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American Journal of Physiology. Renal... Aug 2023Renin cells are precursors for other cell types in the kidney and show high plasticity in postnatal life in response to challenges to homeostasis. Our previous...
Renin cells are precursors for other cell types in the kidney and show high plasticity in postnatal life in response to challenges to homeostasis. Our previous single-cell RNA-sequencing studies revealed that the dual zinc-finger transcription factor , which is important for cell lineage commitment and differentiation, is expressed in mouse renin cells under normal conditions and homeostatic threats. We identified a potential Gata3-binding site upstream of the renin gene leading us to hypothesize that is essential for renin cell identity. We studied adult mice with conditional deletion of in renin cells: ; () and control Gata3; counterparts. Gata3 immunostaining revealed that mice had significantly reduced Gata3 expression in juxtaglomerular, mesangial, and smooth muscle cells, indicating a high degree of deletion of in renin lineage cells. mice exhibited a significant increase in blood urea nitrogen, suggesting hypovolemia and/or compromised renal function. By immunostaining, renin-expressing cells appeared very thin compared with their normal plump shape in control mice. Renin cells were ectopically localized to Bowman's capsule in some glomeruli, and there was aberrant expression of actin-α signals in the mesangium, interstitium, and Bowman's capsule in mice. Distal tubules showed dilated morphology with visible intraluminal casts. Under physiological threat, mice exhibited a lower increase in mRNA levels than controls. Hematoxylin-eosin, periodic acid-Schiff, and Masson's trichrome staining showed increased glomerular fusion, absent cubical epithelial cells in Bowman's capsule, intraglomerular aneurysms, and tubular dilation. In conclusion, our results indicate that is crucial to the identity of cells of the renin lineage. , a dual zinc-finger transcription factor, is responsible for the identity and localization of renin cells in the kidney. Mice with a conditional deletion of in renin lineage cells have abnormal kidneys with juxtaglomerular cells that lose their characteristic location and are misplaced outside and around arterioles and glomeruli. The fundamental role of in renin cell development offers a new model to understand how transcription factors control cell location, function, and pathology.
Topics: Mice; Animals; Renin; GATA3 Transcription Factor; Kidney; Kidney Glomerulus; Kidney Diseases; Zinc
PubMed: 37345845
DOI: 10.1152/ajprenal.00098.2023 -
Nephron 2023In kidney transplant recipients (KTRs) whose primary disease is IgA nephropathy (IgAN), IgAN recurrence occurs in approximately half of patients by 5 years...
Clinical and Pathological Significance of Mesangial C1q Deposition in Kidney Transplant Recipients with Recurrent IgA Nephropathy and Patients with Native IgA Nephropathy.
INTRODUCTION
In kidney transplant recipients (KTRs) whose primary disease is IgA nephropathy (IgAN), IgAN recurrence occurs in approximately half of patients by 5 years postoperatively and is associated with graft survival. Although the alternative and lectin pathways are important in the primary pathogenesis of IgAN, the significance of mesangial C1q deposition, which triggers the classical pathway, is unknown. We investigated the clinicopathological significance of mesangial C1q deposition in both recurrent IgAN in KTRs and native IgAN.
METHODS
Between 2000 and 2021, we conducted a 1:2 matched case-control study of 18 KTRs diagnosed with recurrent IgAN, with a group of native IgAN patients as the control. We evaluated the rate and presence/absence of mesangial C1q deposition in terms of pathological findings and kidney outcomes in each group.
RESULTS
The rate of mesangial C1q deposition was significantly higher in the recurrent IgAN patients in KTRs than in native IgAN patients (11/18 [61.1%] vs. 5/36 [13.9%], p = 0.001). In the former group, the incidence of glomerular crescents was relatively higher in C1q-positive patients. There was no significant difference in the annual rate of estimated glomerular filtration rate decline between C1q-positive and C1q-negative patients in either group.
CONCLUSION
Mesangial C1q deposition was more frequent in KTRs with recurrent IgAN than in patients with native IgAN, but we found no difference in kidney outcomes with respect to mesangial C1q deposition. Further large-scale investigations of the importance of mesangial C1q deposition are needed in both KTRs with recurrent IgAN and patients with native IgAN.
Topics: Humans; Glomerulonephritis, IGA; Complement C1q; Kidney Transplantation; Case-Control Studies; Glomerular Mesangium
PubMed: 37339606
DOI: 10.1159/000530916 -
Zhongguo Ying Yong Sheng Li Xue Za Zhi... Nov 2022To investigate the interventional effects of a new SUR2B/Kir6.1-type K Channel opener iptakalim on injury renal cells (the renal glomerular endothelial, mesangial and...
To investigate the interventional effects of a new SUR2B/Kir6.1-type K Channel opener iptakalim on injury renal cells (the renal glomerular endothelial, mesangial and tubular epithelial cells) and its mechanisms. ①Experimental protocol: control: the cells were treated with with 0 mg/L uric acid for 24 h; model: the cells were treated with with 1 200 mg/L uric acid for 24 h; pretreatment with iptakalim: the cells were pretreated with 0.01,0.1,1,10,100 μmol/L iptakalim for 24 h prior to treatment with 1 200 mg/L uric acid for 24 h; pretreatment with glibenclamide: the cells were preincubated with/without 10 μmol/L glibenclamide for 1 h and then treated with 10 μmol/L iptakalim for 24 h followed by incubation with 1 200 mg/L uric acid for another 24 h. ②The cell viability was measured by MTT assay and flow cytometry; the protein expressions of Kir6.1 and SUR2B and nuclear translocation were detected by immunostaining; the protein expressions of Kir6.1 and SUR2B were determined by Western blot analysis; adhesion of mononuclear cells to endothelial cells were tested by fluorimetric assay; the content of MCP-1 was measured by enzyme linked-immunosorbent assay (ELISA). The renal glomerular endothelial, mesangial and tubular epithelial cells were exposed to 1 200 mg/L uric acid for 24 h. Compared with the control group, 1 200 mg/L uric acid decreased the cell survival rates significantly (<0.01, <0.01, <0.01). Compared with the model group, pretreatment with 0.1, 1, 10, 100 μmol/L iptakalim could remarkably alleviate cellular damages of glomerular endothelium, mesangium cells induced by uric acid (<0.05, <0.01, <0.01, <0.01). The K channel blocker could clearly reduce survival rates of the renal glomerular endothelial, mesangial cells(<0.01) and markedly reverse the inhibitory effects of iptakalim on cell death (<0.05, <0.01), no obvious difference in comparison with the model group (>0.05). Compared with the model group, pretreatment with 10, 100 μmol/L iptakalim could notably attenuate cellular damages of tubular epithelial cells induced by uric acid (<0.05, <0.05). The K channel blocker could obviously damage the tubular epithelial cells (<0.01), no obvious difference in comparison with the model group (>0.05). Compared with control group, exposure of renal tubular epithelial, mesangial and glomerular endothelial cells to 1 200 mg/L uric acid for 24 h caused a significant increase in the protein expressions of Kir6.1 and SUR2B(<0.05). Compared with the model group, the overexpressions of Kir6.1 and SUR2B were suppressed in presence of iptakalim at a concentration of 10 μmol/L (<0.05). These decreases in the expressions of Kir6.1 and SUR2B were prevented by the K channel blocker, no obvious difference in comparison with the model group (>0.05). Compare with the control group, monocytic adhesion to renal glomerular endothelial cells was notably promoted by 1 200 mg/L uric acid for 24 h (<0.01). Pretreatment with 10 μmol/L iptakalim for 24 h significantly reduced the monocytic adhesion in comparison with the model group (<0.05). It was showed that the inhibitory effects of iptakalim were antagonized by the K channel blocker, no obvious difference in comparison with the model group (>0.05). After stimulating glomerular endothelial cells with 1 200 mg/L uric acid for 24 hours, the secretion of MCP-1 was significantly increased compared to the control group (<0.05). Compare with the model group, preincubation with 10 μmol/L iptakalim significantly decreased MCP-1 production (<0.05). K channel blocker suppressed the downregulation of MCP-1 protein synthesis induced by iptakalim. After stimulation with uric acid, translocation of NF-κB from cytoplasms to nuclei of renal glomerular endothelial cells were observed, while that of NF-κB was suppressed in presence of iptakalim at the concentration of 10 μmol/L. This inhibition of NF-κB translocation was clearly prevented by K channel blocker. These results suggests that a new SUR2B/Kir6.1-type K channel opener iptakalim plays interventional roles in renal cells damages caused by uirc acid and its mechanism is involved in activating Kchannels .
Topics: Endothelial Cells; Glyburide; NF-kappa B; Uric Acid; Adenosine Triphosphate
PubMed: 37308403
DOI: 10.12047/j.cjap.6356.2022.110 -
Scientific Reports May 2023To explore the feasibility of mesangium or membrane anatomy theory in thoracolaparoscopic radical esophagectomy for esophageal cancer, 98 patients with esophageal cancer...
To explore the feasibility of mesangium or membrane anatomy theory in thoracolaparoscopic radical esophagectomy for esophageal cancer, 98 patients with esophageal cancer were enrolled including 45 patients in the mesoesophageal esophagectomy group and 53 patients in the non-mesoesophageal esophagectomy group. Thoracolaparoscopic radical esophagecotmy was technically successful in all patients. Compared the non-mesoesophageal group, the mesoesophageal group had significantly (P < 0.05) shorter surgical duration (211.9 ± 42.0 min vs. 282.0 ± 44.5 min), less blood loss during the procedure (68.9 ± 45.9 ml vs. 167.0 ± 91.4 ml), more harvested lymph nodes (25.9 ± 6.3 vs. 21.8 ± 7.3), shorter hospital stay after surgery (10.5 ± 2.5 d vs. 12.5 ± 4.2 d), shorter fasting time or quicker postoperative feeding time (7.3 ± 1.2 d vs. 9.5 ± 3.9 d), and quicker removal of the thoracic drainage tube after surgery (7.7 ± 2.0 d vs. 9.2 ± 4.1 d). The overall incidence of postoperative complications was 46.7% (21/45) in the mesoesophageal group, which was significantly (P = 0.02) fewer than that (69.8% or 37/53) of the non-mesoesophageal group (P = 0.020). During follow-up 20.6 ± 4.3 or 20.8 ± 3.4 months after esophagectomy, liver metastasis occurred in 1 case and lung metastasis in 1 in the mesoesophageal group, whereas liver metastasis occurred in 2 cases, mediastinal metastasis in 2, and anastomotic recurrence in 1 in the non-mesoesophageal group. The mesoesophageal group had significantly better physical function (81.9 ± 7.3 vs. 78.3 ± 7.6), social function (65.1 ± 7.1 vs. 56.2 ± 18.2), global health status (65.3 ± 10.1 vs. 58.7 ± 12.4), and pain improvement (29.5 ± 9.5 vs. 35.6 ± 10.6). The overall survival rate was 82.2% (37/45) in the mesoesophageal group and 71.7% (38/53) in the non-mesoesophageal group (P = 0.26). The disease-free survival rate was 77.8% (35/45) for the mesoesophageal group and 62.3% (33/53) for the non-mesoesophageal group (P = 0.13). In conclusion:, the mesangium or membrane anatomy theory can be used safely and effectively to guide thoracolaparoscopic radical esophagectomy for esophageal cancer, with advantages of shorter surgical time, less bleeding, more lymph node harvest, fewer complications, and faster postoperative recovery.
Topics: Humans; Esophagectomy; Lymph Node Excision; Esophageal Neoplasms; Lymph Nodes; Postoperative Complications; Retrospective Studies
PubMed: 37253750
DOI: 10.1038/s41598-023-35513-w -
Kidney360 May 2023
Topics: Kidney Glomerulus; Glomerular Mesangium; Microvessels; Machine Learning
PubMed: 37229727
DOI: 10.34067/KID.0000000000000111 -
Cureus Apr 2023Focal segmental glomerulosclerosis (FSGS) and IgA nephropathy are among the most common glomerular disorders. FSGS is characterized by focal scarring affecting less than...
Focal segmental glomerulosclerosis (FSGS) and IgA nephropathy are among the most common glomerular disorders. FSGS is characterized by focal scarring affecting less than 50% of glomeruli while IgA nephropathy is characterized by the deposition of IgA in the mesangium of glomeruli. The presence of both of these diseases in a single patient is uncommon, but the presence of both in a young individual with no predisposing factors is exceedingly rare. As such, our case report outlines the unusual presentation of both of these disorders in a young Hispanic female with no known risk factors.
PubMed: 37159790
DOI: 10.7759/cureus.37212 -
Frontiers in Immunology 2023Immunoglobulin A (IgA) is the most abundant isotype of antibodies, provides a first line of defense at mucosal surfaces against pathogens, and thereby contributes to... (Review)
Review
Immunoglobulin A (IgA) is the most abundant isotype of antibodies, provides a first line of defense at mucosal surfaces against pathogens, and thereby contributes to mucosal homeostasis. IgA is generally considered as a non-inflammatory antibody because of its main function, neutralizing pathogenic virus or bacteria. Meanwhile, IgA can induce IgA-mediated diseases, such as IgA nephropathy (IgAN) and IgA vasculitis. IgAN is characterized by the deposition of IgA and complement C3, often with IgG and/or IgM, in the glomerular mesangial region, followed by mesangial cell proliferation and excessive synthesis of extracellular matrix in glomeruli. Almost half a century has passed since the first report of patients with IgAN; it remains debatable about the mechanism how IgA antibodies selectively bind to mesangial region-a hallmark of IgAN-and cause glomerular injuries in IgAN. Previous lectin- and mass-spectrometry-based analysis have revealed that IgAN patients showed elevated serum level of undergalactosylated IgA1 in O-linked glycans of its hinge region, called galactose-deficient IgA1 (Gd-IgA1). Thereafter, numerous studies have confirmed that the glomerular IgA from IgAN patients are enriched with Gd-IgA1; thus, the first hit of the current pathogenesis of IgAN has been considered to increase circulating levels of Gd-IgA1. Recent studies, however, demonstrated that this aberrant glycosylation alone is not sufficient to disease onset and progression, suggesting that several additional factors are required for the selective deposition of IgA in the mesangial region and induce nephritis. Herein, we discuss the current understanding of the characteristics of pathogenic IgA and its mechanism of inducing inflammation in IgAN.
Topics: Humans; Glomerulonephritis, IGA; Immunoglobulin A; Glomerular Mesangium; IgA Vasculitis
PubMed: 37114051
DOI: 10.3389/fimmu.2023.1165394 -
FASEB Journal : Official Publication of... May 2023Glomerulosclerosis is one of the major histopathologic changes in diabetic kidney diseases (DKD), which is characterized by excessive deposition of extracellular matrix...
Glomerulosclerosis is one of the major histopathologic changes in diabetic kidney diseases (DKD), which is characterized by excessive deposition of extracellular matrix (ECM) in the glomerulus mainly produced by mesangial cells in response to transforming growth factor-β (TGF-β) stimuli under diabetic conditions. Despite TGF-β has been implicated as a major pathogenic factor in the development of diabetic glomerulosclerosis, clinical trials of monoclonal antibodies against TGF-β failed to demonstrate therapeutic benefits. Thus, developing alternative therapeutic strategies to effectively block the TGF-β/Smad signaling could be of paramount importance for DKD treatment. Emerging evidence indicates that dysregulation of certain lncRNAs can lead to aberrant activation of TGF-β/Smad signaling. Herein, we identified a novel lncRNA, named DANCR, which could efficiently function as a negative regulator of TGF-β/Smad signaling in mesangial cells. Ectopic expression of DANCR could specifically block the activation of TGF-β/Smad signaling induced by high-glucose or TGF-β in human renal mesangial cells (HRMCs). Mechanistically, DANCR functions to stabilize nemo-like kinase (NLK) mRNA through interaction with insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), resulting in enhanced phosphorylating on the linker region of activated Smad2/3 in the nucleus. Taken together, our data have uncovered an lncRNA-based regulatory modality of the TGF-β/Smad signaling and identified DANCR as an endogenous blocker of TGF-β/Smad signaling in HRMCs, which may represent a potential therapeutic target against the diabetic glomerulosclerosis.
Topics: Humans; Diabetic Nephropathies; Extracellular Matrix; Glomerular Mesangium; Glucose; Mesangial Cells; Protein Serine-Threonine Kinases; RNA, Long Noncoding; RNA, Messenger; RNA-Binding Proteins; Transforming Growth Factor beta; Transforming Growth Factor beta1; Smad Proteins
PubMed: 37052733
DOI: 10.1096/fj.202300146R -
Medicine Apr 2023Polycythemia vera (PV) is a myeloproliferative neoplasm which is characterized by excessive production of erythrocytes as well as myeloid and megakaryocytic...
BACKGROUND
Polycythemia vera (PV) is a myeloproliferative neoplasm which is characterized by excessive production of erythrocytes as well as myeloid and megakaryocytic proliferation. PV associated with IgA nephropathy (IgAN) has rarely been reported in the literature. The long-term renal prognosis of these patients is unknown.
METHODS
Clinical and pathological characteristics of 7 patients with renal biopsy-proven IgAN associated with PV were retrospectively analyzed.
RESULTS
The 7 patients were all males, with a mean age of 49.1 ± 18.8 years when admitted to our hospital. Systemic symptoms include: hypertension in case 2, 3, 5, and 6, splenomegaly in case 2, 4, and 5, and multiple lacunar infarction in case 6. Bone marrow biopsy test revealed relative erythroid hyperplasia and atypical megakaryocyte proliferation which consistent with a chronic myeloproliferative neoplasm. All patients had JAK2V617F and BCR-ABL tested, and JAK2V617F positive in 2 patients. Mild mesangial proliferation was observed in 5 patients and moderate/severe mesangial proliferation in 2patients. Immunofluorescence mainly showed diffuse granular deposition of dominant IgA in mesangium. After follow-up of 56.7 ± 44.0 months, hemoglobin level was 144 ± 29 g/L and hematocrit lever was 0.470 ± 0.03, compared with 187 ± 29 g/L and 0.563 ± 0.087 respectively when admitted to our hospital. The urine protein was 0.85 ± 0.64 g/24 h compared with 3.97 ± 4.68 g/24 h. Case 3 progressed to end stage renal disease and had received hemodialysis for 5 years before renal transplantation.
CONCLUSIONS
The results of this study showed that PV associated with IgAN mainly occurs in males and is often accompanied by hematuria and mild-to-moderate renal insufficiency. The long-term prognosis was good for most patients, and few progressed relatively quickly to end stage renal disease.
Topics: Male; Humans; Adult; Middle Aged; Aged; Glomerulonephritis, IGA; Polycythemia Vera; Retrospective Studies; East Asian People; Kidney Failure, Chronic; Myeloproliferative Disorders
PubMed: 37026962
DOI: 10.1097/MD.0000000000033493