Role of nutrient-sensing signals in the pathogenesis of diabetic nephropathy

Abstract

Diabetic nephropathy is the leading cause of end-stage renal disease worldwide. The multipronged drug approach still fails to fully prevent the onset and progression of diabetic nephropathy. Therefore, a new therapeutic target to improve the prognosis of diabetic nephropathy is urgently required. Nutrient-sensing signals and their related intracellular machinery have evolved to combat prolonged periods of starvation in mammals; and these systems are conserved in the kidney. Recent studies have suggested that the activity of three nutrient-sensing signals, mTORC1, AMPK, and Sirt1, is altered in the diabetic kidney. Furthermore, autophagy activity, which is regulated by the above-mentioned nutrient-sensing signals, is also altered in both podocytes and proximal tubular cells under diabetic conditions. Under diabetic conditions, an altered nutritional state owing to nutrient excess may disturb cellular homeostasis regulated by nutrient-responsible systems, leading to exacerbation of organelle dysfunction and diabetic nephropathy. In this review, we discuss new findings showing relationships between nutrient-sensing signals, autophagy, and diabetic nephropathy and suggest the therapeutic potential of nutrient-sensing signals in diabetic nephropathy.

Figure 1

Nutrient-sensing signal and diseases. The three nutrients-sensing pathways, mTOR, AMPK, and Sirt1, independently and coordinately regulate organ metabolism in multiple organs. Their alterations are involved in the pathogenesis of obesity-related and age-related diseases.

Figure 2

Organelles, such as mitochondria, peroxisome, and ER, dysfunction causes accumulation of reactive oxygen species (ROS) and ER stress in diabetic kidney. Dietary restriction enhances autophagy-lysosomal degradation system, leading to cell or tissue homeostasis. Nutrient-sensing signal and organella maintenance in diabetic nephropathy (DN).