Activation of mesangial cell MAPK in responseto homocysteine

Ingram, Alistair J.; Krepinsky, Joan C.; James, Leighton R.; Austin, Richard C.; Tang, Damu; Salapatek, Anne Marie; Thai, Kerri; Scholey, James W.

doi:10.1111/j.1523-1755.2004.00795.x

Cited by 42 publications

(37 citation statements)

References 70 publications

(87 reference statements)

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“…The role of ERK1/2 in the transduction of proliferative signals to the nucleus in MCs and cardiac fibroblasts is well known (22,41,43). In accordance with previously published data (34,44), our results demonstrate that Aldo-induced MC proliferation depends, in part, on ERK1/2 phosphorylation, because blocking ERK1/2 activation by PD98059 inhibited Aldo-induced cell proliferation.…”

Section: Discussionsupporting

confidence: 81%

Aldosterone-induced mesangial cell proliferation is mediated by EGF receptor transactivation

Huang

Zhang²,

Ding³

et al. 2009

American Journal of Physiology-Renal Physiology

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Huang S, Zhang A, Ding G, Chen R. Aldosterone-induced mesangial cell proliferation is mediated by EGF receptor transactivation. Am J Physiol Renal Physiol 296: F1323-F1333, 2009. First published April 1, 2009 doi:10.1152/ajprenal.90428.2008.-Aldosterone (Aldo) stimulates glomerular mesangial cell (MC) proliferation, in part, through an ERK1/2-dependent pathway. In this study, we examined whether Aldo activation of ERK1/2 in MC is mediated through redox-dependent EGF receptor (EGFR) transactivation, as well as the involvement of other signaling mechanisms in Aldo-induced MC proliferation. Aldo increased human MC proliferation, as determined by [3 H]thymidine incorporation and cell counts. This increase in proliferation was blocked by inhibition of the mineralocorticoid receptor (MR). Continuing our observations downstream in the signaling pathway, we examined the ability of Aldo to activate both the Ras/MAPK and the PI3K signaling pathways. Aldo increased Ki-RasA and Ki-RasA:GTP levels, and sequentially phosphorylated c-Raf, MAPK kinase (MEK1/ 2), and ERK1/2. Ki-RasA small interfering RNA (siRNA), the c-Raf inhibitor GW5074, and the MEK1/2 inhibitor PD98059 reduced Aldo-induced cell proliferation by ϳ65%. Aldo also increased phosphorylation of PI3K, Akt, the mammalian target of rapamycin (mTOR), and the 70-kDa ribosomal S6 kinase (p70S6K1). Inhibition of the PI3K pathways by the selective PI3K inhibitor LY 294002, an Akt inhibitor, or the mTOR inhibitor rapamycin reduced cell proliferation by 51%. Combining LY 294002 and PD98059 completely blocked Aldo-induced MC proliferation. Next, we confirmed that Aldo exerts its effect on MAPK and PI3K activation, as well as on cell proliferation, by activating the EGFR. Pretreatment with the EGFR antagonist AG1478 inhibited MC proliferation, as well as the activation of Ras/MAPK and PI3K/Akt, suggesting that Ras/MAPK and PI3K/Akt activation occur downstream of EGFR activation. Finally, we examined the role of reactive oxygen species (ROS) in Aldoinduced transactivation of the EGFR. Aldo-induced ROS were predominantly generated by mitochondria. Pretreatment with the antioxidant N-acetyl-L-cysteine, catalase, SOD, mitochondrial respiratory chain complex I inhibitor rotenone (Rot), NADPH oxidase inhibitor apocynin, and DPI significantly inhibited Aldo-stimulated MC proliferation as well as EGFR transactivation. However, Rot reduced MC proliferation more potently than apocynin and DPI. In conclusion, Aldo stimulated cell proliferation through MR-mediated, redox-sensitive EGFR transactivation, which was dependent on the Ki-RasA/ c-Raf/MEK/ERK and PI3K/Akt/mTOR/p70S6K1 signaling pathways in human MCs. reactive oxygen species; PI3KA GROWING BODY OF EVIDENCE suggests that the mineralocorticoid aldosterone (Aldo), a key regulator of blood pressure and electrolytic balance, contributes to the development and progression of cardiovascular disease and chronic kidney disease (CKD), by reducing vascular compliance, as well as promoting endothelial dysfunction and myocardial and renal hy...

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Section: Discussionsupporting

confidence: 81%

Aldosterone-induced mesangial cell proliferation is mediated by EGF receptor transactivation

Huang

Zhang²,

Ding³

et al. 2009

American Journal of Physiology-Renal Physiology

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“…It is well known that alteration in mesangial cell function is important to the progression of glomerular disease. Numerous models of chronic renal failure including hHcys-induced glomerular injury are characterized by mesangial cell proliferation and elaboration of extracellular matrix protein resulting in glomerulosclerosis [6, 14]. In agreement with a deterioration in albuminia, histological examinations in this study showed that the glomerular mesangium was expanded with glomerular hypercellularity, capillary collapse and fibrous deposition in the rats with hHcys.…”

Section: Discussionsupporting

confidence: 69%

Podocyte Injury and Glomerulosclerosis in Hyperhomocysteinemic Rats

Yi¹,

Santos²,

Xia³

et al. 2007

Am J Nephrol

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Background/Aims: We previously reported that increase in plasma homocysteine (Hcys) levels by a 6-week methionine treatment produced remarkable glomerular injury. However, the mechanism by which hyperhomocysteinemia (hHcys) produces glomerular injury remains unknown. The present study was to observe when glomerular injury happens during hHcys and to explore the possible role of podocyte injury in the progression of glomerulosclerosis associated with hHcys. Methods: Uninephrectomized Sprague-Dawley rats treated with methionine were used to examine the time course of glomerular injury induced by hHcys. Results: Creatinine clearance was not different until rats were treated with methionine for 6 weeks, although plasma Hcys levels significantly increased at the 1st week of methionine treatment. However, urinary albumin excretion increased at the 2nd week of methionine treatment. Morphological examinations showed that mesangial expansion occurred at the 2nd week and podocyte effacement was also observed as processed glomerular damage during hHcys. Immunofluorescence analyses demonstrated that podocin and nephrin expressions were reduced, while α-actinin-4 increased during hHcys. Conclusions: Increased plasma Hcys level is an important pathogenic factor resulting in glomerular injury even in the very early time of hHcys. These pathogenic effects of Hcys are associated with podocyte injury and changed expression and distribution of podocyte-associated proteins.

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“…Recent studies demonstrated that ERK1/2 participates in MC proliferation in vitro and regulates renal activity in experimental glomerulonephritis (13,34). These studies proposed that ERK is of vital importance in cell cycle regulation.…”

Section: Discussionmentioning

confidence: 99%

Activation of ERK1/2 by NADPH oxidase-originated reactive oxygen species mediates uric acid-induced mesangial cell proliferation

Zhuang

Feng

Ding

et al. 2014

American Journal of Physiology-Renal Physiology

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A, Huang S. Activation of ERK1/2 by NADPH oxidase-originated reactive oxygen species mediates uric acid-induced mesangial cell proliferation. Am J Physiol Renal Physiol 307: F396-F406, 2014. First published February 26, 2014 doi:10.1152/ajprenal.00565.2013.-Hyperuricemia is associated with kidney complications including glomerulosclerosis and mesangial cell (MC) proliferation by poorly understood mechanisms. The present study investigated the underlying mechanisms that mediate uric acid (UA)-induced MC proliferation. A rat MC line, HBZY-1, was treated with various concentrations of UA in the presence or absence of a specific extracellular-regulated protein kinase 1/2 (ERK1/2) inhibitor (U0126), apocynin. UA dose dependently stimulated MC proliferation as shown by increased DNA synthesis and number of cells in the S and G 2 phases in parallel with the upregulation of cyclin A2 and cyclin D1. In addition, UA time dependently promoted MC proliferation and significantly increased phosphorylation of ERK1/2 but not c-Jun NH 2-terminal kinase and p38 MAPK in MCs as assessed by immunoblotting. Inhibition of ERK1/2 signaling via U0126 markedly blocked UA-induced MC proliferation. More importantly, UA induced intracellular reactive oxygen species (ROS) production of MCs dose dependently, which was completely blocked by apocynin, a specific NADPH oxidase inhibitor. Toll-like receptor (TLR)2 and TLR4 signaling had no effect on NADPH-derived ROS and UA-induced MC proliferation. Interestingly, pretreatment with apocynin inhibited ERK1/2 activation, the upregulation of cyclin A2 and cyclin D1, and MC proliferation. In conclusion, UA-induced MC proliferation was mediated by NADPH/ROS/ERK1/2 signaling pathway. This novel finding not only reveals the mechanism of UAinduced MC cell proliferation but also provides some potential targets for future treatment of UA-related glomerular injury.

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Activation of mesangial cell MAPK in responseto homocysteine

Cited by 42 publications

References 70 publications

Aldosterone-induced mesangial cell proliferation is mediated by EGF receptor transactivation

Aldosterone-induced mesangial cell proliferation is mediated by EGF receptor transactivation

Podocyte Injury and Glomerulosclerosis in Hyperhomocysteinemic Rats

Activation of ERK1/2 by NADPH oxidase-originated reactive oxygen species mediates uric acid-induced mesangial cell proliferation

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