Methylglyoxal induces apoptosis through activation of p38 mitogen-activated protein kinase in rat mesangial cells

Liu, Bing-Fen; Miyata, Satoshi; Hirota, Yushi; Higo, Satomi; Miyazaki, Hiroyuki; Fukunaga, Michiru; Hamada, Y.; Ueyama, Shigemitsu; Muramoto, Osamu; Uriuhara, Atsuko; Kasuga, Masato

doi:10.1046/j.1523-1755.2003.00829.x

Cited by 116 publications

(92 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Renal p38 in experimental diabetes R Komers et al lation of products of glycation reactions, and oxidative stress, have been shown to induce p38 signaling in mesangial cells, podocytes and in proximal tubular cells in vitro. 3,16,[23][24][25] In agreement with these findings, present studies, conducted in more clinically relevant settings, show that poor metabolic control is the major determinant of p38 activity in the diabetic kidney. Our findings are also in agreement with limited in vivo evidence in the setting of Type 1 diabetes, suggesting increased expression of P-p38 protein expression in wholekidney homogenates harvested from mice early after induction of STZ-diabetes.…”

Section: Renal P38 In Experimental Diabetessupporting

confidence: 90%

“…These mechanisms could include deleterious effects such as activation of the renin-angiotensin system, 14,23,37 oxidative stress, 37 extracellular matrix (ECM) production and cellular hypertrophy, 2 induction of growth cytokines, 2,3 mesangial and podocyte apoptosis, 16,24 and glucose-induced 12-lipooxygenase pathway signaling, 22 as well as possibly protective effects. such as cytoskeleton reorganization in podocytes that temporarily prevents the development of albuminuria.…”

Section: Renal P38 In Experimental Diabetesmentioning

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: 90%

Section: Renal P38 In Experimental Diabetesmentioning

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

“…19,[22][23][24] The absence of these effects in our study suggests that these diabetic factors induce their cellular effects independently of their ability to modify collagen IV.…”

mentioning

confidence: 55%

Modification of Collagen IV by Glucose or Methylglyoxal Alters Distinct Mesangial Cell Functions

Pozzi¹,

Zent

Chetyrkin³

et al. 2009

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

“…One of the primary signalling pathways through which apoptosis is induced is the MAP kinase pathway. It has been shown that advanced glycation endproducts induce apoptosis in Schwann and mesangial cells partly through p38 map kinase signalling (28,43). Another member of the MAP kinase family, JNK, has been shown to mediate apoptosis of other mediators including TNF-α (29,48).…”

Section: Resultsmentioning

confidence: 99%

Advanced glycation end products stimulate osteoblast apoptosis via the MAP kinase and cytosolic apoptotic pathways

Alikhani

Boyd

et al. 2007

Bone

311

220

View full text Add to dashboard Cite

We have previously shown that diabetes significantly enhances apoptosis of osteoblastic cells in vivo and that the enhanced apoptosis contributes to diabetes impaired new bone formation. A potential mechanism is enhanced apoptosis stimulated by advanced glycation endproducts (AGEs). To investigate this further, an advanced glycation product, carboxymethyl lysine modified collagen (CML-collagen) was injected in vivo and stimulated a 5 fold increase in calvarial periosteal cell apoptosis compared to unmodified collagen. It also induced apoptosis in primary cultures of human or neonatal rat osteoblastic cells or MC-3T3-E1 cells in vitro. Moreover, the apoptotic effect was largely mediated through RAGE receptor. CML-collagen increased p38 and JNK activity 3.2 and 4.4 fold, respectively. Inhibition of p38 and JNK reduced CML-collagen stimulated apoptosis by 45% and 59% and by 90% when used together (P<0.05). The predominant apoptotic pathway induced by CML-collagen involved caspase-8 activation of caspase-3 and was independent of NF-κB activation. When osteoblastic cells were exposed to a long-term low dose incubation with CMLcollagen there was a higher degree of apoptosis compared to short term incubation. In more differentiated osteoblastic cultures apoptosis was enhanced even further. These results indicate that advanced glycation endproducts, which accumulate in diabetic and aged individuals may promote apoptosis of osteoblastic cells and contribute to deficient bone formation.

show abstract

Methylglyoxal induces apoptosis through activation of p38 mitogen-activated protein kinase in rat mesangial cells

Abstract: These results suggest a potential role for MG in glomerular injury through p38 MAPK activation under diabetic conditions and may serve as a novel insight into the therapeutic strategies for diabetic nephropathy.

Cited by 116 publications

References 60 publications

Renal p38 MAP kinase activity in experimental diabetes

Renal p38 MAP kinase activity in experimental diabetes

Modification of Collagen IV by Glucose or Methylglyoxal Alters Distinct Mesangial Cell Functions

Advanced glycation end products stimulate osteoblast apoptosis via the MAP kinase and cytosolic apoptotic pathways

Contact Info

Product

Resources

About