosis and adhesion levels of renal tubular epithelial cells and examined the adhesion levels and crystal aggregation of the cells in high Ca2+ concentrations environment by knockdown and overexpression of the key pyroptosis gene, GSDMD, and we verified the effects of Ca2+ concentration on pyroptosis and adhesion levels, kidney injury, and crystal deposition by in vivo experiments. Bioinformatic results showed that the scores of pyroptosis and cell adhesion in Randall's plaques of patients with kidney stones were significantly higher than those in normal tissues, and pyroptosis was highly positively correlated with cell adhesion. In vitro and in vivo experiments showed that high concentrations of Ca2+ activated the NLRP3/Caspase-1/GSDMD pathway of pyroptosis through ROS and up-regulated the expression of adhesion-related proteins, and GSDMD could regulate the adhesion level of renal tubular epithelial cells by mediating the level of pyroptosis, thereby affecting the adhesion and deposition of calcium oxalate crystals. Our findings reveal that the Ca2+-induced classical pyroptosis pathway may be a potential mechanism to promote calcium oxalate kidney stone formation, which provides new insights into the etiology of kidney stones.

Hyperuricemia (HUA) is a metabolic condition resulting from an abnormality in the process of purine metabolism. Its occurrence has been on the rise globally. The results of relevant studies show that 5% to 12% of HUA patients will eventually develop gout, and one-third of these patients may involve the kidneys and develop kidney disease. Although the severe renal health hazards associated with excessive uric acid levels are well known, the specific molecular mechanisms remain unknown. Therefore, this paper provides insights into the mechanisms and related chain reactions of HUA leading to renal injury from three perspectives: imbalance of intestinal homeostasis, oxidative stress response, and NLRP3 inflammasome. In addition, standing against the background of the strong side effects and high tolerability disadvantages of commercially available uric acid-lowering drugs such as allopurinol, benzbromarone, and febuxostat, the development of a new active anti-hyperuricemic drug with fewer side effects is justified. This article reviews the progress of research on natural actives (probiotics, dietary polyphenols, peptides) with a high safety profile, multi-targeting, and integrative modulatory effects, in an attempt to provide some ideas for drug developers.

Chronic kidney inflammation and podocyte injury are key pathological features of Diabetic Nephropathy (DN). Puerarin has been shown to inhibit podocyte pyroptosis and provide renal protection, although its molecular mechanism remains unclear.

The effects and mechanisms of puerarin on podocyte pyroptosis were investigated in a DN mouse model. In vivo, a DN model was established using streptozotocin (STZ) and treated with puerarin, a SIRT1 agonist, or a SIRT1 inhibitor. In vitro, a podocyte pyroptosis model was induced under high glucose (HG) conditions, and lentivirus transfection was used to either silence or overexpress SIRT1. Techniques including ELISA, transmission electron microscopy, flow cytometry, PCR, and Western blotting were employed to explore the molecular mechanisms by which puerarin inhibits podocyte pyroptosis.

The study showed that SIRT1 expression was significantly downregulated in STZ-induced DN mice and HG-induced MPC-5 cell pyroptosis models. Overexpression of SIRT1 decreased the secretion of inflammatory factors, reduced reactive oxygen species (ROS) release, improved podocyte injury, restored podocyte function, and inhibited the expression of the NLRP3 inflammasome and its downstream factors. Furthermore, puerarin increased SIRT1 expression in DN mice and HG-treated MPC-5 cells, inhibited the activation of the NLRP3/Caspase-1 pathway, reduced podocyte pyroptosis, and alleviated renal inflammatory damage.

These findings suggest that puerarin may inhibit podocyte pyroptosis, reduce podocyte injury, and mitigate renal inflammatory damage by modulating the SIRT1/NLRP3/Caspase-1 pathway.

Heart failure with preserved ejection fraction (HFpEF) is posing a significant medical challenge due to its growing prevalence, high hospitalization rates and limited response to current treatment options. Accumulating evidence suggests that a comorbidity-driven systemic pro-inflammatory state, including activation of the NLRP3 inflammasome, contributes to the pathogenesis of HFpEF. This study aimed to investigate the potential cardiac protective effects of the selective NLRP3 inhibitor MCC950, in a mouse model of HFpEF. HFpEF was obtained in 18-22 months old female mice using high-fat diet (HFD) and angiotensin II (AngII) infusion. Mice developed HFpEF and comorbidities such as obesity, type 2 diabetes, and hypertension. MCC950 was added to HFD and groups were treated for four weeks until the study endpoint. MCC950 treatment resulted in lower plasma IL-18 levels (-47.3 %), illustrating target engagement. First, we observed that MCC950 treatment improved left ventricular function, demonstrated by enhanced global longitudinal strain (GLS, 3.9 %, P<0.01) and reverse peak longitudinal strain (RPLSR, +46.8 %, P<0.05). Second, MCC950 reduced cardiac hypertrophy (cardiomyocyte size -19.5 %, P<0.001) and fibrosis (-32.5 %, P<0.05), accompanied by lower expression of pro-fibrotic genes. Finally, MCC950 treatment reduced macrophage infiltration in left ventricular tissue and attenuated macrophage accumulation in visceral adipose tissue, even more as compared to caloric restriction. Overall, this suggests that NLRP3 inhibition could be a promising treatment for HFpEF patients with a pro-inflammatory profile, potentially improving heart function, systemic inflammation, and metabolic parameters.

Chronic kidney disease (CKD) is the progressive loss of kidney function/structure over a period of at least 3 months. It is characterised histologically by the triad of cell loss, inflammation and fibrosis. This literature review focuses on the forms of cell death that trigger downstream inflammation and fibrosis, collectively called regulated cell death (RCD) pathways. Discrete forms of RCD have emerged as central mediators of CKD pathology. In particular, pathways of regulated necrosis - including mitochondrial permeability transition pore (mPTP)-mediated necrosis, necroptosis, ferroptosis and pyroptosis - have been shown to mediate kidney pathology directly or through the release of danger signals that trigger a pro-inflammatory response, further amplifying tissue injury in a cellular process called necroinflammation. Despite accumulating evidence in pre-clinical models, no clinical studies have yet targeted these RCD modes in human CKD. The review summarizes recent advances in our understanding of RCD pathways in CKD, looks at inter-relations between the pathways (with the emphasis on propagation of death signals) and the evidence for therapeutic targeting of molecules in the RCD pathways to prevent or treat CKD.

The term ferroptosis, coined in 2012, has been widely applied in various disease research fields. Ferroptosis is a newly regulated form of cell death distinct from apoptosis, necrosis, and autophagy, the mechanisms of which have been extensively studied. Chronic kidney disease, characterized by renal dysfunction, is a common disease severely affecting human health, with its occurrence and development influenced by multiple factors and leading to dysfunction in multiple systems. It often lacks obvious clinical symptoms in the early stages, and thus, diagnosis is typically made in the later stages, complicating treatment. While research on ferroptosis and acute kidney injury has made continuous progress, studies on the association between ferroptosis and chronic kidney disease remain limited. This review aims to summarize chronic kidney disease, investigate the mechanism and regulation of ferroptosis, and attempt to elucidate the role of ferroptosis in the occurrence and development of chronic kidney disease.

The cytoplasmic oligomer NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome has been implicated in most inflammatory and autoimmune diseases. Here, we highlight the significance of NLRP3 in diverse renal disorders, demonstrating its activation in macrophages and non-immune tubular epithelial and mesangial cells in response to various stimuli. This activation leads to the release of pro-inflammatory cytokines, contributing to the development of acute kidney injury (AKI), chronic renal injury, or fibrosis. In AKI, NLRP3 inflammasome activation and pyroptotic renal tubular cell death is driven by contrast and chemotherapeutic agents, sepsis, and rhabdomyolysis. Nevertheless, inflammasome is provoked in disorders such as crystal and diabetic nephropathy, obesity-related renal fibrosis, lupus nephritis, and hypertension-induced renal damage that induce chronic kidney injury and/or fibrosis. The mechanisms by which the inflammatory NLRP3/ Apoptosis-associated Speck-like protein containing a Caspase recruitment domain (ASC)/caspase-1/interleukin (IL)-1β & IL-18 pathway can turn on renal fibrosis is also comprehended. This review further outlines the involvement of dopamine and its associated G protein-coupled receptors (GPCRs), including D1-like (D1, D5) and D2-like (D2-D4) subtypes, in regulating this inflammation-linked renal dysfunction pathway. Hence, we identify D-related receptors as promising targets for renal disease management by inhibiting the functionality of the NLRP3 inflammasome.

Fibrosis is a public health issue of great concern characterized by the excessive deposition of extracellular matrix, leading to the destruction of parenchymal tissue and organ dysfunction that places a heavy burden on the global healthcare system due to its high incidence, disability, and mortality. Salvianolic acid B (SalB) has positively affected various human diseases, including fibrosis. In this review, we concentrate on the anti-fibrotic effects of SalB from a molecular perspective while providing information on the safety, adverse effects, and drug interactions of SalB. Additionally, we discuss the innovative SalB formulations, which give some references for further investigation and therapeutic use of SalB's anti-fibrotic qualities. Even with the encouraging preclinical data, additional research is required before relevant clinical trials can be conducted. Therefore, we conclude with recommendations for future studies. It is hoped that this review will provide comprehensive new perspectives on future research and product development related to SalB treatment of fibrosis and promote the efficient development of this field.

Multiple sclerosis (MS) is a complex autoimmune disorder that impacts the central nervous system (CNS), resulting in inflammation, demyelination, and neurodegeneration. The NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome, a multiprotein complex of the innate immune system, serves an essential role in the pathogenesis of MS by regulating the production of pro-inflammatory cytokines (IL-1β & IL-18) and the induction of pyroptotic cell death. Mitochondrial dysfunction is one of the main potential factors that can trigger NLRP3 inflammasome activation and lead to inflammation and axonal damage in MS. This highlights the importance of understanding how mitochondrial dynamics modulate NLRP3 inflammasome activity and contribute to the inflammatory and neurodegenerative features of MS. The lack of a comprehensive understanding of the pathogenesis of MS and the urge for the introduction of new therapeutic strategies led us to review the therapeutic potential of targeting the interplay between mitochondrial dysfunction and the NLRP3 inflammasome in MS. This paper also evaluates the natural and synthetic compounds that can improve mitochondrial function and/or inhibit the NLRP3 inflammasome, thereby providing neuroprotection. Moreover, it summarizes the evidence from animal models of MS that demonstrate the beneficial effects of these compounds on reducing inflammation, demyelination, and neurodegeneration. Finally, this review advocates for a deeper investigation into the molecular crosstalk between mitochondrial dynamics and the NLRP3 inflammasome as a means to refine therapeutic targets for MS.

Macrophages are exceptionally diversified cell types and perform unique features and functions when exposed to different stimuli within the specific microenvironment of various kidney diseases. In instances of kidney tissue necrosis or infection, specific patterns associated with damage or pathogens prompt the development of pro-inflammatory macrophages (M1). These M1 macrophages contribute to exacerbating tissue damage, inflammation, and eventual fibrosis. Conversely, anti-inflammatory macrophages (M2) arise in the same circumstances, contributing to kidney repair and regeneration processes. Impaired tissue repair causes fibrosis, and hence macrophages play a protective and pathogenic role. In response to harmful stimuli within the body, inflammasomes, complex assemblies of multiple proteins, assume a pivotal function in innate immunity. The initiation of inflammasomes triggers the activation of caspase 1, which in turn facilitates the maturation of cytokines, inflammation, and cell death. Macrophages in the kidneys possess the complete elements of the NLRP3 inflammasome, including NLRP3, ASC, and pro-caspase-1. When the NLRP3 inflammasomes are activated, it triggers the activation of caspase-1, resulting in the release of mature proinflammatory cytokines (IL)-1β and IL-18 and cleavage of Gasdermin D (GSDMD). This activation process therefore then induces pyroptosis, leading to renal inflammation, cell death, and renal dysfunction. The NLRP3-ASC-caspase-1-IL-1β-IL-18 pathway has been identified as a factor in the development of the pathophysiology of numerous kidney diseases. In this review, we explore current progress in understanding macrophage behavior concerning inflammation, injury, and fibrosis in kidneys. Emphasizing the pivotal role of activated macrophages in both the advancement and recovery phases of renal diseases, the article delves into potential strategies to modify macrophage functionality and it also discusses emerging approaches to selectively target NLRP3 inflammasomes and their signaling components within the kidney, aiming to facilitate the healing process in kidney diseases.

Lipopolysaccharide (LPS) can induce systemic inflammatory response (SIR) in animals. Understanding the regulatory mechanism of SIR and therapies to ensure healthy growth is urgently needed. Chromatin remodeling plays a crucial role in the expression of genes involved in immune diseases. In the present study, the ATAC-seq analysis revealed 3491 differential open chromatin sites in the spleen of chicks with SIR induced by LPS challenge, and we presented the motifs on these sites and the associated transcription factors. The regulatory network was presented by combining the differential open chromatin data with the mRNAs and exploded cytokines. Interestingly, the LPS challenge could regulate the mRNA expression of 202 genes through chromatin reprogramming, including critical genes such as TLE1 and JUN, which regulate signaling pathways such as I-κB kinase/NF-κB, Toll-like receptor, and downstream cytokine genes. Furthermore, dietary daidzein could inhibit DNA topoisomerase II, which reprograms the spatial conformation of chromatin in the inflammatory response and attenuates SIR. In conclusion, we successfully identified key genes directly regulated by chromatin reprogramming in SIR and demonstrated the chromatin epigenome signatures and transcriptional regulatory network, which provides an important reference for further research on avian epigenetics. There is great potential for alleviating SIR using dietary daidzein.

To evaluate the effects of NLRP3 inflammasome inhibition or knockout in experimental apical periodontitis (AP) induced in mice.

The experimental AP was induced by pulpal exposure. To evaluate NLRP3-specific inhibitor medication (MCC950), WT mice received intraperitoneal injections, while the control received PBS (n = 10). In addition, to evaluate NLRP3 knockout, 35 wild-type (WT) and 35 NLRP3-/- mice were divided into a control group (without pulpal exposure, n = 5) and three experimental groups: after 2, 14 and 42 days after pulpal exposure (n = 10). Microscopic and molecular analyzes were carried out using a significance level of 5%.

Exposure to MCC950 did not affect the periapical lesion size after 14 days (P = 0.584). However, exposed mice had a lower expression of IL-1β, IL-18 and caspase-1 (P = 0.010, 0.016 and 0.002, respectively). Moreover, NLRP3-/- mice showed a smaller periapical lesion after 14 and 42 days (P = 0.023 and 0.031, respectively), as well as a lower expression of IL-1β after 42 days (P < 0.001), of IL-18 and caspase-1 after 14 (P < 0.001 and 0.035, respectively) and 42 days (P = 0.002 and 0.002, respectively). NLRP3-/- mice also showed a lower mRNA for Il-1β, Il-18 and Casp1 after 2 (P = 0.002, 0.036 and 0.001, respectively) and 14 days (P = 0.002, 0.002 and 0.001, respectively).

NLRP3 inflammasome inhibition or knockout can attenuate the inflammatory events that result in the periapical lesion (AP) formation after pulpal exposure in mice.

The NLRP3 inflammasome may be a therapeutic target for AP, and new approaches may verify the impact of its inhibition (through intracanal medications or filling materials) on the bone repair process and treatment success.

Diabetic nephropathy (DN) is a significant clinical microvascular complication associated with diabetes mellitus (DM), and end-stage diabetes giving rise to kidney failure is developing into the major etiological factor of chronic kidney failure. Dapagliflozin is reported to limit podocyte damage in DM, which has proven to protect against renal failure. Mounting evidence has demonstrated that pyroptosis is associated with DM progression. Nevertheless, whether pyroptosis causes DN and the underlying molecular pathways remain obscure. In this study, we aimed to explore the antipyroptotic attributes of dapagliflozin and elucidate the underlying mechanisms of kidney damage in diabetes. In vivo, experiments were conducted in streptozotocin (STZ)-induced type 2 diabetic mice, which were administered dapagliflozin via gavage for 6 weeks. Subsequently, the specific organizational characteristics and expression of pyroptosis-related genes were evaluated. Intragastric dapagliflozin administration markedly reduced renal tissue injury. Meanwhile, dapagliflozin also attenuated the expression level of pyroptosis associated genes, including ASC, cleaved Caspase-1, GSDMD N-termini, NLRP3, IL-18, and IL-1β in renal tissue of dapagliflozin-treated animals. Similar antipyroptotic effects were observed in palmitic acid (PA)-treated mouse podocytes. We also found that heme oxygenase 1 (HO-1) enhanced the protection of mouse podocyte clone 5 cells (MPC5). Moreover, miR-155-5p inhibition increased pyroptosis in PA-treated MPC5 cells, suggesting that miR-155-5p acts as an endogenous stimulator that increases HO-1 expression and reduces pyroptosis. Hence, our findings imply that dapagliflozin inhibits podocyte pyroptosis via the miR-155-5p/HO-1/NLRP3 axis in DM. Furthermore, dapagliflozin substitution may be regarded as an effective strategy for preventing pyroptosis in the kidney, including a therapeutic option for treating pyroptosis-related DN.

Autophagy is a self-renewal mechanism that maintains homeostasis and can promote tissue regeneration by regulating inflammation, reducing oxidative stress and promoting cell differentiation. The interaction between biomaterials and tissue cells significantly affects biomaterial-tissue integration and tissue regeneration. In recent years, it has been found that biomaterials can affect various processes related to tissue regeneration by regulating autophagy. The utilization of biomaterials in a controlled environment has become a prominent approach for enhancing the tissue regeneration capabilities. This involves the regulation of autophagy in diverse cell types implicated in tissue regeneration, encompassing the modulation of inflammatory responses, oxidative stress, cell differentiation, proliferation, migration, apoptosis, and extracellular matrix formation. In addition, biomaterials possess the potential to serve as carriers for drug delivery, enabling the regulation of autophagy by either activating or inhibiting its processes. This review summarizes the relationship between autophagy and tissue regeneration and discusses the role of biomaterial-based autophagy in tissue regeneration. In addition, recent advanced technologies used to design autophagy-modulating biomaterials are summarized, and rational design of biomaterials for providing controlled autophagy regulation via modification of the chemistry and surface of biomaterials and incorporation of cells and molecules is discussed. A better understanding of biomaterial-based autophagy and tissue regeneration, as well as the underlying molecular mechanisms, may lead to new possibilities for promoting tissue regeneration. Video Abstract.

Adult-onset Still's disease (AOSD) is a complex systemic inflammatory disorder, categorized as an 'IL-1 driven' inflammasomapathy. Despite this, the interaction between T and B cells remains poorly understood. We conducted a study, enrolling 7 patients with relapsing AOSD and 15 healthy control subjects, utilizing deep flow cytometry analysis to examine peripheral blood T- and B-cell subsets. T-cell and B-cell subsets were significantly altered in patients with AOSD. Within CD4+ T cells, Th2 cells were decreased. Additionally, Th17 cell and follicular Th cell subsets were altered within CD45RA-CD62L+ and CD45RA-CD62L- Th cells in patients with AOSD compared to healthy controls. We identified changes in CD8+ T cell maturation and 'polarization' in AOSD patients, with an elevated presence of the TEMRA CD8+ T cell subset. Furthermore, the percentage of Tc1 cells was decreased, while the frequency of CCR6-CXCR3- Tc2 cells was elevated. Finally, we determined that the frequency of CD5+CD27- B cells was dramatically decreased in patients with AOSD compared to healthy controls. Further investigations on a large group of patients with AOSD are required to evaluate these adaptive immunity cells in the disease pathogenesis.

Interleukin 1β (IL-1β) is a significant mediator of inflammation and tissue damage in IBD. The balance between IL-1β and its endogenous inhibitor-IL-1Ra-, plays a critical role in both initiation and regulation of inflammation. However, the precise role of IL-1β as a causative factor in IBD or simply a consequence of inflammation remains unclear. This review summarizes current knowledge on the molecular and cellular characteristics of IL-1β, describes the existing evidence on the role of this cytokine as a modulator of intestinal homeostasis and an activator of inflammatory responses, and also discusses the role of microRNAs in the regulation of IL-1β-related inflammatory responses in IBD. Current evidence indicates that IL-1β is involved in several aspects during IBD as it greatly contributes to the induction of pro-inflammatory responses through the recruitment and activation of immune cells to the gut mucosa. In parallel, IL-1β is involved in the intestinal barrier disruption and modulates the differentiation and function of T helper (Th) cells by activating the Th17 cell differentiation, known to be involved in the pathogenesis of IBD. Dysbiosis in the gut can also stimulate immune cells to release IL-1β, which, in turn, promotes inflammation. Lastly, increasing evidence pinpoints the central role of miRNAs involvement in IL-1β-related signaling during IBD, particularly in the maintenance of homeostasis within the intestinal epithelium. In conclusion, given the crucial role of IL-1β in the promotion of inflammation and immune responses in IBD, the targeting of this cytokine or its receptors represents a promising therapeutic approach. Further research into the IL-1β-associated post-transcriptional modifications may elucidate the intricate role of this cytokine in immunomodulation.

Glomerular-tubular crosstalk within the kidney has been proposed, but the paracrine signals enabling this remain largely unknown. The cold-shock protein Y-box binding protein 1 (YBX1) is known to regulate inflammation and kidney diseases but its role in podocytes remains undetermined. Therefore, we analyzed mice with podocyte specific Ybx1 deletion (Ybx1ΔPod). Albuminuria was increased in unchallenged Ybx1ΔPod mice, which surprisingly was associated with reduced glomerular, but enhanced tubular damage. Tubular toll-like receptor 4 (TLR4) expression, node-like receptor protein 3 (NLRP3) inflammasome activation and kidney inflammatory cell infiltrates were all increased in Ybx1ΔPod mice. In vitro, extracellular YBX1 inhibited NLRP3 inflammasome activation in tubular cells. Co-immunoprecipitation, immunohistochemical analyses, microscale cell-free thermophoresis assays, and blunting of the YBX1-mediated TLR4-inhibition by a unique YBX1-derived decapeptide suggests a direct interaction of YBX1 and TLR4. Since YBX1 can be secreted upon post-translational acetylation, we hypothesized that YBX1 secreted from podocytes can inhibit TLR4 signaling in tubular cells. Indeed, mice expressing a non-secreted YBX1 variant specifically in podocytes (Ybx1PodK2A mice) phenocopied Ybx1ΔPod mice, demonstrating a tubular-protective effect of YBX1 secreted from podocytes. Lipopolysaccharide-induced tubular injury was aggravated in Ybx1ΔPod and Ybx1PodK2A mice, indicating a pathophysiological relevance of this glomerular-tubular crosstalk. Thus, our data show that YBX1 is physiologically secreted from podocytes, thereby negatively modulating sterile inflammation in the tubular compartment, apparently by binding to and inhibiting tubular TLR4 signaling. Hence, we have uncovered an YBX1-dependent molecular mechanism of glomerular-tubular crosstalk.

Chronic renal failure (CRF) is defined by a significant decline in renal function that results in decreased salt filtration and inhibition of tubular reabsorption, which ultimately causes volume enlargement. This study evaluated the potential renopreventive effects of the NLRP3 inflammasome inhibitor MCC950 in adenine-induced CRF in rats due to conflicting evidence on the effects of MCC950 on the kidney.

Since the majority of the kidney tubular abnormalities identified in people with chronic renal disease are comparable to those caused by adding 0.75 percent of adenine powder to a rat's diet each day for four weeks, this method has received broad approval as a model for evaluating kidney damage. Throughout the test, blood pressure was checked weekly and at the beginning. Additionally, oxidative stress factors, urine sample examination, histological modifications, and immunohistochemical adjustments of caspase-3 and interleukin-1 beta (IL-1) levels in renal tissues were carried out.

Results revealed that MCC950, an inhibitor of the NLRP3 inflammasome, had a renopreventive effect, which was demonstrated by a reduction in blood pressure readings and an improvement in urine, serum, and renal tissue indicators that indicate organ damage. This was also demonstrated by the decrease in neutrophil gelatinase-associated lipocalin tubular expression (NGAL). The NLRP3 inflammasome inhibitor MCC950 was found to significantly alleviate the worsening renal cellular alterations evidenced by increased expression of caspase-3 and IL-1, according to immunohistochemical tests.

The NLRP3 inflammasome inhibitor MCC950 demonstrated renopreventive effects in the CRF rat model, suggesting that it might be used as a treatment strategy to stop the progression of CRF.

A ketogenic diet limits energy supply from glucose and stimulates lipolysis, lipid oxidation, and ketogenesis, resulting in elevated levels of ketone bodies in the bloodstream. Ketone bodies are synthesized in the mitochondrial matrix of liver cells and β-hydroxybutyric acid (BHB) is the most abundant type of ketone body. Herein, we reviewed published findings on the metabolism of ketone bodies and the role of BHB in renal diseases. Through blood circulation, ketone bodies reach metabolically active tissues and provides an alternative source of energy. BHB, being a signaling molecule, mediates various types of cellular signal transduction and participates in the development and progression of many diseases. BHB also has protective and therapeutic effects on a variety of renal diseases. BHB improves the prognosis of renal diseases, such as diabetic kidney disease, chronic kidney disease, acute kidney injury, and polycystic kidney disease, through its antioxidant, anti-inflammatory, and stress response mechanisms. Previous studies have focused on the role of ketone bodies in regulating inflammation and oxidative stress in immune cells. Investigations into the effect of elevated levels of ketone bodies on the metabolism of renal podocytes and tubular cells remain inconclusive. Further research is needed to investigate the effect of BHB on podocyte damage and podocyte senescence in renal diseases.

Septic acute kidney injury (AKI) contributes to the mortality and morbidity of sepsis patients. Toll-like Receptor 4 (TLR4) has prominent roles in septic AKI. This study investigated the functions of TLR4 in septic AKI. A septic AKI mouse model was established by cecal ligation and puncture surgery. Mouse kidney function and kidney tissue lesion were examined using corresponding kits and H&E staining. The in vitro cell model of septic AKI was established by lipopolysaccharide induction. Cell viability, inflammatory factor (TNF-α, IL-6, IL-4, IL-1β, IL-18) levels, pyroptotic cell number changes, lactate dehydrogenase (LDH) activity, myeloperoxidase (MOP) concentration, and levels of pyroptosis-associated protein and MyD88, TRIF and p38 MAPK phosphorylation were determined by MTT, ELISA, FAM-FLICA Caspase-1 Detection kit, other corresponding kits, and Western blot. TLR4 was highly expressed in septic AKI mouse kidney tissues and human septic AKI cells. TLR4 knockdown alleviated kidney injury, increased cell viability, and reduced LDH activity and MPO concentration. TLR4 knockdown reduced cell pyroptosis by repressing p38 MAPK phosphorylation through MyD88/TRIF, suppressed pro-inflammatory factor (TNF-α, IL-6, IL-4, IL-1β, IL-18) levels, promoted anti-inflammatory factor (IL-4) level, and reduced inflammatory response, thus playing a protective role in septic AKI. Briefly, TLR4 promoted the inflammatory response in septic AKI by promoting p38 MAPK phosphorylation through MyD88/TRIF.

Nonprogrammed cell death (NPCD) and programmed cell death (PCD) are two types of cell death. Cell death is significantly linked to tumor development, medication resistance, cancer recurrence, and metastatic dissemination. Therefore, a comprehensive understanding of cell death is essential for the treatment of cancer. Pyroptosis is a kind of PCD distinct from autophagy and apoptosis in terms of the structure and function of cells. The defining features of pyroptosis include the release of an inflammatory cascade reaction and the expulsion of lysosomes, inflammatory mediators, and other cellular substances from within the cell. Additionally, it displays variations in osmotic pressure both within and outside the cell. Pyroptosis, as evidenced by a growing body of research, is critical for controlling the development of inflammatory diseases and cancer. In this paper, we reviewed the current level of knowledge on the mechanism of pyroptosis and inflammasomes and their connection to cancer and inflammatory diseases. This article presents a theoretical framework for investigating the potential of therapeutic targets in cancer and inflammatory diseases, overcoming medication resistance, establishing nanomedicines associated with pyroptosis, and developing risk prediction models in refractory cancer. Given the link between pyroptosis and the emergence of cancer and inflammatory diseases, pyroptosis-targeted treatments may be a cutting-edge treatment strategy.

Pyroptosis is a proinflammatory form of programmed cell death featured with membrane pore formation that causes cellular swelling and allows the release of intracellular inflammatory mediators. This cell death process is elicited by the activation of the pore-forming proteins named gasdermins, and is intricately orchestrated by diverse regulatory factors in mammalian hosts to exert a prompt immune response against infections. However, growing evidence suggests that bacterial pathogens have evolved to regulate host pyroptosis for evading immune clearance and establishing progressive infection. In this review, we highlight current understandings of the functional role and regulatory network of pyroptosis in host antibacterial immunity. Thereafter, we further discuss the latest advances elucidating the mechanisms by which bacterial pathogens modulate pyroptosis through adopting their effector proteins to drive infections. A better understanding of regulatory mechanisms underlying pyroptosis at the interface of host-bacterial interactions will shed new light on the pathogenesis of infectious diseases and contribute to the development of promising therapeutic strategies against bacterial pathogens.

Prolonged renal inflammation contributes to fibrosis, which may eventually lead to irreversible chronic kidney disease. Our previous work demonstrated that LIM and cysteine-rich domain 1 (LMCD1) are associated with renal interstitial fibrosis in a 21-day unilateral ureteral obstruction (21UUO) mouse model. Interestingly, based on the gene expression omnibus database, we found that LMCD1 is enhanced in the mouse kidney as early as 5, 7, and 10 days following unilateral ureteral obstruction (UUO), suggesting that LMCD1 may exert its function in an earlier phase. To validate this conjecture, a 7UUO mouse model and a tumor necrosis factor-α (TNF-α)-stimulated HK-2 cell model were established, followed by injection of adenovirus vectors carrying short hairpin RNA targeting LMCD1. LMCD1 silencing ameliorated renal collagen deposition and reduced the expression of profibrotic factors in the 7UUO model. LMCD1 silencing alleviated tubulointerstitial inflammation by mitigating F4/80⁺ cell infiltration, monocyte chemoattractant protein-1 release and nuclear factor-κB activation. In addition, LMCD1 silencing suppressed NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation and nuclear factor of activated T cells 1 (NFATc1) nuclear translocation. Consistent results were obtained in TNF-α-stimulated HK-2 cells in vitro. Mechanistically, the transcriptional coactivator LMCD1 cooperates with the transcription factor NFATc1 to increase NLRP3 expression. Collectively, these findings suggest that LMCD1 participates in tubulointerstitial inflammation via an LMCD1-NFATc1/NLRP3 mechanism. LMCD1 may therefore become a potential target for the control of renal inflammation and fibrosis.

Nowadays, diabetic kidney disease (DKD) has become one of the most threatening to the end-stage renal diseases, and the early prevention of DKD is inevitable for Diabetes Mellitus (DM) patients.

Pyroptosis, a programmed cell death that mediates renal inflammation induced early renal injury. The trimethylamine n-oxide (TMAO) was also an independent risk factor for renal injury. Here, the associations between TMAO-induced pyroptosis and pathogenesis of DKD were studied, and the potential mechanism of Zuogui-Jiangtang-Yishen (ZGJTYS) decoction to prevent DKD was further investigated.

Using Goto-Kakizaki (GK) rats to establish the early DKD models. The 16S-ribosomal RNA (16S rRNA) sequencing, fecal fermentation and UPLC-MS targeted metabolism techniques were combined to explore the changes of gut-derived TMAO level under the background of DKD and the effects of ZGJTYS. The proximal convoluted tubule epithelium of human renal cortex (HK-2) cells was adopted to explore the influence of pyroptosis regulated by TMAO.

It was demonstrated that ZGJTYS could prevent the progression of DKD by regulating glucolipid metabolism disorder, improving renal function and delaying renal pathological changes. In addition, we illustrated that gut-derived TMAO could promote DKD by activating the mROS-NLRP3 axis to induce pyroptosis. Furthermore, besides interfering with the generation of TMAO through gut microbiota, ZGJTYS inhibited TMAO-induced pyroptosis with a high-glucose environment and the underlying mechanism was related to the regulation of mROS-NLRP3 axis.

Our results suggested that ZGJTYS inhibited the activation of pyroptosis by gut-derived TMAO via the mROS-NLRP3 axis to prevent DKD.

Cheqianzi Decoction (CQD) is a Traditional Chinese Medicine (TCM) formula comprising four herbs and is recorded in the Ancient Materia Medica "Shengji Zonglu". Individually, these four herbs have been shown to reduce uric acid (UA) levels, to treat hyperuricemia (HUA), and alleviate kidney damage. However, the therapeutic efficacy of the CQD and related mechanism are not yet clear. In this study, high performance liquid chromatography (HPLC) analysis confirmed that the contents of the chemical components of the four herbal medicines were in accordance with the provisions of the Chinese Pharmacopoeia. A total of 99 potential targets were identified in the network pharmacology analysis of CQD, indicating its involvement in the regulation of inflammatory and apoptotic signaling pathways, and potential value for treating HUA and alleviating kidney injury. In vivo pharmacodynamic studies showed that compared with the Model group, significantly decreased levels of serum uric acid (SUA), serum creatinine (SCr), blood urea nitrogen (BUN) (all P < 0.05), and inflammatory factors (P < 0.01) were detected in the CQD group. Quantitative real-time PCR and Western blot analyses showed that compared with the Model group, adenosine triphosphate (ATP)-binding cassette efflux transporter G2 (ABCG2) expression in the CQD group was significantly upregulated (P < 0.01) at both the mRNA and protein levels, while mRNA expression of Caspase3 and NOD-like receptor family member 3 (NLRP3) (P < 0.05) and protein expression of NLRP3 (P < 0.01) were significantly downregulated. In conclusion, CQD promotes UA excretion by activating ABCG2, and induces inflammasome NLRP3-mediated reduction in inflammatory and apoptotic factors to achieve renal protection. Thus, our findings indicate the therapeutic potential of CQD in HUA with kidney injury.

Hyperuricemia may lead to silent tissue damage and increase the risk of some diseases, including kidney diseases. Increased serum uric acid concentration induces inflammatory pathways and promotes kidney damage. This study aimed to determine whether hyperuricemia influences the levels of urinary kidney injury markers in children and adolescents with hyperuricemia, assessed by the urinary concentrations of interleukin-18, a biomarker of inflammation, and kidney injury molecule-1 (KIM-1), a biomarker of kidney injury.

The study included 73 children and adolescents (32 males and 41 females) aged 2-18 years. They were divided into two groups: hyperuricemia (HU) group (n ​= ​48) and normouricemia - reference group (R) (n ​= ​25). The concentrations of urinary interleukin-18 and KIM-1 were measured using an ELISA kit and were normalized for urinary creatinine (cr.) concentration.

The median interleukin-18/cr. Levels in the HU group were significantly higher than in the R group (median, Q1-Q3) 21.83 (11.32-35.96) and 12.68 (7.11-24.04), respectively, (p ​< ​0.05). The KIM-1/cr. in the HU group and the R group were (median, Q1-Q3) 0.79 (0.45-1.03) and 0.81 (0.59-1.01), respectively, and the difference was not significant. KIM-1/cr. did not differ between the groups. Interleukin-18/cr. ratio correlated positively with serum uric acid concentration (r ​= ​0.24, p ​< ​0.05).

Interleukin-18/cr., but not KIM-1/cr. was higher in children with hyperuricemia. Hyperuricemia results in increased IL-18 in urine, in absence of other markers of kidney injury, suggesting inflammation in the kidney. Additional studies on the adults should be done, to confirm this hypothesis.

The pathogenic mechanism of diabetic kidney disease (DKD) is involved in various functions; however, its inadequate characterisation limits the availability of effective treatments. Tubular damage is closely correlated with renal function and is thought to be the main contributor to the injury observed in early DKD. Programed cell death (PCD) occurs during the biological development of the living body. Accumulating evidence has clarified the fundamental role of abnormalities in tubular PCD during DKD pathogenesis. Among PCD types, classical apoptosis, autophagic cell death, and pyroptosis are the most studied and will be the focus of this review. Our review aims to elucidate the current knowledge of the mechanism of DKD and the potential therapeutic potential of drugs targeting tubular PCD pathways in DKD.

Chronic kidney disease (CKD) is a systemic inflammatory syndrome that includes tubulointerstitial inflammation. Lipopolysaccharide (LPS), the outer membrane of Gram-negative bacteria, can increase reactive oxygen species production (ROS) that triggers cell inflammation. Isovitexin (IV) is a flavone that has the potential for anticancer, antioxidant, and anti-inflammatory. This study aimed to hypothesize that IV inhibited LPS-induced renal injury in vitro and in vivo. In vitro study, IV prevented LPS-induced ROS production and increased cell viability on SV40-MES-13 cells. Additionally, IV ameliorated mitochondrial membrane potential, downregulated inflammation and pyroptosis factors on LPS treatment. We found that LPS treatment reduced the expression of autophagy, however, this effect was reversed by IV. In vivo study, the renal injury model in C57BL/6 mice cotreatment with IV was examined. In addition, IV decreased LPS-induced glomerular atrophy and reduced inflammation-related cytokines releases. Further showed that IV could significantly reduce LPS-induced inflammation and pyroptosis factors in mice. Under the immunostaining, increased fluorescence of LC3 autophagy-related protein was recovered by IV. In summary, IV ameliorated renal injury, inflammation and increased protected autophagy by anti-ROS production, anti-inflammation, and anti-pyroptosis. In the future, the safety of isovitexin as a novel perspective for CKD patients should be evaluated in further clinical studies.

This review aimed to trace the inflammatory pathway from the NLRP3 inflammasome to monomeric C-reactive protein (mCRP) in atherosclerotic cardiovascular disease. CRP is the final product of the interleukin (IL)-1β/IL-6/CRP axis. Its monomeric form can be produced at sites of local inflammation through the dissociation of pentameric CRP and, to some extent, local synthesis. mCRP has a distinct proinflammatory profile. In vitro and animal-model studies have suggested a role for mCRP in: platelet activation, adhesion, and aggregation; endothelial activation; leukocyte recruitment and polarization; foam-cell formation; and neovascularization. mCRP has been shown to deposit in atherosclerotic plaques and damaged tissues. In recent years, the first published papers have reported the development and application of mCRP assays. Principally, these studies demonstrated the feasibility of measuring mCRP levels. With recent advances in detection techniques and the introduction of first assays, mCRP-level measurement should become more accessible and widely used. To date, anti-inflammatory therapy in atherosclerosis has targeted the NLRP3 inflammasome and upstream links of the IL-1β/IL-6/CRP axis. Large clinical trials have provided sufficient evidence to support this strategy. However, few compounds target CRP. Studies on these agents are limited to animal models or small clinical trials.

Focal segmental glomerulosclerosis (FSGS) is a major cause of pediatric nephrotic syndrome, and African Americans exhibit an increased risk for developing FSGS compared with other populations. Predisposing genetic factors have previously been described in adults. Here we performed genomic screening of primary FSGS in a pediatric African American population.

Prospective cohort with case-control genetic association study design.

140 African American children with chronic kidney disease from the Chronic Kidney Disease in Children (CKiD) cohort, including 32 cases with FSGS.

Over 680,000 common single-nucleotide polymorphisms (SNPs) were tested for association. We also ran a pathway enrichment analysis and a human leucocyte antigen (HLA)-focused association study.

Primary biopsy-proven pediatric FSGS.

Multivariate logistic regression models.

The genome-wide association study revealed 169 SNPs from 14 independent loci significantly associated with FSGS (false discovery rate [FDR]<5%). We observed notable signals for genetic variants within the APOL1 (P=8.6×10^-7; OR, 25.8 [95% CI, 7.1-94.0]), ALMS1 (P=1.3×10^-7; 13.0% in FSGS cases vs 0% in controls), and FGFR4 (P=4.3×10^-6; OR, 24.8 [95% CI, 6.3-97.7]) genes, all of which had previously been associated with adult FSGS, kidney function, or chronic kidney disease. We also highlighted novel, functionally relevant genes, including GRB2 (which encodes a slit diaphragm protein promoting podocyte structure through actin polymerization) and ITGB1 (which is linked to renal injuries). Our results suggest a major role for immune responses and antigen presentation in pediatric FSGS through (1) associations with SNPs in PTPRJ (or CD148, P=3.5×10^-7), which plays a role in T-cell receptor signaling, (2) HLA-DRB1∗11:01 association (P=6.1×10^-3; OR, 4.5 [95% CI, 1.5-13.0]), and (3) signaling pathway enrichment (P=1.3×10^-6).

Sample size and no independent replication cohort with genomic data readily available.

Our genetic study has identified functionally relevant risk factors and the importance of immune regulation for pediatric primary FSGS, which contributes to a better description of its molecular pathophysiological mechanisms.