Sirtuins and renal diseases: relationship with aging and diabetic nephropathy

Abstract

Sirtuins are members of the Sir2 (silent information regulator 2) family, a group of class III deacetylases. Mammals have seven different sirtuins, SIRT1-SIRT7. Among them, SIRT1, SIRT3 and SIRT6 are induced by calorie restriction conditions and are considered anti-aging molecules. SIRT1 has been the most extensively studied. SIRT1 deacetylates target proteins using the coenzyme NAD+ and is therefore linked to cellular energy metabolism and the redox state through multiple signalling and survival pathways. SIRT1 deficiency under various stress conditions, such as metabolic or oxidative stress or hypoxia, is implicated in the pathophysiologies of age-related diseases including diabetes, cardiovascular diseases, neurodegenerative disorders and renal diseases. In the kidneys, SIRT1 may inhibit renal cell apoptosis, inflammation and fibrosis, and may regulate lipid metabolism, autophagy, blood pressure and sodium balance. Therefore the activation of SIRT1 in the kidney may be a new therapeutic target to increase resistance to many causal factors in the development of renal diseases, including diabetic nephropathy. In addition, SIRT3 and SIRT6 are implicated in age-related disorders or longevity. In the present review, we discuss the protective functions of sirtuins and the association of sirtuins with the pathophysiology of renal diseases, including diabetic nephropathy.

Figure 1. Therapeutic potential of sirtuins on diabetic nephropathy

Sirtuin dysfunction associated with aging and NAD⁺ depletion may contribute to the initiation and progression of diabetic nephropathy, in addition to hyperglycaemia-mediated alterations of metabolism and haemodynamic changes, including RAS abnormality. The therapeutic activation of sirtuins could inhibit diabetic nephropathy. Genetic factors also may contribute to the activity of sirtuins.

Figure 2. Enzymatic activities of sirtuins

(1) NAD⁺ is consumed as a substrate for the deacetylation of target proteins. The acetyl-lysine residues of the target protein serve as substrates for sirtuin deacetylation, which generate nicotinamide and 2′-O-acetyl-ADP-ribose (2′-OAADPr) as by-products. (2) NAD⁺ is also used as a substrate for the reaction of mono-ADP-ribosyl transferase with target proteins. ADP-ribose and nicotinamide are generated by the reaction.

Figure 3. Biological functions of SIRT1

SIRT1 promotes chromatin silencing through chromatin modification, mainly deacetylation, and regulates glucose and lipid metabolism, circadian rhythms, mitochondrial biogenesis, stress responses, apoptosis, inflammation and autophagy by deacetylating non-histone proteins, including transcription factors and transcriptional co-regulatory proteins.

Figure 4. Renoprotective effects of SIRT1

SIRT1 exerts renoprotective effects by conferring resistance to cellular stresses such as hypoxia, reducing interstitial fibrosis, inhibiting tubular and glomerular cell apoptosis and inflammation, inducing autophagy, and regulating Na⁺-handling, blood pressure and renal lipid metabolism.