Idiopathic membranous nephropathy in a patient diagnosed with IgG4-related disease: A case report.

RATIONALE: Immunoglobulin (Ig) G4-related disease (IgG4-RD) is a newly recognized, systemic disease. Membranous nephropathy is the most common glomerular lesion in IgG4- related kidney disease. However, the lack of relationship with IgG4-related kidney disease and monoclonal gammopathy of undetermined significance (MGUS) warrants investigation of the potential mechanisms. PATIENT CONCERNS: A 62-year-old patient was diagnosed with IgG4-RD, tubulointerstitial nephritis, retroperitoneal fibrosis. After 2 years, she was presented with proteinuria, hypoproteinemia, facial, and bilateral lower limb edema. Furthermore, this patient exhibited deposits of IgG k of monoclonal hyperplasia, and bone marrow plasma cell count was 2.5%. DIAGNOSIS: The patient was diagnosed with nephrotic syndrome, acute kidney injury, and MGUS. The pathological diagnosis was IgG4-related tubulointerstitial nephritis, IgG4-related membranous nephropathy. INTERVENTIONS: The patient was treated with intravenous methylprednisolone (40 mg daily), which was changed to oral prednisone 50 mg/d after 2 months. OUTCOMES: After 1 month, the patient exhibited a rapid response only with corticosteroid, and experienced partial remission of serum albumin and proteinuria. LESSONS: This case may suggest a possible relationship between IgG4-RD and MGUS, provide some guidance for investigating the mechanism between them.

Effect of Sleeve Gastrectomy on Glycometabolism via Forkhead Box O1 (FoxO1)/Lipocalin-2 (LCN2) Pathway.

BACKGROUND The mechanism by which sleeve gastrectomy (SG) improves glycometabolism has remained unclear so far. Increasing evidence has demonstrated that bone is a regulator of glucose metabolism, and osteoblast-derived forkhead box O1 (FoxO1) and lipocalin-2 (LCN2) are regulators of energy metabolism. The aim of this study was to investigate whether the FOXO1/LCN2 signaling pathway is involved in the anti-diabetic effect of SG. MATERIAL AND METHODS Insulin resistance was induced in Wistar rats, which were then intraperitoneally injected with streptozotocin to induce a type 2 diabetic state. Levels of fasting blood glucose, serum insulin, HbA1c, and LCN2 were analyzed at corresponding time points after SG and sham surgeries. The expressions of FOXO1, LCN2, and the melanocortin 4 receptor (MC4R) in bone and hypothalamus were detected by immunofluorescence. FOXO1 siRNA was applied to downregulate FOXO1 expression in osteoblasts of rats. The influence of FOXO1 gene on expression of LCN2 was investigated in cultured osteoblasts by western blot and PCR. RESULTS Glucose metabolism in the SG group was significantly improved. The LCN2 expression in bone in the SG group was higher than that in the sham group, whereas FOXO1 expression in the SG group was lower than that in the sham group. The binding rate of LCN2 and MC4R in the hypothalamus was also higher in the SG group compared with that in the sham group. The downregulation of FOXO1 expression in osteoblasts was accompanied by upregulation of LCN2 expression. CONCLUSIONS These results suggest that the FOXO1/LCN2 signaling pathway participates in the anti-diabetic effect of SG.

Effect of Sleeve Gastrectomy on Bone Metabolism and Serum 5-Hydroxytryptamine in Obese Rats.

BACKGROUND Studies have shown that bariatric surgery, such as sleeve gastrectomy (SG), has an adverse effect on bone, including decreased bone mineral density (BMD) and bone metabolism. Peripheral 5-hydroxytryptamine (5-HT) has an adverse regulatory effect on bone formation. Here, we assessed changes in bone metabolism and whether 5-HT is involved in the effect of SG on bone metabolism. MATERIAL AND METHODS A rat model of obesity was established using Wistar rats. After successful modeling, rats were randomly assigned to 2 groups - the SG group and the Sham group - with 10 rats in each group. We then performed sleeve gastrectomy or sham operation. Bone metabolic markers and BMD of rats were measured at 2 and 16 weeks after the operation and the level of 5-HT in serum was determined. Rats were killed at 16 weeks after the operation, and bones of the hind limbs were harvested to measure 5-HT by immunofluorescence. RESULTS BMD was decreased and bone metabolism demonstrated a trend of bone destruction in the rats after SG. A significantly increasing trend in the level of serum 5-HT was found, and bone immunofluorescence showed increased expression of 5-HT. CONCLUSIONS BMD was decrease and bone metabolism demonstrated a trend of bone destruction after SG. SG can affect the level of 5-HT in serum or bone tissue and the 5-HT may be involved in the process through which SG affects bone metabolism.

HIV-1 inhibition in cells with CXCR4 mutant genome created by CRISPR-Cas9 and piggyBac recombinant technologies.

The C-X-C chemokine receptor type 4 (CXCR4) is one of the major co-receptors for human immunodeficiency virus type 1 (HIV-1) entry and is considered an important therapeutic target. However, its function in maintaining the development of hematopoietic stem cells (HSC) makes it difficult to be used for HIV-1 gene therapy with HSC transplantation. A previous report showed that the natural CXCR4 P191A mutant inhibits HIV-1 infection without any defect in HSC differentiation, which could provide a basis for the development of new approaches for HIV-1 gene therapy. In the present study, we used CRISPR-Cas9 combined with the piggyBac transposon technologies to efficiently induce the expression of the CXCR4 P191A mutant in an HIV-1 reporter cell line, leading to no detectable exogenous sequences. In addition, no off-target effects were detected in the genome-edited cells. The decline of HIV-1 replication in biallelic CXCR4 gene-edited cells suggests that individuals equipped with homologous recombination of the CXCR4 P191A mutant could prevent or reduce HIV-1 infection. This study provides an effective approach to create a CXCR4 mutation with HIV-1 infection inhibition function and without leaving any genetic footprint inside cells, thereby shedding light on an application in HIV-1 gene therapy and avoiding side effects caused by deficiency or destruction of CXCR4 function.

Down-regulation of miR-23a inhibits high glucose-induced EMT and renal fibrogenesis by up-regulation of SnoN.

It has been reported that transforming growth factor-ß1 (TGF-ß1) signaling plays an important role in the development of diabetic nephropathy (DN). The nuclear transcription co-repressor Ski-related novel protein N (SnoN) is a critical negative regulator of TGF-ß1/Smad signal pathway, involving in tubule epithelial-mesenchymal transition (EMT), extracellular matrix (ECM) accumulation, and tubulointerstitial fibrosis. In this study, we focused on miR-23a as a regulator of SnoN. Our purpose is to study the effects of miR-23a on high glucose (HG)-induced EMT process and ECM deposition in HK2 cells. We found that miR-23a was up-regulated in renal tissues of diabetic patients and HG-induced HK2 cells. Besides, the high level of miR-23a was closely associated with decreased SnoN expression. Knockdown of miR-23a increased SnoN expression and in turn suppressed HG-induced EMT and renal fibrogenesis. Introduction of miR-23a decreased SnoN expression and enhanced the profibrogenic effects of HG on HK2 cells. Next, bioinformatics analysis predicted that the SnoN was a potential target gene of miR-23a. Luciferase reporter assay demonstrated that miR-23a could directly target SnoN. We demonstrated that overexpression of SnoN was sufficient to inhibit HG-induced EMT and renal fibrogenesis in HK2 cells. Furthermore, down-regulation of SnoN partially reversed the protective effect of miR-23a knockdown on HG-induced EMT and renal fibrogenesis in HK2 cells. Collectively, miR-23a and SnoN significantly impact on the progression of HG-induced EMT and renal fibrogenesis in vitro, and they may represent novel targets for the prevention strategies of renal fibrosis in the context of DN.

Role of ESAT-6 in renal injury by regulating microRNA-155 expression via TLR4/MyD88 signaling pathway in mice with Mycobacterium tuberculosis infection.

The study aims to investigate the underlying mechanism involved in the early secretory antigenic target-6 (ESAT-6) in renal injury through regulation of the expression of miR-155 through the oll-like receptor (TLR)-4 (TLR4)/myeloid differentiation factor 88 (MyD88) signaling pathway in Mycobacterium tuberculosis (MTB)-infected mice. Sixty C57BL/6 mice with MTB-induced renal injury were randomly assigned into control, MTB, mimic, inhibitor, inhibitor + ESAT6, and inhibitor + ESAT6 + TAK242 groups. Body weight, the ratio of kidney weight to body weight (Kw/Bw), blood urea nitrogen (BUN), and serum creatinine (Scr) of mice were measured. Flow cytometry was used to detect renal activation in mice. Expressions of miR-155 and ESAT6 were detected by quantitative real-time PCR (qRT-PCR), and Western blotting was used to examine the expressions of ESAT6, TLR4, and MyD88. Expressions of tumor necrosis factor-α (TNF-α), interleukin-17 (IL-17), and interferon-γ (IFN-γ) were measured by qRT-PCR and ELISA. Compared with the control group, the BUN and Scr levels as well as the expression levels of miR-155, TLR4, MyD88, TNF-α, IL-17, and IFN-γ increased, while Kw/Bw decreased in the MTB and mimic groups. In comparison with the MTB group, the above indexes except Kw/Bw were elevated in the mimic group, but were reduced in the inhibitor group, while the Kw/Bw dropped in the mimic group but increased in the inhibitor group. Compared with the inhibitor group, the Kw/Bw decreased while the rest of the indexes increased in the inhibitor + ESAT6 group. ESAT6 may induce renal injury by promoting miR-155 expression through the TLR-4/MyD88 signaling pathway in MTB-infected mice.