Lipotoxicity, Nutrient-Sensing Signals, and Autophagy in Diabetic Nephropathy

Abstract

Diabetic nephropathy is a leading cause of proteinuria, kidney fibrosis, and subsequent end-stage renal disease. The renal prognosis of diabetic patients with refractory proteinuria is extremely poor. Therefore, identification of novel therapeutic targets to combat this serious condition and improve renal prognosis is urgently necessary. In diabetic patients, in addition to blood glucose levels, serum levels of free fatty acids (FFAs) are chronically elevated, even during postprandial periods. Of the various types of FFAs, saturated FFAs are highly cytotoxic and their levels are elevated in the serum of patients with diabetes. Thus, an increase in saturated FFAs is currently thought to contribute to proximal tubular cell damage and podocyte injury in diabetic nephropathy. Therefore, protecting both types of kidney cells from saturated FFA-related lipotoxicity may become a novel therapeutic approach for diabetic patients with refractory proteinuria. Interestingly, accumulating evidence suggests that controlling intracellular nutrient signals and autophagy can ameliorate the FFA-related kidney damage. Here, we review the evidence indicating possible mechanisms underlying cell injury caused by saturated FFAs and cell protective roles of intracellular nutrient signals and autophagy in diabetic nephropathy.

Keywords: Free fatty acid; autophagy; lipotoxicity; podocyte; proteinuria; proximal tubular cell.

Figure 1.

Glucose and free fatty acid (FFA) metabolism during fasting, the postprandial period, and diabetes. Insulin’s physiological action in glucose and lipid metabolism includes enhancing glucose uptake, glycogen synthesis and lipogenesis in peripheral tissues such as skeletal muscle and the liver and stopping gluconeogenesis in the liver and FFA release from adipose tissue. Thus, during fasting, decreased insulin secretion stimulates glucose production via gluconeogenesis in the liver and FFA release from adipose tissue and inhibits glucose utilization by skeletal muscle (left). In contrast, postprandial increases in insulin secretion stimulate glucose uptake, glucose utilization, and lipogenesis and inhibit FFA release (middle). In diabetes, insufficient insulin action due to insulin resistance and/or deficient insulin secretion causes hyperglycemia and sustained FFA release even during postprandial periods. Thus, hyperglycemia accompanied by sustained high levels of plasma FFA is a unique metabolic alteration only shown in diabetes (right). Hyperglycemia due to loss of insulin action to the liver and skeletal muscle has long been focused as a pathogenesis of diabetic vascular complications. Higher plasma FFA due to loss of insulin action to adipose tissue is another specific metabolic alteration in diabetes, which has been recently focused as a pathogenic factor in diabetic complications including nephropathy.

Figure 2.

Proposal mechanism underlying saturated free fatty acids-induced cell damage. Saturated FFAs damage proximal tubular cells via multiple mechanisms such as DAG-PKCθ pathway, TLR4-dependent pathway, oxidative stress, and ER stress (left). In addition to unsaturated FFAs, several agonists or other methods to activate certain molecules and cellular system including autophagy can antagonize cell damage by saturated FFAs. Similarly, saturated FFAs damage podocytes via activation of TLR4 and mTORC1 signal (right). Unsaturated FFAs, mTORC1 inhibitor, and autophagy activation may be useful to prevent the damage. FFAs, free fatty acids; DAG, diacylglycerol; PKC, protein kinase C; TLR4, toll-like receptor 4; 1-MNA, 1-methylnicotinamide. SIRT; silent information regulator; ER, endoplasmic reticulum; PPAR, peroxisome proliferator-activated receptor.