Usp9x contributes to the development of sepsis-induced acute kidney injury by promoting inflammation and apoptosis in renal tubular epithelial cells via activation of the TLR4/nf-κb pathway.

As a pattern recognition receptor, Toll-like receptor 4 (TLR4) is crucial for the development and progression of acute kidney injury (AKI). This study aims to explore whether the deubiquitinase Usp9x influences the TLR4/NF-B pathway to cause sepsis-induced acute kidney injury (S-AKI). The model of AKI was established in Sprague-Dawley rats using the cecal ligation and puncture (CLP) method, while renal tubular epithelial cell NRK-52E was stimulated with lipopolysaccharide (LPS) in vitro. All plasmids were transfected into NRK-52E cells according to the indicated group. The deubiquitinase of TLR4 was predicted by the online prediction software Ubibrowser. Subsequently, Western blot and Pearson correlation analysis identified Usp9x protein as a potential candidate. Co-IP analysis verified the interaction between TLR4 and Usp9x. Further research revealed that overexpression of Usp9x inhibited degradation of TLR4 protein by downregulating its ubiquitination modification levels. Both in vivo and in vitro experiments observed that interference with Usp9x effectively alleviated the inflammatory response and apoptosis of renal tubular epithelial cells (RTECs) induced by CLP or LPS, whereas overexpression of TLR4 reversed this situation. Transfection with sh-Usp9x in NRK-52E cells suppressed the expression of proteins associated with the TLR4/NF-κB pathway induced by LPS. Moreover, the overexpression of TLR4 reversed the effect of sh-Usp9x transfection. Therefore, the deubiquitinase Usp9x interacts with TLR4, leading to the upregulation of its expression through deubiquitination modification, and the activation of the TLR4/NF-κB signaling pathway, thereby promoting inflammation and apoptosis in renal tubular epithelial cells and contributing to sepsis-induced acute kidney injury.

A subtype of laminopathies: Generalized lipodystrophy-associated progeroid syndrome caused by LMNA gene c.29C>T mutation.

The term laminopathies refers to a group of congenital diseases characterized by accelerated degeneration of human tissues. Mutations in LMNA, LMNB, ZMPSTE24, and other genes lead to structural and functional abnormalities associated with lamins. One subtype of laminopathy is the generalized lipodystrophy-associated progeroid syndrome (GLPS), which occurs in patients with heterozygous mutations of the LMNA gene c.29C>T(p.T10I). This paper reports the first case of GLPS in China and compares the clinical features of other GLPS patients with literature reports. A 16-year-old male patient was treated for diabetic ketoacidosis, presenting with premature aging appearance, systemic lipodystrophy, severe fatty liver, and decreased bone density. After peripheral blood DNA extraction and second-generation sequencing, a heterozygous mutation of exon 1 of the LMNA gene c.29C>T(p.T10I) was detected. This case of GLPS may provide a diagnostic and therapeutic basis for potential patients.

Efficacy and safety of rituximab in the treatment of membranous nephropathy: A systematic review and meta-analysis.

BACKGROUND AND OBJECTIVES: Rituximab (RTX) is considered to be a promising drug for curing membranous nephropathy. However, the efficacy and safety of RTX in treating membranous nephropathy remain uncertain. This meta-analysis aimed to investigate the efficacy and safety of RTX in patients with membranous nephropathy. METHODS: A literature search was performed using Pubmed, Embase, OVID, and Cochrane Library and randomized controlled trials (RCTs) case-controls and cohort studies published till 30 July 2019 were assessed. The studies assessing the efficacy and safety of RTX in patients with membranous nephropathy were included. RESULTS: Eight relevant trials involving 542 patients were included in the meta-analysis. It was found that RTX did not significantly improve serum albumin levels and e-GFR when compared with the control group (including cyclosporine and cyclophosphamide, chlorambucil, prednisone, non-immunosuppressive anti-proteinuria treatment), serum albumin levels (OR = 0.31, 95%CI-0.12-0.74, P = .15), e-GFR (OR = -1.49, 95%CI-17.14-14.17, P = .85). However, RTX did reduce the serum creatinine (OR = -0.01, 95%CI-0.36-0.34, P = .95) and urinary protein (OR = -2.39, 95%CI -7.30 -2.53, P = .34) levels. Also, in comparison to the control group, RTX did improve the total remission rate (OR = 1.63, 95%CI 0.48-5.54, P = .43), achieve a higher rate of complete remission (OR = 2.54, 95%CI 1.65-3.90, P < .01) and also reduced the amount of M-type phospholipase A2 receptor-Antibody depletion in patients (OR = 5.59, 95%CI 1.81-17.2, P = .003). RTX-related adverse events were mostly mild (most infusion-related reactions) in nature and serious adverse events were rare. CONCLUSION: RTX proved to be efficient, well-tolerated and a safe drug in the treatment of membranous nephropathy. Most patients reach complete remission during the follow-up period, and relapse is rare. RTX may turn out to be promising in membranous nephropathy patients.

Clinicopathological features and prognosis in patients with idiopathic membranous nephropathy with hypertension.

The present study analyzed the clinicopathological features and prognosis in patients with idiopathic membranous nephropathy (IMN) with hypertension. In the hypertension group, significant differences were found in the age, hypertension history, systolic blood pressure, diastolic blood pressure (DBP), mean arterial pressure, albumin, serum creatinine, low-density lipoprotein, 24 h urine protein levels, calculated estimated glomerular filtration rate (e-GFR), glomerular sclerosis, segmental sclerosis, ischemic sclerosis, interstitial fibrosis, tubular atrophy and vascular lesion compared with the non-hypertension group (P<0.05). The average follow-up time was 35.70 months (5.10-103.77 months). In total, 54 patients reported a 50% decline in e-GFR, eight patients reported progression of disease to end-stage renal disease (ESRD) and nine cases of mortality were reported. Survival analysis results suggested that patients with hypertension had a lower cumulative renal survival rate than those without hypertension (P=0.034). Multivariate Cox hazards regression analysis results suggested that DBP [hazard ratio (H), 5.160; CI, 0.865-0.989; P=0.023], age (H, 4.839; CI, 1.008-1.142; P=0.028), sex (H, 5.680; CI, 0.031-0.714; P=0.017), serum creatinine (H, 20.920; CI, 1.035-1.089; P<0.001), uric acid (H, 4.783; CI, 0.982-0.0.999; P=0.029), 24 h urine protein (H, 6.318; CI, 1.079-1.850; P=0.012), e-GFR (H, 4.008; CI, 1.001-1.062; P=0.045) and glomerular sclerosis (H, 8.722; CI, 1.860-21.559; P=0.003), segmental sclerosis (H, 7.737; CI, 7.770-13.219; P=0.005), percentage of ischemic sclerosis (H, 4.729; CI, 1.444-11.945; P=0.030), crescents (H, 5.938; CI, 0.003-0.526; P=0.015), interstitial fibrosis and tubular atrophy (H, 8.128; CI, 0.005-1.052; P=0.043), and vascular lesion (H, 4.049; CI, 1.030-9.766; P=0.044) were risk factors for the development of IMN into ESRD. The results suggested that DBP may be an independent risk factor for the development of IMN with hypertension.