The Role of Renal Macrophage, AIM, and TGF-β1 Expression in Renal Fibrosis Progression in IgAN Patients

ObjectiveTo analyze the expression of macrophages, AIM, TGF-β1 in the kidney of IgAN patients, and to explore the role of macrophages, AIM, TGF-β1 in the progression of renal fibrosis in IgAN patients.MethodsThe paraffin specimens of renal tissue from 40 IgAN patients were selected as the observation group. At the same time, paraffin specimens of normal renal tissue from 11 patients treated by nephrectomy were selected as the normal control group. We observed the distribution of macrophages, the expression of AIM and TGF-β1 by immunohistochemical staining and/or immunofluorescence.ResultThe number of M0, M1, M2 macrophages could be found increased in IgAN patients. M0 macrophages are mainly polarized towards M2 macrophages. The expression of AIM and TGF-β1 were significantly higher in IgAN patients than in NC. M2 macrophage, AIM and TGF-β1 were positively correlated with serum creatinine and 24-hour proteinuria, but negatively correlated with eGFR. M2 macrophages, AIM, TGF-β1 were positively correlated with fibrotic area.ConclusionM2 macrophages, AIM and TGF-β1 play important roles in the process of IgAN fibrosis, and the three influence each other.

USP39 Promotes Malignant Proliferation and Angiogenesis of Renal Cell Carcinoma by Inhibiting VEGF-A Alternative Splicing

Objective: To investigate the function and mechanism of USP39 in promoting malignant proliferation and angiogenesis of RCC.Methods: We applied ONCOMINE database to analyze the correlation between USP39 expression level and the clinical characteristics of RCC. The effect of USP39 on RCC was evaluated by MTT assay, cell cycle analysis, colony formation assay and tubule formation assay. The interaction between USP39 and VEGF-A alternative splicing was assessed by co-immunoprecipitation and Western blot assays. Results: The mRNA expression level of USP39 in RCC was significantly higher than that in normal renal tissue (P<0.001), and negatively correlated with the survival rate of RCC patients (P<0.01). Silencing of USP39 in 786-O and ACHN cells obviously inhibited cell proliferation and colony formation, and induced S phase arrest. USP39 overexpression significantly increased the number of tubules (P<0.05) and branches (P<0.01) formed by HUVEC cells, and USP39 knockdown produced an opposite effect (P<0.05). The USP39 (101-565) fragment directly mediated its binding to SRSF1 and SRPK1, and promoted the phosphorylation of SRSF1 to regulate VEGF-A alternative splicing. USP39 knockdown upregulated the expression of VEGF-A165b, and USP39 overexpression downregulated the expression of VEGF-A165b significantly (both P<0.05).Conclusion: USP39 acted as a pro-tumor factor by motivating the malignant biological processes of RCC, probably through promoting VEGF-A alternative splicing and regulating SRSF1 and SRPK1. USP39 may prove to be a potential therapeutic target for RCC.

The kidney in systemic disease

Many systemic diseases can affect the kidney, including autoimmune conditions, malignancies, infections, and vascular diseases. Autoimmune conditions can cause inflammation of the glomeruli or tubules, or deposition of inflammatory proteins (AA amyloidosis). Malignancy can cause infiltration of normal renal tissue, immunoglobulin deposition in the renal vessels, glomeruli or tubules, or paraneoplastic renal dysfunction as occurs in secondary focal segmental glomerulosclerosis. Infections can cause inflammation in glomeruli, in association with immune complex deposition. Vascular disease and vasculitis reduce kidney blood supply and cause renal ischaemia. This chapter provides an overview of these diseases.

Intervention

Imaging technology allows complex yet minimally invasive diagnostic and therapeutic interventions in the genitourinary tract. It provides precise targeting for tissue biopsy to allow accurate diagnosis. Percutaneous nephrolithotomy is invaluable in the treatment of complex stone disease and percutaneous nephrostomy insertion preserves normal renal tissue in the patient with malignant or benign urinary tract obstruction. (Percutaneous nephrolithotomy and percutaneous nephrostomy are very different.) Antegrade ureteric procedures allow strictures, stones, and tumours to be dealt with, often with much greater ease than the retrograde approach. Collections and leaks can be drained and urine can be diverted to facilitate healing. Minimally invasive endovascular techniques can arrest iatrogenic or trauma-related haemorrhage from the renal tract. Although interventional radiological procedures are generally safe, they do come with risks of specific complications that the nephrologist needs to be aware of. Nephrologists need to be familiar with interventional uroradiological techniques to allow appropriate counseling and care of patients who require these procedures.

Comprehensive kinase profiling to classify clear cell (cc)-renal cell carcinoma (RCC).

409 Background: Comprehensive high throughput functional kinase activity in localized cc-RCC tumors may assist in devising a classification system and help identify potential therapeutic targets. Methods: Patients (pts) with localized tumors undergoing surgery with minimum follow-up of 18 months underwent kinomics of fresh frozen cc-RCC tumors and matched normal renal tissue using the PamStation12 high-content phospho-peptide substrate microarray system (PamGene). The protein tyrosine kinome (PTK) and serine/threonine kinome (STK) PamChips were used to measure global kinase activity. Advanced network modeling of altered phospho-peptides was performed using MetaCore while upstream kinase prediction scoring was based off of phosphonet (phosphonet.ca). Both unsupervised analyses and supervised analyses of kinomics were done guided by tumor recurrence. Kinomics of tumor and matched normal tissue were compared. Results: Of 41 evaluable pts, the median age was 61 and pathologic stage was 1, 2, 3 and 4 in 19, 1, 20 and 1 pts, respectively. Unsupervised clustering analyses of tumor kinomics showed 3 groups: A (N=12), B (N=16), C (N=13). Potential driver kinases implicated were PFTK1, PKG1 and SRC in groups A, B, and C, respectively. Network modeling of these groups identified many Process Mappings including, but not limited to Inflammation pathways (A), translation initiation (B) and immune response and cell adhesion pathways(C). 5 of 9 pts who progressed were classified as Group C, 1 progressor was in Group B, and 3 were in Group A. Supervised analysis showed decreased CDK1, RSK1-4, ERK1-2, PKG2 and AKT2 kinase activity in those who progressed compared to others. 12 tumors showed increased PIM1 and MAPKAPK3, and decreased JNK2 and CDK1 compared to adjacent normal tissue. Conclusions: Comprehensive kinomics of localized cc-RCC was used to classify tumors based on unsupervised clustering, which appeared to confer differential long-term outcomes while supervised analysis also identified potential pathways related to recurrence. Kinases amplified in renal tumors compared to adjacent normal renal tissue were also identified. Significant heterogeneity of kinases was found with no single dominant kinase across all analyses.