Autophagy and its therapeutic potential in diabetic nephropathy

Abstract

Diabetic nephropathy (DN), the leading cause of end-stage renal disease, is the most significant microvascular complication of diabetes and poses a severe public health concern due to a lack of effective clinical treatments. Autophagy is a lysosomal process that degrades damaged proteins and organelles to preserve cellular homeostasis. Emerging studies have shown that disorder in autophagy results in the accumulation of damaged proteins and organelles in diabetic renal cells and promotes the development of DN. Autophagy is regulated by nutrient-sensing pathways including AMPK, mTOR, and Sirt1, and several intracellular stress signaling pathways such as oxidative stress and endoplasmic reticulum stress. An abnormal nutritional status and excess cellular stresses caused by diabetes-related metabolic disorders disturb the autophagic flux, leading to cellular dysfunction and DN. Here, we summarized the role of autophagy in DN focusing on signaling pathways to modulate autophagy and therapeutic interferences of autophagy in DN.

Keywords: autophagy; cellular stress; diabetic nephropathy; nutrient-sensing pathway; renal cell.

Figure 1

The diagram of resident cells in the glomerulus and proximal tubule. There are four kinds of major resident cells in the glomerulus, glomerular endothelial cells (GEnCs), podocytes, glomerular mesangial cells (GMCs), and parietal epithelial cells. Tubular epithelial cells form the extension of Bowman’s capsule, that is, the renal tubule. Podocytes with their interdigitating foot processes are arranged on the lateral side of the glomerular basement membrane (GBM). GMCs located between glomerular capillary loops, adjacent to endothelial cells or basement membranes are irregularly shaped. GEnCs are flat cells attached to the GBM. GEnCs and podocytes form the glomerular filtration barrier.

Figure 2

Regulation of autophagy during diabetic nephropathy. Hyperglycemia is considered a state of overnutrition, leading to over-activation of the mammalian target of rapamycin (mTOR) and inhibition of adenosine 5’-monophosphate-activated protein kinase (AMPK) and silent information regulator of transcription 1 (Sirt1). The activated mTOR inhibits autophagy by blocking unc-51-like kinase 1 (ULK1) activation by AMPK and its downstream target phosphoprotein 70 ribosomal protein S6 kinase (p70S6K). The inhibition of AMPK blocks the dissociation of the beclin1/Bcl-2 (B-cell lymphoma-2) complex and the phosphorylation of ULK1, while promotes mTOR activity to reduce autophagy. The inactivated Sirt1 reduces the deacetylation of several target genes like forkhead box O3 (FoxO3), FoxO1, nuclear factor kappa-B (NF-κB), p53, and peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) to inhibit autophagy. In addition, other cellular events, including reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, and hypoxia, can also regulate autophagy to affect the development of diabetic nephropathy. Hypoxia-inducible factor 1α (HIF-1α) induced by hypoxia promotes the transcription of Bcl-2/adenovirus E1V19-kDa interacting protein 3 (BNIP3) and induces autophagy. ER stress enhances the expression of ER membrane proteins like protein kinase RNA-like ER kinase (PERK), inositol-requiring enzyme 1α (IRE1α), and activating transcription factor 6 (ATF6), leading to autophagy. In addition, autophagy under ER stress may be associated with the signaling pathway of PERK/α-subunit of eukaryotic initiation factor 2 (eIF2α)/ATF4 and IRE1α/c-Jun N-terminal kinase (JNK)/beclin1. Significantly, the endogenous autophagy induced by ER stress, oxidative stress and hypoxia in diabetes is hampered, which aggravates the progression of diabetic nephropathy. Thus, impaired autophagy accelerates the progression of diabetic nephropathy, resulting in a series of renal pathological damages. Rheb, ras homolog enriched in brain; PI3K, class III phosphatidylinositol-3-kinase; Akt, protein kinase B.