Renal p38 MAP kinase activity in experimental diabetes

Radko Komers, Jessie N. Lindsley, Terry T. Oyama, David Cohen, Sharon Anderson

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

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-β-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.

Original languageEnglish (US)
Pages (from-to)548-558
Number of pages11
JournalLaboratory Investigation
Volume87
Issue number6
DOIs
StatePublished - Jun 2007

Fingerprint

p38 Mitogen-Activated Protein Kinases
Kidney
Dual Specificity Phosphatase 1
Diabetic Nephropathies
Mitogen-Activated Protein Kinase 6
Insulin
Albuminuria
Mitogen-Activated Protein Kinase 3
Experimental Diabetes Mellitus
Transforming Growth Factors
Mitogen-Activated Protein Kinases
Type 1 Diabetes Mellitus
Protein Kinases
Carrier Proteins
Phosphotransferases
Down-Regulation
Proteins

Keywords

  • Diabetic nephropathy
  • Hyperglycemia
  • p38 mitogen-activated protein kinase
  • Proteinuria
  • Signaling

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Renal p38 MAP kinase activity in experimental diabetes. / Komers, Radko; Lindsley, Jessie N.; Oyama, Terry T.; Cohen, David; Anderson, Sharon.

In: Laboratory Investigation, Vol. 87, No. 6, 06.2007, p. 548-558.

Research output: Contribution to journalArticle

Komers, Radko ; Lindsley, Jessie N. ; Oyama, Terry T. ; Cohen, David ; Anderson, Sharon. / Renal p38 MAP kinase activity in experimental diabetes. In: Laboratory Investigation. 2007 ; Vol. 87, No. 6. pp. 548-558.
@article{aa1d86cafd07496ab90a551f5295bb97,
title = "Renal p38 MAP kinase activity in experimental diabetes",
abstract = "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-β-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.",
keywords = "Diabetic nephropathy, Hyperglycemia, p38 mitogen-activated protein kinase, Proteinuria, Signaling",
author = "Radko Komers and Lindsley, {Jessie N.} and Oyama, {Terry T.} and David Cohen and Sharon Anderson",
year = "2007",
month = "6",
doi = "10.1038/labinvest.3700549",
language = "English (US)",
volume = "87",
pages = "548--558",
journal = "Laboratory Investigation",
issn = "0023-6837",
publisher = "Nature Publishing Group",
number = "6",

}

TY - JOUR

T1 - Renal p38 MAP kinase activity in experimental diabetes

AU - Komers, Radko

AU - Lindsley, Jessie N.

AU - Oyama, Terry T.

AU - Cohen, David

AU - Anderson, Sharon

PY - 2007/6

Y1 - 2007/6

N2 - 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-β-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.

AB - 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-β-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.

KW - Diabetic nephropathy

KW - Hyperglycemia

KW - p38 mitogen-activated protein kinase

KW - Proteinuria

KW - Signaling

UR - http://www.scopus.com/inward/record.url?scp=34249017571&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34249017571&partnerID=8YFLogxK

U2 - 10.1038/labinvest.3700549

DO - 10.1038/labinvest.3700549

M3 - Article

VL - 87

SP - 548

EP - 558

JO - Laboratory Investigation

JF - Laboratory Investigation

SN - 0023-6837

IS - 6

ER -