Role of the energy sensor AMP-activated protein kinase in renal physiology and disease

Abstract

The ultrasensitive energy sensor AMP-activated protein kinase (AMPK) orchestrates the regulation of energy-generating and energy-consuming pathways. AMPK is highly expressed in the kidney where it is reported to be involved in a variety of physiological and pathological processes including ion transport, podocyte function, and diabetic renal hypertrophy. Sodium transport is the major energy-consuming process in the kidney, and AMPK has been proposed to contribute to the coupling of ion transport with cellular energy metabolism. Specifically, AMPK has been identified as a regulator of several ion transporters of significance in renal physiology, including the cystic fibrosis transmembrane conductance regulator (CFTR), the epithelial sodium channel (ENaC), the Na(+)-K(+)-2Cl(-) cotransporter (NKCC), and the vacuolar H(+)-ATPase (V-ATPase). Identified regulators of AMPK in the kidney include dietary salt, diabetes, adiponectin, and ischemia. Activation of AMPK in response to adiponectin is described in podocytes, where it reduces albuminuria, and in tubular cells, where it reduces glycogen accumulation. Reduced AMPK activity in the diabetic kidney is associated with renal accumulation of triglyceride and glycogen and the pathogenesis of diabetic renal hypertrophy. Acute renal ischemia causes a rapid and powerful activation of AMPK, but the functional significance of this observation remains unclear. Despite the recent advances, there remain significant gaps in the present understanding of both the upstream regulating pathways and the downstream substrates for AMPK in the kidney. A more complete understanding of the AMPK pathway in the kidney offers potential for improved therapies for several renal diseases including diabetic nephropathy, polycystic kidney disease, and ischemia-reperfusion injury.

Fig. 1.

Structural features of AMP-activated protein kinase (AMPK) subunit isoforms. Known phosphorylation sites are shown. The midsection of the β-subunit contains a carbohydrate binding module (CBM). Regulation of AMPK by AMP is explained by the binding of AMP to the Bateman domains of the γ-subunit. Each Bateman domain consists of 2 cystathione-β-synthase (CBS) domains. Various phosphorylated residues in the α- and β-subunits are shown, including the Thr-172 site, which must be phosphorylated by upstream kinases for AMPK to have catalytic activity.

Fig. 2.

Proposed role for AMPK in the kidney in coupling catabolic pathways requiring ATP hydrolysis (primarily sodium transport) with metabolic pathways leading to ATP synthesis (primarily fatty acid and glucose oxidation). +, Activating pathway; −, inhibitory pathway.