Renal p38 MAP kinase activity in experimental diabetes.
Renal cell activity of p38 mitogen-activated protein kinase (p38) is increased in the diabetic milieu. p38 mediates signals relevant for the development of diabetic nephropathy (DN). However, renal p38 in Type 1 diabetes in vivo, particularly in conditions reflecting the differences in metabolic control, and its activity in advanced stages of DN, has received less attention. We examined the p38 pathway in renal cortex of rats with streptozotocin diabetes (4 weeks) with poor (DS), moderate (DM), and intensive (DII) metabolic control, achieved by varying doses of insulin therapy. Renal p38 was also studied in 12-month diabetic rats with established nephropathy (DM12) and compared with age-matched controls. p38 activity (in vitro kinase assay and expression of phosphorylated (active) p38 (P-p38)) was increased in DM and DS rats, as compared with non-diabetic controls, and attenuated by intensive insulin treatment. In all groups, P-p38 was predominantly localized in macula densa cells. Diabetic rats also demonstrated P-p38 immunoreactivity in the distal tubule and glomeruli. Enhanced p38 activity in DS and DM rats was not associated with increases in expression of active mitogen-activated protein kinase 3/6, an activator of p38, but paralleled with increased expression of scaffolding protein transforming growth factor-beta-activated protein kinase 1-binding protein 1. Expression of mitogen-activated protein phosphatase-1 (MKP-1), one of the phosphatases involved in inactivation of mitogen-activated protein kinase signaling, was increased in all diabetic groups, irrespective of metabolic control. Renal p38 activation was also detectable in D12 rats with established albuminuria and glomerulosclerosis. In summary, renal cortical p38 activity was increased in diabetic rats at early and advanced stages of nephropathy, as compared with non-diabetic animals, and attenuated by improved metabolic control. p38 activation in diabetes is likely to occur via multiple pathways and cannot be explained by downregulation of MKP-1.
Komers
Radko
R
Division of Nephrology and Hypertension, Oregon Health and Science University, Portland, OR 97239-2940, USA. komersr@ohsu.edu
Lindsley
Jessie N
JN
Oyama
Terry T
TT
Cohen
David M
DM
Anderson
Sharon
S
D051698:Activating Transcription Factor 2 / Q000032:analysis; D000419:Albuminuria; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005500:Follow-Up Studies; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007150:Immunohistochemistry; D007328:Insulin / Q000627:therapeutic use; D007672:Kidney Cortex / Q000201:enzymology* / Q000473:pathology; D007678:Kidney Glomerulus / Q000201:enzymology* / Q000378:metabolism; D007686:Kidney Tubules, Distal / Q000201:enzymology* / Q000473:pathology; D008297:Male; D010766:Phosphorylation; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D016896:Treatment Outcome; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D051698:Activating Transcription Factor 2; C497107:Atf2 protein, rat; D007004:Hypoglycemic Agents; D007328:Insulin; D048051:p38 Mitogen-Activated Protein Kinases