Myeloid PTEN deficiency aggravates renal inflammation and fibrosis in angiotensin II‐induced hypertension

Abstract

Hypertension is a major cause of chronic kidney disease. However, the pathogenesis of hypertensive kidney disease is not fully understood. Recently, we have shown that CXCL16/phosphoinositide-3 kinase γ (PI3Kγ) plays an important role in the development of renal inflammation and fibrosis in angiotensin II (AngII) induced hypertensive nephropathy. In the present study, we examined the role of phosphatase and tensin homolog (PTEN), a major regulator of PI3K signaling, in the pathogenesis of renal inflammation and fibrosis in an experimental model of hypertension induced by AngII. We generated myeloid PTEN conditional knockout mice by crossing PTEN flox/flox mice with LysM-driven Cre mice. Littermate LysM-Cre −/− PTEN flox/flox mice were used as a control. Both myeloid PTEN knockout mice and their littermate control mice exhibited similar blood pressure at baseline. AngII treatment resulted in an increase in blood pressure that was comparable between myeloid PTEN knockout mice and littermate control mice. Compared with littermate control mice, myeloid PTEN knockout mice developed more severe kidney dysfunction, proteinuria, and fibrosis following AngII treatment. Furthermore, myeloid PTEN deficiency exacerbated total collagen deposition and extracellular matrix protein production and enhanced myeloid fibroblast accumulation and myofibroblast formation in the kidney following AngII treatment. Finally, myeloid PTEN deficiency markedly augmented infiltration of F4/80 + macrophages and CD3 + T cells into the kidneys of AngII-treated mice. Taken together, these results indicate that PTEN plays a crucial role in the pathogenesis of renal inflammation and fibrosis through the regulation of infiltration of myeloid fibroblasts, macrophages, and T lymphocytes into the kidney.

STAT6 Deficiency Attenuates Myeloid Fibroblast Activation and Macrophage Polarization in Experimental Folic Acid Nephropathy

“…Recent studies have indicated that bone-marrow-derived fibroblasts, termed fibrocytes, make an important contribution to the populations of activated fibroblasts and have a crucial role in renal fibrosis development [4][5][6][7][8][9]. Bone-marrow-derived fibroblasts share the characteristics of fibroblasts, such as the expression of collagen I, platelet-derived growth factor receptor-β (PDGFR-β), and vimentin, as well as the characteristics of hematopoietic cells, such as the expression of CD45 and CD11b [10,11]. Our previous studies have demonstrated that these cells contribute significantly to the pathogenesis of renal fibrosis [12][13][14].…”

SAKit: an all-in-one analysis pipeline for identifying novel protein caused by variant events at genomic and transcriptic level

“…After obtaining the FLNC, the cluster module of isoseq3 is further used to cluster FLNC reads using hierarchical n*log(n) alignment and iterative cluster merging. In the novel variant isoform (NVI) calling step following pre-processing step described above, we utilized the collapse_isoforms_by_sam.py of cDNAcupcake [17], which takes bam file as input obtained by mapping cluster.fasta files to the pre-defined reference using minimap2 [18], to collapse two or more identical transcript isoforms into a unique transcript isoform. [Fig2A] Simultaneously, the number of full-length reads corresponding to different unique isoforms was also obtained, which are important supporting evidence for the called isoforms, and will be used as the parameter in the following filter step.…”

“…Based on this principle, neoantigen-based immunotherapy has been developed by pharmaceutical companies or research institutions as a promising cancer treatment [4][5][6]. Additionally, novel proteins are also associated with other complex diseases, for instance, Alzheimer's [7], type II diabetes [8], liver disease [9][10][11][12][13][14], kidney disease [15][16][17][18][19][20], Obesity [21][22][23][24][25], and cardiovascular disease [26]. Therefore, effective identification of novel proteins is imperative for understanding human diseases and developing corresponding therapies.…”

Kidney diseases and long non-coding RNAs in the limelight

“…It was also observed that the lncRNA TapSAKI promotes the expression of phosphatase and tensin homolog (PTEN), TLR4/NF-κB pathway–related proteins TLR4 and P-p65, and apoptotic protein cleaved caspase-3 through negative regulation of miR-22 in renal injury induced by urinary sepsis. The miR-22/PTEN/TLR4/NF-κB pathway promotes the inflammatory injury of HK-2 cells and myeloid PTEN deficiency aggravates renal inflammation and fibrosis ( Shen et al, 2019 ; An et al, 2022 ). Another lncRNA, HOXA cluster antisense RNA 2, showed a protective effect in sepsis-induced AKI by targeting miR-106B-5p and blocking the Wnt/β-catenin and NF-κB pathways ( Wu et al, 2020 ).…”