Absence of K‐Ras Reduces Proliferation and Migration But Increases Extracellular Matrix Synthesis in Fibroblasts

Abstract

[EN]he small GTPase K-Ras (V-Ki-ras2, Kirsten rat sarcoma viraloncogene) is the Ras isoform predominantly expressed in renalfibroblasts. The K-ras gene encodes twoisoforms, K-Ras4A and K-Ras4B, by alternative splicing of exon4. Expression of K-Ras is essential during the developmentalstage in mice, and K-Ras knock-out (KO) mice die duringembryonic development due to liver defects and anemia.K-Ras is located in different plasma-membranemicrodomains and subcellular compartments where itactivates several effector pathways, includingphosphatidylinositol 3-kinase/protein kinase B (PI3K-AKT) andmitogen-activated protein kinase/extracellular signal-regulatedkinase (MAPK-ERK1/2). Activation of theseeffectors controls key cellular processes such as cell motility,proliferation, survival, differentiation, and apoptosis.The incidence of end-stage kidney disease, characterized byfibrosis, is increasing progressively in all countries. Fibrosis could bedefined as a failed wound healing process as a consequence ofdifferent types of insults, whereactivated fibroblasts, exhibiting deregulated proliferation andmigration, produce large amounts of extracellular matrix(ECM). Several fibrogenic growth factors modulate renal