Renal activity of Akt kinase in experimental Type 1 diabetes.
Akt kinase regulates numerous cell functions including glucose metabolism, cell growth, survival, protein synthesis, and control of local hemodynamics. mTOR is one of down-stream effectors of Akt involved in the initiation of protein translation. However, renal Akt signaling in Type 1 diabetes (DM) in vivo, in particular under the conditions reflecting differences in metabolic control, has received less attention. Renal cortical activity and expression of Akt and mTOR (kinase assay, western blotting) were determined in streptozotocin-diabetic rats (D) with different levels of glycemic control (blood glucose 22.0+/-1.0, 13.4+/-1.5, 8.1+/-0.4 mmol/l, p<0.05 between the groups), achieved by varying insulin treatment (0, 4 and 12 IU/day), and in control rats with (C4) or without (C) chronic insulin administration. Renal Akt activity was reduced in D rats without insulin treatment and severe hyperglycemia (D-0, -62 %, p<0.01 vs. C), partially restored in moderately hyperglycemic rats (D-4, -30 %, p<0.05 vs. C), and normalized in D rats with intensive insulin and tight metabolic control (D-12). Expression of active mTOR paralleled Akt activity in D-0 (-51 %, p<0.01 vs. C), but not in D-4 and D-12 that demonstrated increases in active mTOR (+55 %, +80 % resp., p<0.05) as compared to C. Moreover, insulin activated renal Akt (+82 %, p<0.01), but not mTOR in C4. In conclusion, glycemic control and intensity of insulin treatment are important modulators of renal Akt and mTOR activity in diabetes. While Akt activity is reversible by tight metabolic control, combination of hyperglycemia and insulin treatment resulted in enhancement of mTOR activity. In addition to Akt, other signaling pathways likely contribute to regulation of renal mTOR activity in diabetes.
Ždychová
J
J
Diabetes Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
Veselá
J
J
Kazdová
L
L
Komers
R
R
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy / Q000201:enzymology*; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000188:drug therapy / Q000201:enzymology*; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology; D004305:Dose-Response Relationship, Drug; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007328:Insulin / Q000097:blood / Q000627:therapeutic use; D007672:Kidney Cortex / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3