Involvement of extracellular signal-regulated kinase and p38 in human diabetic nephropathy

Sakai, Norihiko; Wada, Takashi; Furuichi, Kengo; Iwata, Yasunori; Yoshimoto, Keiichi; Kitagawa, Kiyoki; Kokubo, Satoshi; Kobayashi, Motoo; Hara, Akinori; Yamahana, Junya; Okumura, Tomoko; Takasawa, Kazuya; Takeda, Shin‐ichi; Yoshimura, Mitsuhiro; Kida, Hiroshi; Yokoyama, Hitoshi

doi:10.1053/j.ajkd.2004.08.039

Cited by 148 publications

(107 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The observed increases in renal cortical p38 activity and expression are attributable to the large tubular pool of the kinase. This notion is supported by the available immunohistochemical findings in established human Type 2 diabetic nephropathy 17,18 and in STZ-diabetic mice 8 months after induction of diabetes, 17 suggesting a substantial tubular pool of active kinase.…”

Section: Renal P38 In Experimental Diabetessupporting

confidence: 70%

“…2,15 However, in Type 2 diabetic patients with biopsy-proven nephropathy, p38 immunoreactivity localized both in glomerular and nonglomerular renal compartments, suggesting that renal cortical p38 activation could be detected even in more advanced stages of the disease. 17,18 Thus, whether p38 activation could be detected in advanced stages of the disease in Type 1 diabetes remains to be elucidated.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Renal p38 MAP kinase activity in experimental diabetes

Komers

Lindsley

Oyama

et al. 2007

Laboratory Investigation

View full text Add to dashboard Cite

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-b-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 High glucose concentrations, and potentially other factors in the diabetic milieu, trigger pathophysiological signals mediated by the activation of specific kinase cascades. Altered activation of mitogen-activated protein (MAP) kinases (MAPK) occurs under these conditions and results in a broad spectrum of acute and long-term effects including mobilization of intracellular calcium and induction of gene expression. 1 In the kidney, such aberrant activation of MAPK cascades may perturb the balance of humoral and cytokine systems responsible for regulating vascular tone, permeability, renal cellular growth, and composition of the extracellular/mesangial matrix (ie, factors associated with the development of diabetic nephropathy). 2,3 p38 mitogen-activated protein kinase (p38), a member of the MAPK family, is activated by a number of stimuli. As a stress-activated kinase, p38 is activated by physical and ch...

show abstract

Section: Renal P38 In Experimental Diabetessupporting

confidence: 70%

mentioning

confidence: 99%

Renal p38 MAP kinase activity in experimental diabetes

Komers

Lindsley

Oyama

et al. 2007

Laboratory Investigation

View full text Add to dashboard Cite

show abstract

“…Phosphorylated p38-positive cells in patients with diabetic nephropathy reflects the severity of tubulointerstitial lesions. 32 Phosphorylated p38 is also detected in interstitial cells of mouse models. 33 NF-kB was identified (b) MCP-1 protein expression in Mdk À/À TEC exposed to 100 ng/ml MK was equal to that in Mdk þ / þ under high glucose conditions.…”

Section: Discussionmentioning

confidence: 99%

Midkine is involved in tubulointerstitial inflammation associated with diabetic nephropathy

Kosugi

Yuzawa

Sato

et al. 2007

Laboratory Investigation

View full text Add to dashboard Cite

The concept that inflammation plays a crucial role in the pathogenesis of diabetic nephropathy has been recently emerging, although the principal pathology of diabetic nephropathy comprises glomerular sclerosis and associated changes in nephrons. Here, we identified the growth factor midkine (MK) as a novel key molecule involved in inflammation associated with Streptozotocin-induced diabetic nephropathy. The tubulointerstitial damage, as assessed as morphological changes, osteopontin expression, collagen I deposition and macrophage infiltration, were strikingly less in MK-deficient (Mdk À/À ) mice than in Mdk þ / þ mice. Monocyte chemoattractant protein (MCP)-1 expression, but not that of intercellular adhesion molecule-1, was also lower in Mdk À/À mice. High glucose upregulated MK expression in primarycultured tubular epithelial cells, and induced MCP-1 to a larger extent in Mdk þ / þ cells than in Mdk À/À cells. Correspondingly, the combination of exogenous MK and high glucose enhanced MCP-1 expression in Mdk À/À cells. Furthermore, high glucose and oxidant stress enhanced MK expression in macrophages. Consistent with the findings in the mouse model, MK expression was detected in the glomeruli, tubular epithelium and interstitium of kidneys from patients with diabetic nephropathy. Our data indicate that MK plays a critical role in the tubulointerstitial inflammation associated with diabetic nephropathy through activation of the MCP-1 pathway.

show abstract

“…For patients with CreGN, the percentages of crescent formation were evaluated. For DN patients, the severity of the diffuse lesions of glomeruli was graded on a scale of 0 to IV as described previously [20]. For LN patients, ISN/RPS 2003 classification was used for light microscopic classification of LN.…”

Section: Pathological Studiesmentioning

confidence: 99%

“…Similarly, for evaluation of glomerulosclerosis, mean mesangial area (black on PAM staining) per glomerulus was examined from more 6 than 10 glomeruli using Mac Scope version 6.02 (Mitani Shoji Co., Ltd.) as reported previously [20].…”

Section: Pathological Studiesmentioning

confidence: 99%