Dissecting the Involvement of Ras GTPases in Kidney Fibrosis

Abstract

Many different regulatory mechanisms of renal fibrosis are known to date, and those related to transforming growth factor-β1 (TGF-β1)-induced signaling have been studied in greater depth. However, in recent years, other signaling pathways have been identified, which contribute to the regulation of these pathological processes. Several studies by our team and others have revealed the involvement of small Ras GTPases in the regulation of the cellular processes that occur in renal fibrosis, such as the activation and proliferation of myofibroblasts or the accumulation of extracellular matrix (ECM) proteins. Intracellular signaling mediated by TGF-β1 and Ras GTPases are closely related, and this interaction also occurs during the development of renal fibrosis. In this review, we update the available in vitro and in vivo knowledge on the role of Ras and its main effectors, such as Erk and Akt, in the cellular mechanisms that occur during the regulation of kidney fibrosis (ECM synthesis, accumulation and activation of myofibroblasts, apoptosis and survival of tubular epithelial cells), as well as the therapeutic strategies for targeting the Ras pathway to intervene on the development of renal fibrosis.

Folate Deficiency Enhanced Inflammation and Exacerbated Renal Fibrosis in High-Fat High-Fructose Diet-Fed Mice

“…The positive correlation between leptin and phosphorylated STAT3 ratio, as well as TGF-β1 and phosphorylated Smad2/3 ratio in renal tissues, revealed the mechanisms of effects of the HFF diet and folate deficiency. In addition to STAT3 and Smad2/3 signaling, there are several crucial pathways involved in renal extracellular matrix deposition and fibrosis, such as the RAS superfamily, mammalian target of rapamycin complex 1, and hypoxia-inducible factor-1α [ 51 , 52 ]. These may be clues and strategies for us to further explore the mechanism in greater depth of folate nutritional status on renal fibrosis in the future.…”

Endothelial Activin Receptor-Like Kinase 1 (ALK1) Regulates Myofibroblast Emergence and Peritubular Capillary Stability in the Early Stages of Kidney Fibrosis

“…Renal myofibroblasts are the main source of ECM proteins during tubule-interstitial fibrosis ( LeBleu and Kalluri, 2011 ). Myofibroblasts are activated fibroblasts with high contractile capacity, and with a high capacity to synthesize ECM proteins such as collagens, fibronectin or laminin ( Munoz-Felix and Martinez-Salgado, 2021 ). These cells emerge during the first steps of the fibrotic process from different origins.…”

“…Specifically, in chronic kidney disease (CKD), a progressive and irreversible loss of renal function and renal tissue integrity, is associated with tubulo-interstitial fibrosis resulting from excessive deposition of ECM proteins by myofibroblasts. Different sources of myofibroblasts contribute to renal fibrosis ( Grande and López-Novoa, 2009 ; Munoz-Felix and Martinez-Salgado, 2021 ). During years, the epithelial-to-mesenchymal transition (EMT) was considered the main source ( Sato et al, 2003 ; Zeisberg et al, 2003 ; Grande and López-Novoa, 2009 ; Grande et al, 2010 ) (of myofibroblasts).…”

Acarbose Protects Glucolipotoxicity-Induced Diabetic Nephropathy by Inhibiting Ras Expression in High-Fat Diet-Fed db/db Mice

“…Ras family members are downstream convergence points for signal cascades mediated by many cell surface receptors with the ligands expressed in renal injury, such as transforming the growth factor β (TGF-β), platelet-derived growth factor, angiotensin II, and epidermal growth factor, allowing for the transduction of the signal to the downstream pro-fibrotic effectors. In a renal fibrosis model, tubulointerstitial fibrosis increased the Ras, ERK, and Akt activation [ 31 ]. Ras protein is associated with DN.…”