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.

AMPK Potentiates Hypertonicity-induced Apoptosis by Suppressing NFκB/COX-2 in Medullary Interstitial Cells

“…27 Evidence has emerged that AMPK also has an important role in renal physiology and pathophysiology. 28 Several studies have demonstrated that energy sensing by AMPK may be a physiologically relevant mechanism by which renal tubular cells maintain tight coupling between energy metabolism and tubular transport. 29 Also, AMPK is renoprotective in attenuating renal hypertrophy in diabetic rats 30 and oxidative stress in podocytes.…”

Stanniocalcin-1 Inhibits Renal Ischemia/Reperfusion Injury via an AMP-Activated Protein Kinase-Dependent Pathway

“…AMPK regulates cellular metabolism and is a key component of the cellular adaptive responses to ischemia in the kidney. 19,20 Recent studies suggest that pretreatment with AMPK activators (5-aminoimidazol-4-carboxamide-1-b-d-ribofuranoside and metformin) may have a protective role in renal I/R injury. 21 We, therefore, hypothesized that STC1 protects from I/R through activation of AMPK.…”

Targeting AMPK for Therapeutic Intervention in Type 2 Diabetes

“…This is exemplified by renal nephropathy, myocardial disease, stroke, Alzheimer's and Parkinson's disease (Almdal et al, 2004;Biessels et al, 2006;Burdo et al, 2009;Hallows et al, 2010;Hu et al, 2007;Maher & Schubert, 2009;Schernhammer et al, 2011). Several drugs are currently used in the clinical setting to activate AMPK in patients suffering from type 2 diabetes or obesity.…”

“…Under some conditions, it could be desirable to preferentially modulate these processes that are associated with cytoplasmic AMPK targets. A possible example of such a scenario is the diabetic kidney (Cammisotto et al, 2008;Hallows et al, 2010;Lee et al, 2007;McMahon et al, 2009). Diabetes-induced renal hypertrophy correlates with diminished AMPK activity and, at the same time, with increased protein synthesis under high glucose conditions (Hallows et al, 2010).…”

“…A possible example of such a scenario is the diabetic kidney (Cammisotto et al, 2008;Hallows et al, 2010;Lee et al, 2007;McMahon et al, 2009). Diabetes-induced renal hypertrophy correlates with diminished AMPK activity and, at the same time, with increased protein synthesis under high glucose conditions (Hallows et al, 2010). AICAR and metformin reduce protein synthesis triggered by high glucose , but these compounds also produce effects that are unrelated to AMPK activation (Mantovani & Roy, 2011).…”