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Review
. 2014 Jan;34(1):62-71.
doi: 10.1016/j.semnephrol.2013.11.009. Epub 2013 Nov 22.

Regulation of Autophagy by TGF-β: Emerging Role in Kidney Fibrosis

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Free PMC article
Review

Regulation of Autophagy by TGF-β: Emerging Role in Kidney Fibrosis

Yan Ding et al. Semin Nephrol. .
Free PMC article

Abstract

Autophagy is a highly conserved homoeostatic mechanism for cell survival under conditions of stress, and is widely implicated as an important pathway in many biological processes and diseases. In progressive kidney diseases, fibrosis represents the common pathway to end-stage kidney failure. Transforming growth factor-β1 (TGF-β1) is a pleiotropic cytokine that has been established as a central mediator of kidney fibrosis. A recently emerging body of evidence from studies in renal cells in culture and experimental animal models suggests that TGF-β1 regulates autophagy and that autophagy regulates many critical aspects of normal and disease conditions associated with kidney fibrosis, such as tubulointerstitial fibrosis, glomerulosclerosis, and diabetic nephropathy. Here, we review the recent advances exploring the process of autophagy, its regulation by TGF-β1, and the implication in the pathogenesis of progressive kidney fibrosis and injury responses. Understanding the cellular and molecular bases of this process is crucial for identifying potential new diagnostic and therapeutic targets of kidney fibrosis.

Keywords: Autophagy; chronic kidney disease; fibrosis; transforming growth factor-β1.

Conflict of interest statement

Conflict of interest statements: none.

Figures

Fig. 1
Fig. 1
Autophagy in mesangial cells. (A) TGF-β1 signals via the MKK3/p38 to enhance type I collagen mRNA and protein (Col-Iα1 and Col-I, respectively) in mesangial cells. TGF-β1-induced autophagy negatively regulates matrix production in mesangial cells by promoting degradation of intracellular type I collagen (Col-I). Treatment with inducers of autophagy, trifluoperazine (TFP) and low-dose carbon monoxide (CO), also results in decreased type I collagen protein levels induced by TGF-β1, without alterations in collagen (Col-Iα1) mRNA. (B) Treatment with autophagy inhibitor 3-MA and genetic knockdown of Atg7 decrease Col-I, α-SMA and -PDGFR protein expression in mouse mesangial cells.
Fig. 2
Fig. 2
Autophagy and tubular interstitial fibrosis. (A) TGF-1 oversexpression in tubular epithelial cells induces autophagy in vivo and in vitro, through ROS, resulting in tubulointerstitial fibrosis, tubular apoptosis and decomposition. (B) Autophagy is activated in a model of renal fibrosis induced by unilateral ureteral obstruction (UUO), and is associated with inhibition of tubular apoptosis and interstitial fibrosis in the obstructed kidney, and reduces cell proliferation in the contralateral kidney. Antioxidant sulforaphane preserves mitochondrial function and suppresses UUO-induced renal oxidative stress, inflammation, fibrosis, autophagy, apoptosis, and pyroptosis. (C) Long-term use of Cyclosporine causes tubular atrophy, interstitial fibrosis and glomerulosclerosis and impairs renal function. Autophagy is activated via induction of ER stress by cyclosporine and protects tubular cells from cell death.
Fig. 3
Fig. 3
Autophagy and glomerulosclerosis. (A) In podocyte-specific Atg5 knockout mice (Atg5podocyte), compensatory proteasome activity decreases with aging, leading to severe proteinuria, loss of podocytes, and glomerulosclerosis. Knockdown of ATG5 in podocyte increases susceptibility to drug puromycin (PAN)-, adriamycin (ADR)-, albumin (BSA)-, and lipopolysaccharide (LPS)-induced glomerular injury. (B) Podocyte-specific Vps34 knockout mice (Vps34podocyte) develop significant glomerulosclerosis, interstitial fibrosis, severe albuminuria, and podocyte loss through inhibiting the formation of phagophore and the mTOR pathway. (C) Autophagy is activated in podocytes in both human proteinuric glomerular diseases and in experimental model of albumin (BSA)-overload-induced glomerular injury.
Fig. 4
Fig. 4
Autophagy and endothelial cell-induced fibrosis. BAMBI localizes to the endothelial cells in the kidney, and autophagy regulates turnover of BAMBI protein. Both serum starvation and rapamycin induce BAMBI protein degradation through activation of autophagy. BAMBI may function as a regulator of TGF-β/Smad signaling in endothelial cells, and hence modulate TGF-β actions, and thereby fibrosis.

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