Potential therapeutic targets for membranous nephropathy: proteome-wide Mendelian randomization and colocalization analysis.

Background: The currently available medications for treating membranous nephropathy (MN) still have unsatisfactory efficacy in inhibiting disease recurrence, slowing down its progression, and even halting the development of end-stage renal disease. There is still a need to develop novel drugs targeting MN. Methods: We utilized summary statistics of MN from the Kiryluk Lab and obtained plasma protein data from Zheng et al. We performed a Bidirectional Mendelian randomization analysis, HEIDI test, mediation analysis, Bayesian colocalization, phenotype scanning, drug bank analysis, and protein-protein interaction network. Results: The Mendelian randomization analysis uncovered 8 distinct proteins associated with MN after multiple false discovery rate corrections. Proteins related to an increased risk of MN in plasma include ABO [(Histo-Blood Group Abo System Transferase) (WR OR = 1.12, 95%CI:1.05-1.19, FDR=0.09, PPH4 = 0.79)], VWF [(Von Willebrand Factor) (WR OR = 1.41, 95%CI:1.16-1.72, FDR=0.02, PPH4 = 0.81)] and CD209 [(Cd209 Antigen) (WR OR = 1.19, 95%CI:1.07-1.31, FDR=0.09, PPH4 = 0.78)], and proteins that have a protective effect on MN: HRG [(Histidine-Rich Glycoprotein) (WR OR = 0.84, 95%CI:0.76-0.93, FDR=0.02, PPH4 = 0.80)], CD27 [(Cd27 Antigen) (WR OR = 0.78, 95%CI:0.68-0.90, FDR=0.02, PPH4 = 0.80)], LRPPRC [(Leucine-Rich Ppr Motif-Containing Protein, Mitochondrial) (WR OR = 0.79, 95%CI:0.69-0.91, FDR=0.09, PPH4 = 0.80)], TIMP4 [(Metalloproteinase Inhibitor 4) (WR OR = 0.67, 95%CI:0.53-0.84, FDR=0.09, PPH4 = 0.79)] and MAP2K4 [(Dual Specificity Mitogen-Activated Protein Kinase Kinase 4) (WR OR = 0.82, 95%CI:0.72-0.92, FDR=0.09, PPH4 = 0.80)]. ABO, HRG, and TIMP4 successfully passed the HEIDI test. None of these proteins exhibited a reverse causal relationship. Bayesian colocalization analysis provided evidence that all of them share variants with MN. We identified type 1 diabetes, trunk fat, and asthma as having intermediate effects in these pathways. Conclusions: Our comprehensive analysis indicates a causal effect of ABO, CD27, VWF, HRG, CD209, LRPPRC, MAP2K4, and TIMP4 at the genetically determined circulating levels on the risk of MN. These proteins can potentially be a promising therapeutic target for the treatment of MN.

Proteinuria selectivity index in renal disease.

One of the main barriers to early detection and subsequent prevention of kidney diseases is the accessibility and feasibility of testing, especially in urine research. The proteinuria selectivity index (PSI or SI) is a method used to assess changes in glomerular permeability in glomerular diseases. It describes the pattern of proteinuria by comparing the clearance rates of large molecular proteins and transferrin, categorizing it as selective or non-selective. PSI is widely applied for kidney disease classification, prediction of corticosteroid efficacy, and prognosis. Herein, we reviewed the clinical applications and recent advancements of PSI in glomerular diseases, compared it with commonly used renal function biomarkers, and discussed the future research directions for PSI as a potential predictive marker for response to specific biologics.

Lead exposure dose-dependently affects oxidative stress, AsA-GSH, photosynthesis, and mineral content in pakchoi (Brassica chinensis L.).

Lead (Pb) is a heavy metal pollutant and negatively affects agriculture and ecosystems. Pb can cause oxidative stress and abnormal plant growth. The ascorbic acid-glutathione (AsA-GSH) cycle mainly exists in chloroplasts and resists oxidative stress, scavenges reactive oxygen radicals, and maintains normal photosynthesis. However, the dosage related effects of Pb on pakchoi photosynthesis, via oxidative stress and the AsA-GSH system, remains unclear. In this study, various Pb dosage stress models were tested (low: 300 mg/kg; medium: 600 mg/kg; high: 900 mg/kg). Pb stress induced a dose-dependent increase in Pb content in pakchoi leaves (P < 0.05). Principal component analysis showed that Se, B, and Pb were significantly and negatively correlated. Pb stress also increased MDA content and decreased antioxidant enzymes SOD, GSH-Px, and T-AOC activities (P < 0.05). We also found that Vc content, as well as the GSH/GSSG ratio, decreased. Additionally, Pb stress destroyed chloroplast structure, decreased photosynthesis indicators Pn, Tr, Gs, Ci and VPD, and attenuated Fv/Fm and Fv/Fo (P < 0.05). In the high-dose group, the contents of chlorophyll a, chlorophyll b, and carotenoids decreased significantly, while the expression of chloroplast development genes (GLK, GLN2) decreased (P < 0.05). Our data suggest that Pb stress leads to dosage-dependent, aberrant photosynthesis by inhibiting the AsA-GSH system in pakchoi. This study expands the Pb toxicology research field and provides indications for screening antagonists.