A role for AMP-activated protein kinase in diabetes-induced renal hypertrophy

Abstract

We tested the hypothesis that AMP-activated protein kinase (AMPK), an energy sensor, regulates diabetes-induced renal hypertrophy. In kidney glomerular epithelial cells, high glucose (30 mM), but not equimolar mannitol, stimulated de novo protein synthesis and induced hypertrophy in association with increased phosphorylation of eukaryotic initiation factor 4E binding protein 1 and decreased phosphorylation of eukaryotic elongation factor 2, regulatory events in mRNA translation. These high-glucose-induced changes in protein synthesis were phosphatidylinositol 3-kinase, Akt, and mammalian target of rapamycin (mTOR) dependent and transforming growth factor-beta independent. High glucose reduced AMPK alpha-subunit theronine (Thr) 172 phosphorylation, which required Akt activation. Changes in AMP and ATP content could not fully account for high-glucose-induced reductions in AMPK phosphorylation. Metformin and 5-aminoimidazole-4-carboxamide-1beta-riboside (AICAR) increased AMPK phosphorylation, inhibited high-glucose stimulation of protein synthesis, and prevented high-glucose-induced changes in phosphorylation of 4E binding protein 1 and eukaryotic elongation factor 2. Expression of kinase-inactive AMPK further increased high-glucose-induced protein synthesis. Renal hypertrophy in rats with Type 1 diabetes was associated with reduction in AMPK phosphorylation and increased mTOR activity. In diabetic rats, metformin and AICAR increased renal AMPK phosphorylation, reversed mTOR activation, and inhibited renal hypertrophy, without affecting hyperglycemia. AMPK is a newly identified regulator of renal hypertrophy in diabetes.

AICAR ameliorates high-fat diet-associated pathophysiology in mouse and ex vivo models, independent of adiponectin

“…AICAR did not affect the total number of renal macrophages in the mouse model used, but rather shifted their phenotype towards resolution by reducing the percentage of CD11c + M1 macrophages. Collectively, this supports previous work from our group and others, demonstrating that AICAR attenuates both HFD-induced [12,13] and diabetes-induced [14,15] kidney disease. Importantly, in this study, we now also demonstrate that AICAR-mediated protection against kidney disease is independent of adiponectin.…”

“…Evidence from experimental models has shown that AICAR may attenuate metabolic [6][7][8], hepatic [9][10][11] and renal pathophysiology [12][13][14][15]. However, the use of AICAR could be compromised as some reports indicate that AICAR increases adiponectin production [13].…”

Resveratrol prevents renal lipotoxicity and inhibits mesangial cell glucotoxicity in a manner dependent on the AMPK–SIRT1–PGC1α axis in db/db mice

“…Restriction of energy intake augments insulin-stimulated PI3K activity in response to a physiological insulin concentration (60 μU/ml) [29]. In contrast, at the supraphysiological concentration of insulin, such as in db/db (more than 200 μU/ml) mice, PI3K would be activated in the kidney [44].…”

Reduced Krüppel-Like Factor 2 Aggravates Glomerular Endothelial Cell Injury and Kidney Disease in Mice with Unilateral Nephrectomy

“…20 Briefly, 10-week-old anesthetized mice were injected retroorbitally with dialyzed 5% fluorescein isothiocyanate-inulin. Blood was collected from the tail at 3,5,7,10,15,35,56, and 75 minutes after injection. Separated serum was buffered in 0.5 mol/L HEPES, pH 7.4, and fluorescence was measured as described previously.…”

“…3e9 Among KLF proteins, KLF2 is a key regulator of vascular hemodynamic forces in vivo 10 and mediates flowdependent phenotype in endothelial cells. 3,11 KLF2 has been shown to be essential in maintenance of endothelial integrity in adult mice 12 as well as in mouse embryonic vasculature.…”