Control of glycogen synthase through ADIPOR1-AMPK pathway in renal distal tubules of normal and diabetic rats

Am J Physiol Renal Physiol. 2008 Apr;294(4):F881-9. doi: 10.1152/ajprenal.00373.2007. Epub 2008 Feb 6.

Abstract

Diabetic nephropathies are characterized by glycogen accumulation in distal tubular cells, which eventually leads to their apoptosis. The present study aims to determine whether adiponectin and AMPK are involved in the regulation of glycogen synthase (GS) in these structures. Western blots of isolated distal tubules revealed the presence of adiponectin receptor ADIPOR1, catalytic AMPK subunits alpha(1) and alpha(2), their phosphorylated active forms, and the glycogen-binding AMPK subunit beta(2). ADIPOR2 was not detected. Expression levels of ADIPOR1, AMPKalpha(1), AMPKalpha(2), and AMPKbeta(2) were increased in streptozotocin-treated diabetic rats, whereas phosphorylated active AMPK levels were strongly decreased. Immunohistochemistry revealed the presence of ADIPOR1 on the luminal portion of distal tubules and thick ascending limb cells. Catalytic subunits alpha(1) and alpha(2), their phosphorylated active forms, and the glycogen-binding subunit beta(2) were also found in the same cells, confirming immunoblot results. In vitro, 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR; 2 mM) and globular adiponectin (10 mug/ml) activated catalytic AMPK in distal tubules isolated from kidneys of normal rats but much more weakly in those from diabetic rats. GS inhibition paralleled AMPK activation in both groups of animals: active GS levels were low in control animals and elevated in diabetic ones. Finally, glucose-6-phosphate, an allosteric activator of GS, was also increased in diabetic rats. These results demonstrate that in distal tubular cells, adiponectin through luminal ADIPOR1 activates AMPK, leading to the inhibition of GS. During hyperglycemia, this regulation is altered, which may explain, at least in part, the accumulation of large glycogen deposits.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenylate Kinase / drug effects
  • Adenylate Kinase / metabolism*
  • Adiponectin / pharmacology*
  • Aminoimidazole Carboxamide / analogs & derivatives*
  • Aminoimidazole Carboxamide / pharmacology
  • Animals
  • Diabetes Mellitus, Experimental / enzymology
  • Diabetes Mellitus, Experimental / physiopathology*
  • Glycogen Synthase / antagonists & inhibitors
  • Glycogen Synthase / drug effects
  • Glycogen Synthase / metabolism*
  • Immunohistochemistry
  • Kidney / drug effects
  • Kidney / pathology
  • Kidney Tubules, Distal / drug effects
  • Kidney Tubules, Distal / enzymology
  • Kidney Tubules, Distal / physiopathology*
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Adiponectin / drug effects
  • Receptors, Adiponectin / metabolism*
  • Ribonucleotides / pharmacology*

Substances

  • Adiponectin
  • Receptors, Adiponectin
  • Ribonucleotides
  • adiponectin receptor 1, rat
  • Aminoimidazole Carboxamide
  • Glycogen Synthase
  • Adenylate Kinase
  • AICA ribonucleotide