Autophagy as a Therapeutic Target for Chronic Kidney Disease and the Roles of TGF-β1 in Autophagy and Kidney Fibrosis

Abstract

Autophagy is a lysosomal protein degradation system that eliminates cytoplasmic components such as protein aggregates, damaged organelles, and even invading pathogens. Autophagy is an evolutionarily conserved homoeostatic strategy for cell survival in stressful conditions and has been linked to a variety of biological processes and disorders. It is vital for the homeostasis and survival of renal cells such as podocytes and tubular epithelial cells, as well as immune cells in the healthy kidney. Autophagy activation protects renal cells under stressed conditions, whereas autophagy deficiency increases the vulnerability of the kidney to injury, resulting in several aberrant processes that ultimately lead to renal failure. Renal fibrosis is a condition that, if chronic, will progress to end-stage kidney disease, which at this point is incurable. Chronic Kidney Disease (CKD) is linked to significant alterations in cell signaling such as the activation of the pleiotropic cytokine transforming growth factor-β1 (TGF-β1). While the expression of TGF-β1 can promote fibrogenesis, it can also activate autophagy, which suppresses renal tubulointerstitial fibrosis. Autophagy has a complex variety of impacts depending on the context, cell types, and pathological circumstances, and can be profibrotic or antifibrotic. Induction of autophagy in tubular cells, particularly in the proximal tubular epithelial cells (PTECs) protects cells against stresses such as proteinuria-induced apoptosis and ischemia-induced acute kidney injury (AKI), whereas the loss of autophagy in renal cells scores a significant increase in sensitivity to several renal diseases. In this review, we discuss new findings that emphasize the various functions of TGF-β1 in producing not just renal fibrosis but also the beneficial TGF-β1 signaling mechanisms in autophagy.

Keywords: ATG; TGF-β1; autophagy; chronic kidney disease; mTOR; proximal tubular epithelial cells.

Figure 1

The transition from a healthy kidney to a chronically diseased kidney is associated with changes in autophagy patterns. 1. Demonstrates structurally healthy and physiologically efficient healthy kidney cells with high basal autophagy 2. Depicts the state of renal capillaries following damage caused by an underlying illness, toxins, drugs, or infection. In the extracellular areas, fibroblasts begin to release collagen and fibronectin proteins, and autophagy functions as a protective response, which can be reversible (adaptive repair). 3. AKI worsens to chronic kidney disease, and autophagic activities decline. This stage is characterized by morphological damage to the renal parenchyma and extracellular matrix deposition (maladaptive repair). 4. chronic kidney disease with significant fibrous protein deposition, and no evidence of autophagy.

Figure 2

Podocytes are seen in the illustration surrounding capillaries in a glomerulus. Podocytes have higher basal autophagy levels than other glomerular cell types, which is a quality-control mechanism for cytoprotection. As illustrated above, foot effacement is seen in the absence of autophagy which leads to podocyte loss and is a morphologic hallmark of chronic kidney disease.

Figure 3

Molecular pathways involved in autophagy as explained thoroughly in the text above. Briefly, energy depletion leads to the activation of autophagy pathways by inducing LC3 signaling pathways. This leads to the formation of autophagosomes, which fuse into the lysosome forming autolysosomes.

Figure 4

Schematic showing the autophagic factors responsible for inducing and inhibiting kidney fibrosis. p-Smad signaling increases collagen I production deposition leading to the development of renal fibrosis. On the other hand, non-Smad signaling inhibits fibrosis by inhibiting autophagy-mediated degradation of TGF-β1.