Membranous lupus nephritis secondary to secukinumab therapy: A case report and literature review.

The interleukin (IL)-17 axis is involved in many inflammatory and autoimmune diseases. Secukinumab, an IL-17 inhibitor, has been approved for psoriasis treatment. There are accumulating cases of lupus erythematosus induced by IL-17 inhibition. Lupus nephritis after IL-17 inhibition has not been reported. We report the case of a 57-year-old man who developed membranous lupus nephritis after secukinumab treatment for psoriasis. Anti-SSA and PM-Scl antibodies were positive. dsDNA, anti-Smith, and anti-histone antibodies were negative, and serum complement was low. Secukinumab was discontinued, while tacrolimus was initiated, subsequently switched to cyclosporin, belimumab, glucocorticosteroid, and hydroxychloroquine with a good response. The relationship between lupus erythematosus and IL-17 inhibition requires further research.

Systematic review and meta-analysis of the clinical features of MGRS.

BACKGROUND: It is crucial to identify patients with monoclonal gammopathy of renal significance (MGRS) from those without MGRS but with monoclonal gammopathy and concomitant kidney diseases. However, there have been few studies with large sample sizes, and their findings were inconsistent. This study aimed to conduct a meta-analysis of MGRS to describe the general characteristics of MGRS and its predictive factors. METHODS: Cohort or case-control studies published through December 2022 and related to clinicopathological features of MGRS were retrieved from the PubMed, Cochrane Library, Web of Science, Scopus, and Embase databases. Two researchers searched for studies that met the inclusion criteria. In the univariate analysis, fixed- or random- effects models were used to obtain pooled estimates of the weighted mean difference (WMD) and odds ratio (OR) for risk factors. In the multivariate analysis, the ORs of the independent risk factors from each study were pooled after transforming the original estimates. RESULTS: The meta-analysis included six studies. Univariate analysis showed that the following variables were statistically significant in MGRS: age (WMD = 1.78, 95%CI 0.21-3.35), hypertension (OR = 0.54, 95%CI 0.4-0.73), diabetes (OR = 0.42, 95%CI 0.29-0.59), albumin (WMD = - 0.26, 95%CI - 0.38--0.14), urinary protein level (WMD = 0.76, 95%CI 0.31-1.2), urinary protein ≥ 1.5 g/d (OR = 1.98, 95%CI 1.46-2.68), lambda-chain value (WMD = 29.02, 95%CI 16.55-41.49), abnormal free light-chain ratio (OR = 4.16, 95%CI 1.65-10.47), bone marrow puncture rate (OR = 5.11, 95% CI 1.31-19.95), and abnormal bone marrow outcome rate (OR = 9.63, 95%CI 1.98-46.88). Multivariate analysis showed urinary protein ≥ 1.5 g/d (OR = 2.80, 95%CI 1.53-5.15) and an abnormal free light-chain ratio (OR = 6.98, 95%CI 4.10-11.91) were associated with predictors of MGRS. CONCLUSIONS: Compared with non-MGRS patients with monoclonal gammopathy and concomitant kidney diseases, patients with MGRS were older, had fewer underlying diseases, more urinary protein, more abnormal free light-chain ratio, and more abnormal bone marrow results. Urinary protein ≥ 1.5 g/d and an abnormal free light-chain ratio were independent risk factors for MGRS.

Pembrolizumab induced-C3 glomerulonephritis and RBC cast nephropathy: a case report.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are increasingly being used in the treatment of several cancers. Pembrolizumab is an anti-programmed cell death-1 (anti-PD-1) monoclonal antibody that is approved for the treatment of metastatic non-small cell lung cancer (NSCLC). Pembrolizumab-associated renal toxicity is relatively rare, even in pembrolizumab-associated glomerulonephritis. In this study, we report a rare case of pembrolizumab-induced C3 glomerulonephritis (C3GN) and RBC cast nephropathy. CASE PRESENTATION: A 68-year-old man with NSCLC was receiving treatment with pembrolizumab. After 19 cycles of pembrolizumab therapy, he presented with gross hematuria, severe lower-limb edema and oliguria. Laboratory tests revealed hypoalbuminemia, increased serum creatinine and low serum C3 level. Renal biopsy revealed a typical membranoproliferative glomerulonephritis accompanied by remarkable RBC casts in tubular cavities and tubulointerstitial infiltration of CD8-positive lymphocytes. Based on C3-only immunofluorescence deposit on glomeruli, a diagnosis of C3GN was made. Pembrolizumab was considered the cause of C3GN. Pembrolizumab was discontinued immediately, and 60 mg/day of prednisone was initiated. One dose of cyclophosphamide (400 mg, IV) was also administered. Upon treatment, his symptoms improved rapidly and serum creatinine decreased a lot. However, the patient became dialysis dependent eventually. CONCLUSION: This is the first case of C3GN with RBC cast nephropathy caused by ICIs. This rare case caused by the prolonged use of pembrolizumab further strengthens the relationship between ICIs and C3GN. Thus, periodic evaluation of urine and renal function is recommended in patients receiving pembrolizumab and other ICIs.

[Genetic analysis of novel MKKS variants in a Chinese patient with Bardet-Biedl syndrome].

OBJECTIVE: To explore the genetic basis of a Chinese patient with Bardet-Biedl syndrome (BBS). METHODS: Clinical data of the patient was analyzed. Next-generation sequencing was carry out to screen pathogenic variants, and candidate variants were verified by Sanger sequencing and subjected to bioinformatic analysis based on the guidelines from the American College of Medical Genetics and Genomics. RESULTS: Next-generation sequencing revealed that the proband has harbored two pathogenic variants of the MKKS gene (c.635C>T and c.1664C>G) and one likely pathogenic variant of the TMEM67 gene (c.2498T>C). Sanger sequencing of the proband and her mother confirmed that the proband has harbored two compound heterozygous MKKS variants and a heterozygous TMEM67 variant. Both of the MKKS variants were previously unreported and located in a highly conserved domain and predicted to be disease-causing by bioinformatic analysis. CONCLUSION: The two novel MKKS/BBS6 variants probably underlay the BBS in the proband. The TMEM67 variant may have an epistatic effect on mutations of BBS-associated loci.

Lipoprotein glomerulopathy induced by ApoE Kyoto mutation in ApoE-deficient mice.

BACKGROUND: Lipoprotein glomerulopathy (LPG) is a rare autosomal dominant kidney disease that is most commonly caused by mutations in ApoE Kyoto (p.R43C) and ApoE Sendai (p.R163P). Differences in phenotype among the various ApoE mutations have been suggested, but the pathogenic role of ApoE Kyoto has not been validated in an animal model. This study intended to establish an ApoE Kyoto murine model and to further compare the pathologic differences between ApoE Kyoto and ApoE Sendai. METHOD: Male ApoE-deficient mice, 3 months of age, were divided into five groups, including the AD-ApoE Sendai, AD-ApoE Kyoto, AD-ApoE3, AD-eGFP, and ApoE (-/-) groups. The first four groups received recombinant adenovirus that contained the entire coding regions of the human ApoE Sendai and ApoE Kyoto, apoE3, and eGFP genes, respectively. Fasting blood and urine samples were collected at multiple time points. Lipid profiles and urine albumin-creatinine ratio were measured. Renal and aortic histopathologic alterations were analyzed. RESULTS: After virus injection, plasma human ApoE was detected and rapidly reached the maximum level at 4-6 days in the AD-ApoE Kyoto and AD-ApoE Sendai groups (17.4 ± 3.1 µg/mL vs.: 22.2 ± 4.5 µg/mL, respectively) and at 2 days in the AD-ApoE3 group (38.4 µg/mL). The serum total cholesterol decreased by 63%, 65%, and 73% in the AD-ApoE Kyoto, AD-ApoE Sendai and AD-ApoE3 groups, respectively. There were no significant changes in serum triglyceride and urinary albumin-creatinine ratio among the five groups. Typical lipoprotein thrombi with positive ApoE staining were detected in the AD-ApoE Kyoto and AD-ApoE Sendai groups. The Oil-red O-positive glomerular area tended to be higher in the AD-ApoE Kyoto group (9.2%) than in the AD-ApoE Sendai (3.9%), AD-ApoE3 (4.8%), AD-eGFP (2.9%), and ApoE (-/-) (3.6%) groups. The atherosclerotic plaque area in the aorta was lower in the group injected with various ApoE mutations than in the group without injection of ApoE mutation. CONCLUSIONS: In this animal study, we first established an ApoE Kyoto mutation murine model and confirmed its pathogenic role in LPG. Our results suggested that LPG may be more severe with the ApoE Kyoto than with the ApoE Sendai.

Resolution of huge thrombi in bilateral ventricles caused by severe lupus cardiomyopathy.

Ventricular thrombus is an uncommon, severe condition with high morbidity and mortality. Simultaneous left and right ventricular thrombi caused by lupus myocardiopathy have not been previously reported in the literature. This case presents a 42-year-old woman who has bilateral ventricular thrombi with reduced left ventricular ejection fraction (35.4%) and acute kidney injury. Pro-brain natriuretic peptide was >35000 pg/mL. Systemic lupus erythematosus was confirmed based on multiorgan injuries including malar rash, anemia, renal injury, positive antinuclear, anti-Smith antibodies, and decreased complements. Renal biopsy revealed lupus nephritis class III + V. Low molecular weight heparin, steroids, and mycophenolate mofetil were initiated, after which the patient experienced transient numbness in the right limbs and hemoptysis. She then recovered quickly and improved significantly with recovery of left ventricular systolic function (left ventricular ejection fraction 46%) and the eventual disappearance of thrombi. Simultaneous left and right ventricular thrombi are rare but life-threatening condition, prompting consideration of myocardiopathy caused by autoimmune diseases such as lupus. Timely treatment with immunosuppressants and anticoagulants may resolve the thrombi and improve cardiac function.

C3 glomerulonephritis associated with ANCA positivity: a case report.

BACKGROUND: C3 glomerulopathy (C3G) is a recent disease classification that is characterized by the presence of glomerular deposits (composed of C3) in the absence of significant amounts of immunoglobulin and comprises dense deposit disease and C3 glomerulonephritis (C3GN). Most C3GN manifests as membranoproliferative, mesangial proliferative glomerulonephritis patterns via light microscopy. Pure membranous nephropathy (MN)-like glomerular lesions are rare manifestations of C3GN. Anti-neutrophil cytoplasmic antibodies (ANCAs) are also seldomly reported to be positive in C3GN. Herein, we report the case of a C3GN patient presenting with an MN-like glomerular pattern with ANCA positivity. CASE PRESENTATION: A 68-year-old woman was admitted to a local hospital with elevated serum creatinine for two weeks. Laboratory tests showed a hemoglobin level of 85 g/L. Urinalysis was positive for 2 + protein and 360 RBCs/HPF. Blood biochemistry analysis revealed the following concentrations: albumin, 30.3 g/L; globulin, 46.2 g/L; blood urea nitrogen, 19.9 mmol/L; and serum creatinine, 234 µmol/L. The serum C3 level was 0.4950 g/L, and the serum C4 level was 0.1050 g/L. The direct Coombs test was positive. Serologic testing for ANCA revealed the presence of p-ANCA (1:10) by indirect immunofluorescence microscopy assay, as well as the presence of PR3 1.2 (normal range < 1) and MPO 3.5 (normal range < 1) by enzyme immunoassay. Renal biopsy sample pathology showed 2/6 cellular crescents and thickened glomerular basement membranes. Immunofluorescence testing revealed only diffuse, finely granular depositions of C3 along the glomerular capillary walls in frozen and paraffin-embedded tissue sections. Electron microscopy demonstrated the presence of subepithelial electron-dense deposits, similar to those that are observed in membranous nephropathy. Corticosteroid and cyclophosphamide were administered, with a subsequent improvement in renal function. CONCLUSIONS: We present the rare case of a patient with MN-like C3GN with ANCA positivity. C3GN with ANCA positivity may be represented by more crescents, severe renal dysfunction and more extrarenal manifestations. More cases are needed to elucidate the clinicopathologic features and optimal treatments of these patients.

[Discovery of a Chinese Tibetan patient with lipoprotein glomerulopathy due to APOE Osaka/Kurashiki variant].

OBJECTIVE: To detect variant of APOE gene in a Chinese Tibetan patient with lipoprotein glomerulopathy (LPG) confirmed by renal biopsy and to explore its pathogenesis. METHODS: Clinical and pathological data was collected. DNA was extracted from peripheral blood sample of the patient and subjected to PCR and Sanger sequencing. Pathogenicity of the variant was analyzed by bioinformatics software. RESULTS: Renal biopsy of the patient has confirmed the diagnosis of LPG. DNA sequencing suggested that the patient has carried a heterozygous c.527G>C (p.R176P) variant of the APOE gene (APOE Osaka/Kurashiki). Four cases of LPG have been found to carry the same variant, and the encoded amino acid (p.176R) is highly conserved during evolution. Bioinformatic analysis using SIFT, PolyPhen2 and PANTHER software all predicted the variant to be pathogenic. CONCLUSION: The discovery of author's patient provided further evidence for the pathogenicity of APOE Osaka/Kurashiki and, more importantly, provide new evidence for the multiracial origin of LPG-related APOE variants.

Simultaneous occurrence of IgG4-related Tubulointerstitial nephritis and colon adenocarcinoma with hepatic metastasis: a case report and literature review.

BACKGROUND: Understanding the uncommon association of IgG4-related disease with other disorders is essential for the accurate diagnosis and effective treatment of patients. To the best of our knowledge, there have been only few reports of patients with IgG4-related kidney disease coexisting with metastasis of malignancy. Here, we report a rare case of simultaneous occurring IgG4-related tubulointerstitial nephritis and colon adenocarcinoma with hepatic metastasis. CASE PRESENTATION: A 71-year-old Chinese man presented with dysuria and was initially diagnosed as benign prostatic hyperplasia for one year. He was admitted to the hospital for surgery. After admission, the renal function tests revealed a rapid increase of serum creatinine from 291.0 µmol/L to 415 µmol/L. The hemoglobin level was 89 g/L. Fecal occult blood testing was positive. Urinalysis revealed mild proteinuria. The serum IgG4 level was 13.9 g/L. The abdominal imaging examination revealed multiple solid nodules in the liver. The gastrointestinal endoscopy combined with the biopsy revealed colon adenocarcinoma. Kidney biopsy showed massive IgG4-positive plasma cells and storiform fibrosis infiltration in the tubulointerstitial area, thus establishing the diagnosis of IgG4-related tubulointerstitial nephritis. Corticosteroid therapy was initiated, and subsequently, the renal function dramatically improved without the diminution of the liver nodules. The liver biopsy was performed and a diagnosis of metastatic colon adenocarcinoma was confirmed. CONCLUSIONS: We here reported a rare case of simultaneous occurring of IgG4-related tubulointerstitial nephritis, colon adenocarcinoma with hepatic metastasis. The case highlights the importance of screening for malignancy in patients with IgG4-related disease, and the nature of the mass in other organs of patients with coexisting IgG4-related disease and malignancy should be carefully checked.

A novel ADCK4 mutation in a Chinese family with ADCK4-Associated glomerulopathy.

AarF domain-containing kinase 4 (ADCK4)-associated glomerulopathy (ADCK4-GN) is an inherited mitochondrial nephropathy caused by mutations in the ADCK4 gene. Herein, we report a case of ADCK4-GN. The patient, a 14-year-old Chinese male, presented with asymptomatic proteinuria and steroid resistance. A renal biopsy showed focal segmental glomerulosclerosis (FSGS) and dysmorphic mitochondria in podocytes. Coenzyme Q10 treatment was partially effective. No adverse events were observed. Next generation and Sanger sequencing analyses revealed compound heterozygous mutations (c.625C > G, p.D209H and c.918G > T, p.C306X). Both inherited mutations are located in the highly conserved ABC1 domain. The unreported nonsense mutation causes a loss of 197 amino acids from the C-terminal portion of ADCK4, suggesting a deleterious effect of the truncating mutation by abolishing ADCK4 function. In conclusion, we identified a novel ABC1 domain-localized pathogenic mutation responsible for ADCK4-GN, further supporting the importance of the C-terminal portion of ADCK4. Next generation sequencing facilitated the early diagnosis. CoQ10 treatment may reduce proteinuria and postpone ADCK4-GN progression.

Mycophenolate Mofetil Combined With Prednisone Versus Full-Dose Prednisone in IgA Nephropathy With Active Proliferative Lesions: A Randomized Controlled Trial.

BACKGROUND: Observational studies suggest that patients with immunoglobulin A nephropathy (IgAN) with active proliferative lesions show a good response to immunosuppressive treatment. STUDY DESIGN: Multicenter, prospective, randomized, controlled trial. SETTING & PARTICIPANTS: 176 patients with IgAN with active proliferative lesions (cellular and fibrocellular crescents, endocapillary hypercellularity, or necrosis), proteinuria with protein excretion ≥ 1.0g/24h, and estimated glomerular filtration rate > 30mL/min/1.73m2. INTERVENTION: Mycophenolate mofetil (MMF) group: MMF, 1.5g/d, for 6 months and prednisone, 0.4 to 0.6mg/kg/d, for 2 months and then tapered by 20% per month for the next 4 months; prednisone group: prednisone, 0.8 to 1.0mg/kg/d, for 2 months and then tapered by 20% per month for the next 4 months. All patients were followed up for another 6 months. OUTCOMES: The primary end point was complete remission rate at 6 and 12 months. RESULTS: At baseline, median estimated glomerular filtration rates were 90.2 and 94.3mL/min/1.73m2 and mean proteinuria was protein excretion of 2.37 and 2.47g/24h in the MMF and prednisone groups, respectively. At 6 months, complete remission rates were 37% (32 of 86 patients) and 38% (33 of 88 patients); the between-group difference was not statistically significant (P=0.9). At 12 months, complete remission rates were 48% (35 of 73 patients) and 53% (38 of 72 patients) in the MMF and prednisone groups, respectively; the between-group difference was not statistically significant (P=0.6). Incidences of Cushing syndrome and newly diagnosed diabetes mellitus were lower in the MMF group than in the prednisone group. LIMITATIONS: Not all participants were treated with renin-angiotensin system blockers, relatively short follow-up. CONCLUSIONS: MMF plus prednisone versus full-dose prednisone did not differ in reducing proteinuria, but patients treated with the former had fewer adverse events in patients with IgAN with active proliferative lesions.

[Study of a family affected with focal segmental glomerulosclerosis due to mutation of COL4A5 gene].

OBJECTIVE: To analyze the clinicopathologic features and genetic mutation in a patient diagnosed with focal segmental glomerulosclerosis (FSGS). METHODS: Clinicopathologic data of the patient, who was diagnosed with primary FSGS by renal biopsy, was collected. Mutations of FSGS-related genes were screened with next-generation sequencing. Suspected pathogenic mutation was verified with Sanger sequencing. RESULTS: Next-generation sequencing detected a missense mutation (c.2215C to G, p.P739A) in exon 28 of the COL4A5 gene in the patient. The same mutation was also detected in his mother who was asymptomatic. Another missense mutation (c.2215C to T, p.P739S) in the same codon has been related with Alport syndrome. CONCLUSION: The c.2215C to G (p.P739A) mutation may be one of pathogenic mutations underlying FSGS. This has provided further evidence for the phenotypic heterogeneity of COL4A5 gene mutations.

Early Impairment of Cardiac Function and Asynchronization of Systemic Amyloidosis with Preserved Ejection Fraction Using Two-Dimensional Speckle Tracking Echocardiography.

AIMS: To observe the ventricular global and regional function of the patients with systemic amyloidosis using two-dimensional speckle tracking echocardiography. METHODS: The study enrolled 31 consecutive biopsy-proved patients with systemic amyloidosis who underwent echocardiographic examination and EF ≥ 55% and 37 age- and gender-matched healthy controls. We compared systolic strain and strain rate, diastolic strain rate, time to peak strain, peak delay time in longitudinal, radial, circumferential directions in 16 left ventricular segments. The global peak systolic longitudinal and radial strain of left ventricle, peak systolic longitudinal strain and strain rate, diastolic strain rate of right ventricular free wall were also compared. RESULTS: (1) Global peak systolic longitudinal strain (GPSLS), peak systolic longitudinal strain (PSLS) and strain rate (PSLSR), peak early diastolic longitudinal strain rate (PELSR) in 16 segments were decreased in case (P < 0.05). (2) Peak systolic radial strain and strain rate of inferoseptum and inferolateral at the level of papillary muscle were lower (P < 0.05), and peak early diastolic radial strain rate (PERSR) was reduced (P < 0.05). (3) Peak early diastolic circumferential strain rate was lower (P < 0.05). (4) Time to peak systolic longitudinal, radial, circumferential strain was longer, and peak delay time at the same level retarded (P < 0.05). (5) Into right ventricular wall, PSLS and PSLSR at mid-segment, and PSLSR, PELSR, peak atrial systolic longitudinal strain rate (PALSR) at basal were reduced (P < 0.05). (6) Inverse correlation between interventricular septum (IVS) thickness and GPSLS and GPSRS was found (P < 0.05). CONCLUSION: Systolic and diastolic dysfunction existed in systemic amyloidosis with preserved EF. Mechanical contraction disorder may be one reason for systolic dysfunction. GPLSR and GPRSR were negatively related to IVS thickness.

Mammalian target of rapamycin complex 1 activation in podocytes promotes cellular crescent formation.

Podocytes play a key role in the formation of cellular crescents in experimental and human diseases. However, the underlying mechanisms for podocytes in promoting crescent formation need further investigation. Here, we demonstrated that mammalian target of rapamycin complex 1 (mTORC1) signaling was remarkably activated and hypoxia-inducible factor (HIF) 1α expression was largely induced in cellular crescents from patients with crescentic glomerular diseases. Specific deletion of Tsc1 in podocytes led to mTORC1 activation in podocytes and kidney dysfunction in mice. Interestingly, 33 of 36 knockouts developed cellular or mixed cellular and fibrous crescents at 7 wk of age (14.19±3.86% of total glomeruli in knockouts vs. 0% in control littermates, n=12-36, P=0.04). All of the seven knockouts developed crescents at 12 wk of age (30.92±11.961% of total glomeruli in knockouts vs. 0% in control littermates, n=4-7, P=0.002). Most notably, bridging cells between the glomerular tuft and the parietal basement membrane as well as the cellular crescents were immunostaining positive for WT1, p-S6, HIF1α, and Cxcr4. Furthermore, continuously administrating rapamycin starting at 7 wk of age for 5 wk abolished crescents as well as the induction of p-S6, HIF1α, and Cxcr4 in the glomeruli from the knockouts. Together, it is concluded that mTORC1 activation in podocytes promotes cellular crescent formation, and targeting this signaling may shed new light on the treatment of patients with crescentic glomerular diseases.

Hereditary features, treatment, and prognosis of the lipoprotein glomerulopathy in patients with the APOE Kyoto mutation.

Lipoprotein glomerulopathy is a rare inherited renal disease, caused by mutation of the APOE gene, characterized by proteinuria and nephrotic syndrome with elevated serum apoE. Since its treatment and outcome are unknown, we retrospectively studied 35 patients within 31 unrelated Han families with biopsy-proven lipoprotein glomerulopathy residing in the same county in southwest China. DNA sequencing detected the APOE Kyoto mutation (p. Arg25Cys) in all patients and 28 asymptomatic relatives. All shared the same ɛ3 allele. The patients presented with proteinuria, higher total triglyceride, and serum apoE levels relative to non-carriers. The serum apoE and triglyceride levels of asymptomatic carriers were between those of the patients and non-carriers. Sixteen patients received fenofibrate treatment for over 12 months. Six reached complete remission (proteinuria under 0.3 g/day with stable serum creatinine) with intensive control of their lipid profile (normalized serum apoE and triglycerides under 100 mg/dl). Eight reached partial remission. At 3 years of follow-up, patients treated with fenofibrate had superior survival and stable renal function. Thus, fenofibrate can induce lipoprotein glomerulopathy remission and the fibrate effects depend on the degree of lipid control and baseline proteinuria. Moreover, normalization of serum apoE and triglycerides can be used to judge the efficacy of lipid-lowering treatment.

Omega-3 polyunsaturated fatty acids protect peritoneal mesothelial cells from hyperglycolysis and mesothelial-mesenchymal transition through the FFAR4/CaMKKß/AMPK/mTOR signaling pathway.

Peritoneal fibrosis is a severe clinical complication associated with peritoneal dialysis (PD) and impacts its efficacy and patient outcomes. The process of mesothelial-mesenchymal transition (MMT) in peritoneal mesothelial cells plays a pivotal role in fibrogenesis, whereas metabolic reprogramming, characterized by excessive glycolysis, is essential in MMT development. No reliable therapies are available despite substantial progress made in understanding the mechanisms underlying peritoneal fibrosis. Protective effect of omega-3 polyunsaturated fatty acids (ω3 PUFAs) has been described in PD-induced peritoneal fibrosis, although the detailed mechanisms remain unknown. It is known that ω3 PUFAs bind to and activate the free fatty acid receptor 4 (FFAR4). However, the expression and role of FFAR4 in the peritoneum have not been investigated. Thus, we hypothesized that ω3 PUFAs would alleviate peritoneal fibrosis by inhibiting hyperglycolysis and MMT through FFAR4 activation. First, we determined FFAR4 expression in peritoneal mesothelium in humans and mice. FFAR4 expression was abnormally decreased in patients on PD and mice and HMrSV5 mesothelial cells exposed to PD fluid (PDF); this change was restored by the ω3 PUFAs (EPA and DHA). ω3 PUFAs significantly inhibited peritoneal hyperglycolysis, MMT, and fibrosis in PDF-treated mice and HMrSV5 mesothelial cells; these changes induced by ω3 PUFAs were blunted by treatment with the FFAR4 antagonist AH7614 and FFAR4 siRNA. Additionally, ω3 PUFAs induced FFAR4, Ca2+/calmodulin-dependent protein kinase kinase ß (CaMKKß), and AMPK and suppressed mTOR, leading to the inhibition of hyperglycolysis, demonstrating that the ω3 PUFAs-mediated FFAR4 activation ameliorated peritoneal fibrosis by inhibiting hyperglycolysis and MMT via CaMKKß/AMPK/mTOR signaling. As natural FFAR4 agonists, ω3 PUFAs may be considered for the treatment of PD-associated peritoneal fibrosis.

CELF2 Deficiency Demonstrates Autism-Like Behaviors and Interferes with Late Development of Cortical Neurons in Mice.

CELF2 variants have been linked to neurodevelopmental disorders (NDD), including autism spectrum disorder (ASD). However, the molecular mechanisms remain unclear. We generated Celf2 Nestin-Cre knockout mice.Our findings revealed that Celf2 Nestin-Cre heterozygous knockout mice exhibited social impairment and anxiety, an autism-like behavior, though no manifestations of repetitive stereotyped behavior, learning cognitive impairment, or depression were observed. Immunofluorescence assay showed an underdeveloped cerebral cortex with significantly reduced cortical thickness, albeit without abnormal cell density. Further in vitro neuronal culture demonstrated a significant reduction in dendritic spine density and affected synaptic maturation in Celf2 deficient mice, with no notable abnormalities in total neurite and axon length. RNA-seq and RIP-seq analysis of the cerebral cortex revealed differentially expressed genes post Celf2 gene knockout compared with the control group. Enrichment analysis highlighted significant enrichment in dendrite and synapse-related biological processes and pathways. Our study delineated the behavioral and neurodevelopmental phenotypes of Celf2, suggesting its potential involvement in autism through the regulation of target genes associated with dendritic spines and synapse development. Further research is needed to elucidate the specific mechanisms involved.

Growth hormone promotes myelin repair after chronic hypoxia via triggering pericyte-dependent angiogenesis.

White matter injury (WMI) causes oligodendrocyte precursor cell (OPC) differentiation arrest and functional deficits, with no effective therapies to date. Here, we report increased expression of growth hormone (GH) in the hypoxic neonatal mouse brain, a model of WMI. GH treatment during or post hypoxic exposure rescues hypoxia-induced hypomyelination and promotes functional recovery in adolescent mice. Single-cell sequencing reveals that Ghr mRNA expression is highly enriched in vascular cells. Cell-lineage labeling and tracing identify the GHR-expressing vascular cells as a subpopulation of pericytes. These cells display tip-cell-like morphology with kinetic polarized filopodia revealed by two-photon live imaging and seemingly direct blood vessel branching and bridging. Gain-of-function and loss-of-function experiments indicate that GHR signaling in pericytes is sufficient to modulate angiogenesis in neonatal brains, which enhances OPC differentiation and myelination indirectly. These findings demonstrate that targeting GHR and/or downstream effectors may represent a promising therapeutic strategy for WMI.