Roles of the Skp2/p27 axis in the progression of chronic nephropathy

Abstract

S-phase kinase-associated protein 2 (Skp2) is an F-box protein component of the Skp/Cullin/F-box-type E3 ubiquitin ligase that targets several cell cycle regulatory proteins for degradation through the ubiquitin-dependent pathway. Skp2-mediated degradation of p27, a cyclin-dependent kinase inhibitor, is involved in cell cycle regulation. Tubular epithelial cell proliferation is a characteristic feature of renal damage that is apparent in the early stages of nephropathy. The p27 level is associated with the progression of renal injury, and increased Skp2 expression in progressive nephropathy is implicated in decreases of p27 expression. In Skp2−/− mice, renal damage caused by unilateral ureteral obstruction (UUO) was ameliorated by p27 accumulation, mainly in tubular epithelial cells. However, the amelioration of UUO-induced renal injury in Skp2−/− mice was prevented by p27 deficiency in Skp2−/−/p27−/− mice. These results suggest that the Skp2-mediated reduction in p27 is a pathogenic activity that occurs during the progression of nephropathy. Here, we discuss the roles of the Skp2/p27 axis and/or related signaling pathways/components in the progression of chronic nephropathy.

TRPM7 contributes to progressive nephropathy

“…Inhibition of tubular epithelial cell proliferation is an essential component in the prevention of progressive renal fibrosis 17,18,28 . Morphologically, NS8593 treatment reduced the collapse of renal tubules in vivo (Fig.…”

“…A recent study supports this hypothesis, as genetic suppression of TRPM7 in a kidney transplantation mouse model alleviated progressive inflammatory kidney fibrosis 15 .In the kidney, cell proliferation is a central response to injury that culminates in the development of fibrosis and renal failure. Unilateral ureteral obstruction (UUO) is a widely used mouse model of kidney disease associated with progressive tubulointerstitial injury [16][17][18] . It has been used to identify many of the molecular and cellular events that occur in progressive kidney fibrosis.…”

“…The myofibroblasts produce excessive ECM, including deposits of collagen, fibronectin and vimentin. The TGF-β1/Smad signaling pathway stimulates tubular epithelial cells to trans-differentiate into mesenchymal cells 18,19 , which infiltrate the renal tubular interstitium through the broken tubular basement membrane. Trans-differentiated mesenchymal cells further differentiate into ECM-producing myofibroblasts, thus undergoing hyperproliferation and resulting in irreversible progression of renal interstitial fibrosis 18 .…”

Expression of p27(Kip1), a Cyclin-Dependent Kinase Inhibitor, in Human Peripheral Blood Mononuclear Cells Is Inversely Associated with Potential Carcinogenic Risk in Obese Type 2 Diabetic Individuals Relative to Lean Normal Controls

“…Multiple articles regarding the role of p27 and other factors in the kidney disease have been published [17]- [29], but one examplemight be cited that suggests the complexity of the underlying molecular mechanisms of the expression of p27 in diabetic nephropathy. In this example, it was proposed that the increased expression of S-phase kinase-associated protein 2 (Skp2) in progressive nephropathy with a consequent Skp2-mediated reduction in p27 might be the pathogenic activity that occurs during the progression of nephropathy [30]. This study was performed in the context that the tubular epithelial cell proliferation had been known to be a characteristic feature of the renal damage that is apparent in the early stages of nephropathy [30].…”

Skp2 expression exhibits a negative correlation with P27Kip1 in lungs of SD rat stress model induced by lipopolysaccharide

“…Cell cycle is basic biological mechanism (Suzuki et al, 2013) for proliferation of eukaryotic cell which requires sequential activation of cyclin-dependent kinases (CDKs) (Harper, 2001) and CDK inhibitors (CDKIs). SCF (Skp1-Cullin-F-box) complex involves in cell cycle progression and signal transduction, not only influence transcription and post-transcription levels by specific recognition of substrate and subsequent degradation of target protein (especially P27 Kip1 ) via ubiquitination, but are closely related with G1-S phase transformation.…”