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Chronic kidney disease (CKD) is a leading cause of morbidity and mortality globally. Maternal obesity during pregnancy is linked to systemic inflammation and elevated levels of the pro-inflammatory cytokine interleukin-6 (IL-6). In our previous work, we demonstrated that increased maternal IL-6 during gestation impacts intrauterine development in mice. We hypothesized that IL-6-induced inflammation alters gene expression in the developing fetus. To test this, pregnant mice were administered IL-6 or saline during mid-gestation. Newborn mouse kidneys were analyzed using mRNA-seq, miRNA-seq and whole-genome bisulfite-seq (WGBS). A multi-omics approach was employed to quantify mRNA gene expression, miRNA expression and DNA methylation, using advanced bioinformatics and data integration techniques. Our analysis identified 19 key genes present in multiple omics datasets, regulated by epigenetics and miRNAs. We constructed a regulatory network for these genes, revealing disruptions in pathways such as Mannose type O-glycan biosynthesis, the cell cycle, apoptosis and FoxO signaling. Notably, the Atp7b gene was regulated by DNA methylation and miR-223 targeting, whereas the Man2a1 gene was controlled by DNA methylation affecting energy metabolism. These findings suggest that these genes may play a role in fetal programming, potentially leading to CKD later in life due to gestational inflammation. [ABSTRACT FROM AUTHOR]

Background: Amphetamine and other substances induced psychotic disorder and associated suicidal risk among hospitalized US veterans is not clear. Aims: To understand the demographic profile, substance use trends, psychotic disorders and suicide attempts in veterans hospitalized with acute Mental Health Conditions (MHC). Methods: Veterans Affairs Informatics and Computing Infrastructure Database and ICD codes were used to identify veterans hospitalized with MHC diagnosis between 10/1/1999 and 02/27/2022. Laboratory records were used to determine types of substances used, hospitalization frequency, all-cause mortality, suicide attempts and suicide outcomes. SAS was used for statistical analysis. Results: Psychosis, manic-bipolar and PTSD were common diagnosis among veterans with MHC. Psychosis was comparatively less common among males above 50 years of age, but was prevalent among Hispanics. Substances use was significantly higher among veterans with MHC. Amphetamines were most used substance, followed by cannabis codeine, morphine, cocaine, barbiturates, fentanyl, and PCP. Amphetamine induced psychotic disorder persisted in 22.28%, whereas other substance induced psychotic disorder persisted in 77.72% of veterans hospitalized with MHC. Psychosis was associated with higher rates of hospitalization, suicide attempts, and suicide death. Conclusions: Amphetamine was most used substance associated with higher rates of psychotic disorders, hospitalization, suicide attempts, and death among US Veterans with MHC. [ABSTRACT FROM AUTHOR]

Epilepsy is one of the most prevalent and serious brain disorders and affects over 70 million people globally. Antiseizure medications (ASMs) relieve symptoms and prevent the occurrence of future seizures in epileptic patients but have a limited effect on epileptogenesis. Addressing the multifaceted nature of epileptogenesis and its association with the Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated neuroinflammation requires a comprehensive understanding of the underlying mechanisms of these medications for the development of targeted therapeutic strategies beyond conventional antiseizure treatments. Several types of NLRP3 inhibitors have been developed and their effect has been validated both in in vitro and in vivo models of epileptogenesis. In this review, we discuss the advances in understanding the regulatory mechanisms of NLRP3 activation as well as progress made, and challenges faced in the development of NLRP3 inhibitors for the treatment of epilepsy. [ABSTRACT FROM AUTHOR]

Glomerular capillary filtration barrier characteristics are determined in part by the slit-pore junctions of glomerular podocytes. Protein tyrosine phosphatase receptor-O (PTPro) is a transmembrane protein expressed on the apical surface of podocyte foot processes. Tyrosine phosphorylation of podocyte proteins including nephrin may control the filtration barrier. To determine whether PTPro activity is required to maintain glomerular macromolecular permeability, albumin permeability ([P.sub.alb]) was studied after incubation of glomeruli from normal animals with a series of monoclonal (mAb) and polyclonal antibodies. Reagents included mAbs to rabbit and rat PTPro and polyclonal rabbit immune IgG to rat PTPro. mAb 4C3, specific to the amino acid core of PTPro, decreased its phosphatase activity and increased [P.sub.alb] of rabbit glomeruli in a time-and concentration-dependent manner. In contrast, mAb P8E7 did not diminish phosphatase activity and did not alter [P.sub.alb]. Preincubation of 4C3 with PTPro extracellular domain fusion protein blocked glomerular binding and abolished permeability activity. In parallel experiments, [P.sub.alb] of rat glomeruli was increased by two mAbs (IB4 and 1D1) or by polyclonal anti-rat PTPro. We conclude that PTPro interaction with specific antibodies acutely increases [P.sub.alb]. The identity of the normal ligand for PTPro and of its substrate, as well as the mechanism by which phosphatase activity of this receptor affects the filtration barrier, remain to be determined. glomerulus; podocyte; slit-pore junction; filtration barrier

Chronic kidney disease (CKD) is associated with decreased renal nitric oxide (NO) production and increased plasma levels of methylarginines. The naturally occurring guanidino-methylated arginines N-monomethyl-L-arginine (L-NMMA) and asymmetric dimethyl-L-arginine (ADMA) inhibit NO synthase activity. We hypothesized that ADMA and L-NMMA compromise the integrity of the glomerular filtration barrier via NO depletion. We studied the effect of ADMA on albumin permeability ([P.sub.alb]) in isolated glomeruli and examined whether this effect involves NO- and superoxide ([O.sup.*-.sub.2])-dependent mechanisms. ADMA at concentrations found in circulation of patients with CKD decreased cGMP and increased [P.sub.alb] in a dose-dependent manner. A similar increase in [P.sub.alb] was caused by L-NMMA but at a concentration two orders of magnitude higher than that of ADMA. NO donor DETA-NONOate or cGMP analog abrogated the effect of ADMA on [P.sub.alb] . The SOD mimetic tempol or the NAD(P)H oxidase inhibitor apocynin also prevented the ADMA-induced increase in [P.sub.alb] . The NO-independent soluble guanylyl cyclase (sGC) activator BAY 41-2272, at concentrations that increased glomerular cGMP production, attenuated the ADMA-induced increase in [P.sub.alb] . Furthermore, sGC incapacitation by the heine site-selective inhibitor ODQ increased [P.sub.alb]. We conclude that ADMA compromises the integrity of the filtration barrier by altering the bioavailability of NO and [O.sup.*-.sub.2] and that NO-independent activation of sGC preserves the integrity of this barrier under conditions of NO depletion. NO-independent activation of sGS may be a useful pharmacotherapeutic approach for preservation of glomerular function in CKD thereby reducing the risk for cardiovascular events. chronic kidney disease; cardiorenal disease

This study examined the effect of transfer of overlapping regions of chromosome 5 that includes ([4A.sup.+]) or excludes ([4A.sup.-]) the cytochrome P-450 4A (CYP4A) genes from the Lewis rat on the renal production of 20-hydroxyeicosatetraenoic acid (20-HETE) and the development of hypertension-induced renal disease in congenic strains of Dahl salt-sensitive (Dahl S) rats. The production of 20-HETE was higher in the outer medulla of [4A.sup.+] than in Dahl S or [4A.sup.-] rats. Mean arterial pressure (MAP) rose to 190 [+ or -] 7 and 185 [+ or -] 3 mmHg in Dahl S and [4A.sup.-] rats fed a high-salt (HS) diet for 21 days but only to 150 [+ or -] 5 mmHg in the [4A.sup.+] strain. Protein excretion increased to 423 [+ or -] 40 and 481 [+ or -] 37 mg/day in Dahl S and [4A.sup.-] rats vs. 125 [+ or -] 15 mg/day in the [4A.sup.+] strain. Baseline glomerular capillary pressure (Pgc) was lower in [4A.sup.+] rats (38 [+ or -] 1 mmHg) than in Dahl S rats (42 [+ or -] 1 mmHg). Pgc increased to 50 [+ or -] 1 mmHg in Dahl S rats fed a HS diet, whereas it remained unaltered in [4A.sup.+] rats (39 [+ or -] 1 mmHg). Baseline glomerular permeability to albumin ([P.sub.alb]) was lower in [4A.sup.+] rats (0.19 [+ or -] 0.05) than in Dahl S or [4A.sup.-] rats (0.39 [+ or -] 0.02). [P.sub.alb] rose to ~0.61 [+ or -] 0.03 in [4A.sup.-] and Dahl S rats fed a HS diet for 7 days, but it remained unaltered in the [4A.sup.+] rats. The expression of transforming growth factor-[beta]2 was higher in glomeruli of Dahl S rats than in [4A.sup.+] rats fed either a low-salt (LS) or HS diet. Chronic administration of a 20-HETE synthesis inhibitor (HET0016; 10 mg x [kg.sup.-1] x [day.sup.-1] sc) reversed the fall in MAP and renoprotection seen in [4A.sup.+] rats. These results indicate that the introgression of the CYP4A genes from Lewis rats into the Dahl S rats increases the renal formation of 20-HETE and attenuates the development of hypertension and renal disease. hypertension; glomerulosclerosis; 20-hydroxyeicosatetraenoic acid; transforming growth factor-[beta]; Dahl salt-sensitive rats; Rattus norvegicus 5; epoxyeicosatrienoic acids; dihydroxyeicosatrienoic acids; glomerulus; renal hemodynamics; kidney