Sirtuins play critical and diverse roles in acute kidney injury

Abstract

Acute kidney injury (AKI) is an extremely common medical affliction affecting both adult and pediatric patients resulting from hypoxic, nephrotoxic, and septic insults affecting approximately 20% of all hospital patients and up to 50% of patients in the intensive care unit. There are currently no therapeutics for patients who suffer AKI. Much recent work has focused on designing and implementing therapeutics for AKI. This review focuses on a family of enzymes known as sirtuins that play critical roles in regulating many cellular and biological functions. There are 7 mammalian sirtuins (SIRT1-7) that play roles in regulating the acylation of a wide variety of pathways. Furthermore, all but one of the mammalian sirtuins have been shown to play critical roles in mediating AKI based on preclinical studies. These diverse enzymes show exciting potential for therapeutic manipulation. This review will focus on the specific roles of each of the investigated sirtuins and the potential for manipulation of the various sirtuins and their effector pathways in mediating kidney injury.

Keywords: AKI; Acute kidney injury; Acylation; Metabolism; Sirtuins; Therapy.

Fig. 1

Sirtuin roles in limiting kidney injury. Sirtuins are expressed in different subcellular compartments and regulate different cellular and biological functions to impact kidney injury. SIRT3 and SIRT5 are mitochondrial sirtuins. SIRT3 maintains mitochondrial dynamics and energy homeostasis and promotes autophagy. SIRT5 is involved in fatty acid oxidation and energy metabolism. SIRT1, SIRT6, and SIRT7 are nuclear sirtuins. SIRT1 has a strong role in maintaining mitochondria as well as in regulating apoptosis. SIRT6 is important for the maintenance of podocyte and glomerular function. SIRT 7 is involved in inflammation through regulation of NF-κB. SIRT2 shuttles between the nucleus and cytoplasm. Nuclear SIRT2 regulates MKP-1 to promote inflammation. Sirtuins in green font are renoprotective, whereas those in red font were renoprotective when deleted. Only Sirt4 has not been studied in the context of kidney injury