Regulation of autophagy by natural polyphenols in the treatment of diabetic kidney disease: therapeutic potential and mechanism

Abstract

Diabetic kidney disease (DKD) is a major microvascular complication of diabetes and a leading cause of end-stage renal disease worldwide. Autophagy plays an important role in maintaining cellular homeostasis in renal physiology. In DKD, the accumulation of advanced glycation end products induces decreased renal autophagy-related protein expression and transcription factor EB (TFEB) nuclear transfer, leading to impaired autophagy and lysosomal function and blockage of autophagic flux. This accelerates renal resident cell injury and apoptosis, mediates macrophage infiltration and phenotypic changes, ultimately leading to aggravated proteinuria and fibrosis in DKD. Natural polyphenols show promise in treating DKD by regulating autophagy and promoting nuclear transfer of TFEB and lysosomal repair. This review summarizes the characteristics of autophagy in DKD, and the potential application and mechanisms of some known natural polyphenols as autophagy regulators in DKD, with the goal of contributing to a deeper understanding of natural polyphenol mechanisms in the treatment of DKD and promoting the development of their applications. Finally, we point out the limitations of polyphenols in current DKD research and provide an outlook for their future research.

Keywords: autophagy; diabetic kidney disease; lysosome; natural polyphenols; transcription factor EB.

Figure 1

Characteristics of autophagy in DKD. (The mTOR, AMPK, and SIRT1-regulated autophagy pathway is an important protective mechanism for DKD. Mitophagy and lipophagy are critical to DKD. There is a close crosstalk between autophagy and inflammation. Lysosomes promote the degradation of AGEs).

Figure 2

Autophagy as a therapeutic target in DKD. (Autophagy is inhibited in DKD. Autophagy-lysosome dysfunction mediates podocyte injury leading to glomerulosclerosis and massive proteinuria and mediates renal proximal tubular epithelial cells injury aggravating renal fibrosis, and mediates mesangial cell injury and endothelial-to-mesenchymal transition promoting the production of mesangial matrix and aggravating glomerulosclerosis and proteinuria. In addition, inhibition of macrophage autophagy aggravated renal inflammation leading to glomerulosclerosis, proteinuria, and renal fibrosis).

Figure 3

Polyphenols are used to regulate autophagy in DKD. (Natural polyphenols are potential autophagy regulators. Polyphenols are mainly through the SIRT1 pathway, mTOR pathway, and AMPK pathway is involved in the regulation of various links of autophagy. In addition, polyphenols can also improve the autophagy-lysosome pathway by activating TFEB and promoting its nuclear translocation. In conclusion, polyphenols play an important role in improving DKD by regulating autophagy-lysosome pathway to improve renal inflammation, lipid metabolism, mitochondrial homeostasis, apoptosis, and fibrosis.