Arg tyrosine kinase modulates TGF-β1 production in human renal tubular cells under high-glucose conditions.
Renal tubular cells are involved in the tubular interstitial fibrosis observed in diabetic nephropathy. It is debated whether epithelial-mesenchymal transition (EMT) affects tubular cells, which under high-glucose conditions overproduce transforming growth factor-β (TGF-β), a fibrogenic cytokine involved in interstitial fibrosis development. Our study investigated the involvement of non-receptor tyrosine kinase Arg (also called Abl2) in TGF-β production. Human primary tubular cell cultures exposed to high-glucose conditions were used. These cells showed an elongated morphology, stress fibers and vimentin increment but maintained most of the epithelial marker expression and distribution. In these cells exposed to high glucose, which overexpressed and secreted active TGF-β1, Arg protein and activity was downregulated. A further TGF-β1 increase was induced by Arg silencing with siRNA, as with the Arg tyrosine kinase inhibitor Imatinib. In the cells exposed to high glucose, reactive oxygen species (ROS)-dependent Arg kinase downregulation induced both RhoA activation, through p190RhoGAPA (also known as ARHGAP35) modulation, and proteasome activity inhibition. These data evidence a new specific involvement of Arg kinase into the regulation of TGF-β1 expression in tubular cells under high-glucose conditions and provide cues for new translational approaches in diabetic nephropathy.
School of Medicine and Surgery, Milano-Bicocca University, Monza 20900, Italy.
Barbara
B
Torsello
School of Medicine and Surgery, Milano-Bicocca University, Monza 20900, Italy.
Cristina
0000-0001-6305-1487
C
Bianchi
School of Medicine and Surgery, Milano-Bicocca University, Monza 20900, Italy.
Chiara
C
Meregalli
School of Medicine and Surgery, Milano-Bicocca University, Monza 20900, Italy.
Vitalba
V
Di Stefano
School of Medicine and Surgery, Milano-Bicocca University, Monza 20900, Italy.
Lara
L
Invernizzi
School of Medicine and Surgery, Milano-Bicocca University, Monza 20900, Italy.
Sofia
S
De Marco
Anatomo-Pathology Unit, San Gerardo Hospital, Monza 20900, Italy.
Giorgio
G
Bovo
Clinical Pathology Unit, San Gerardo Hospital, Monza 20900, Italy.
Rinaldo
R
Brivio
Urology Unit, Bassini ICP Hospital, Milano 20092, Italy.
Guido
G
Strada
School of Medicine and Surgery, Milano-Bicocca University, Monza 20900, Italy.
Silvia
S
Bombelli
School of Medicine and Surgery, Milano-Bicocca University, Monza 20900, Italy roberto.perego@unimib.it.
Roberto A
0000-0003-3053-3476
RA
Perego
D000328:Adult; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D020868:Gene Silencing / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology; D007684:Kidney Tubules / Q000166:cytology*; D051379:Mice; D041681:NIH 3T3 Cells; D010641:Phenotype; D019000:Phosphotyrosine / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D022502:Stress Fibers / Q000187:drug effects / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis*; D025801:Ubiquitin / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D015415:Biomarkers; D020662:Guanine Nucleotide Exchange Factors; D061988:Proteasome Inhibitors; D017382:Reactive Oxygen Species; D053773:Transforming Growth Factor beta1; D025801:Ubiquitin; D019000:Phosphotyrosine; D000068877:Imatinib Mesylate; C426236:ARG tyrosine kinase; D011505:Protein-Tyrosine Kinases; D020742:rhoA GTP-Binding Protein; D005947:Glucose
Abl2; Arg; High glucose; ROS; Renal tubular cell; TGF-β; p190RhoGAP