Protein kinase C signals thromboxane induced increases in fibronectin synthesis and TGF-β bioactivity in mesangial cells

Studer, Rebecca K.; Negrete, Hilmer; Craven, Patricia A.; DeRubertis, Frederick R.

doi:10.1038/ki.1995.310

Cited by 83 publications

(39 citation statements)

References 44 publications

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“…TGF-␤ mediates increases in collagen synthesis induced by other G-protein-coupled receptor agonists, including angiotensin II (40) and thromboxane (41). We determined the amount of active TGF-␤ present in the culture medium from untreated and des-Arg 10 -kallidin-treated fibroblasts using the bioassay in which MLEC growth was inhibited in a dose-dependent manner by active TGF-␤.…”

Section: Resultsmentioning

confidence: 99%

Des-Arg10-kallidin Engagement of the B1 Receptor Stimulates Type I Collagen Synthesis via Stabilization of Connective Tissue Growth Factor mRNA

Ricupero¹,

Romero²,

Rishikof³

et al. 2000

Journal of Biological Chemistry

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Expression of the kinin B1 receptor is up-regulated in chronic inflammatory and fibrotic disorders; however, little is known about its role in fibrogenesis. We examined human embryonic lung fibroblasts that constitutively express the B1 receptor and report that engagement of the B1 receptor by des-Arg 10 -kallidin stabilized connective tissue growth factor (CTGF) mRNA, stimulated an increase in ␣1(I) collagen mRNA, and stimulated type I collagen production. These events were not observed in B2 receptor-activated fibroblasts. In addition, B1 receptor activation by des-Arg 10 -kallidin induced a rise in cytosolic Ca 2؉ that is consistent with B1 receptor pharmacology. Our results show that the desArg 10 -kallidin-stimulated increase in ␣1(I) collagen mRNA was time-and dose-dependent, with a peak response observed at 20 h with 100 nM des-Arg 10 -kallidin. The increase in CTGF mRNA was also time-and dosedependent, with a peak response observed at 4 h with 100 nM des-Arg 10 -kallidin. The increase in CTGF mRNA was blocked by the B1 receptor antagonist desArg 10 ,Leu 9 -kallidin. Inhibition of protein synthesis by cycloheximide did not block the des-Arg 10 -kallidin-induced increase in CTGF mRNA. These results suggest that engagement of the kinin B1 receptor contributes to fibrogenesis through increased expression of CTGF.Kinins are involved in the regulation of a variety of physiological and cellular functions, including smooth muscle tone, pain perception, inflammation, and cellular proliferation (1, 2). Molecular biological and pharmacological studies have identified two G-protein-coupled kinin receptors, B1 and B2 (3-5). Activation of the B1 receptor induces cellular and physiological responses that often mimic the responses observed following activation of the B2 receptor. For instance, both receptors activate nuclear factor B in fibroblasts (6), modulate vascular tone (7), and activate phospholipase C in mesangial cells (8). However, receptor-specific physiological responses induced by the kinin receptors are demonstrated in the kinin-mediated bronchoconstriction of asthmatic airways. The B2 receptor agonists bradykinin (BK) 1 and kallidin (Lys-BK) are potent bronchoconstrictors (9), whereas the B1 receptor agonist des-Arg 10 -kallidin does not induce bronchoconstriction (10).The B2 receptor, the classical bradykinin receptor, is widely expressed and binds both BK and kallidin with high affinity. In wound repair, activation of the B2 receptor induces a variety of effects, including increased neutrophil proliferation, stimulation of macrophage spreading, release of histamine from mast cells, synthesis of platelet-activating factor and prostaglandins in endothelial cells, release of tachykinin and acetylcholine from sensory nerve endings, increased microvascular permeability, and fibroblast proliferation (2).Early studies described the B1 receptor as an inducible receptor whose expression is up-regulated following exposure to interleukin-1␤ or other pro-inflammatory agents (11). A recent study has identified expre...

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Section: Resultsmentioning

confidence: 99%

Des-Arg10-kallidin Engagement of the B1 Receptor Stimulates Type I Collagen Synthesis via Stabilization of Connective Tissue Growth Factor mRNA

Ricupero¹,

Romero²,

Rishikof³

et al. 2000

Journal of Biological Chemistry

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“…Recently, it was shown that normalizing levels of mitochondrial reactive oxygen species prevents the three major pathways caused by hyperglycemia: PKC, advanced glycation end products (AGEs), and the aldose reductase pathway (Nishikawa et al, 2000). PKC and AGEs have been shown to increase TGF-␤ expression in mesangial cells (Yang et al, 1994;Studer et al, 1995). Oxidative stress might stimulate TGF-␤-stimulated matrix synthesis in the glomeruli through the activation of PKC and AGE-mediated pathways.…”

Section: Discussionmentioning

confidence: 99%

Tranilast Prevents the Progression of Experimental Diabetic Nephropathy through Suppression of Enhanced Extracellular Matrix Gene Expression

Akatsuka¹,

Ota²,

Torita³

et al. 2005

J Pharmacol Exp Ther

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The present study was performed to investigate the effects of the antiallergic drug tranilast on the development of diabetic nephropathy in streptozotocin (50 mg/kg)-induced diabetic spontaneously hypertensive rats (SHR). Diabetic SHR were given standard chow or chow containing tranilast at a dose of 1400 mg/kg for 24 weeks. The effects of tranilast on urinary albumin excretion, mesangial expansion, expression of transforming growth factor-␤ (TGF-␤) and type I collagen mRNAs, number of anionic sites on the glomerular basement membrane (GBM), and urinary TGF-␤ and 8-hydroxy-2Ј-deoxyguanosine (8-OHdG) excretion were assessed. Tranilast did not affect the blood glucose concentration or blood pressure in diabetic SHR. Urinary albumin excretion rate and creatinine clearance were markedly increased in diabetic SHR. Tranilast treatment decreased albuminuria and hyperfiltration. Tranilast inhibited the diabetes-induced expansion of mesangial and tuft areas, as well as the increase in urinary TGF-␤ and 8-OHdG excretion, loss of anionic sites of GBM, and overexpression of TGF-␤ as determined immunohistochemically. The levels of TGF-␤ and type I collagen mRNA expression were increased in the renal cortex in untreated diabetic SHR at 24 weeks, as determined by real-time quantitative polymerase chain reaction. Tranilast treatment inhibited the up-regulation of TGF-␤ and type I collagen mRNA expression by 65 and 36%, respectively, in diabetic SHR. In conclusion, tranilast decreased albuminuria by suppressing glomerular hyperfiltration, mesangial expansion, and loss of the charge barrier via regulation of extracellular matrix gene expression and oxidative stress. Tranilast may be clinically useful in the treatment of diabetic nephropathy.

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“…Binding of Ang II to AT1 receptor stimulates PI-PLC, increases protein tyrosine phosphorylation, and activates Ras and several protein kinases, such as PI3K, PKC, MAP kinase, Ca 2ϩ /calmodulin kinase, and S6K (24,74). Previous studies propose an important role for PKC as an intracellular mediator of the effects of several hypertrophic growth stimuli (22), including mesangial cell FN production (75). In this study, we showed that Ang II-mediated expression of FN mRNA was inhibited by PKC inhibitors, suggesting that activation of PKC is involved in Ang II responses.…”

Section: Fig 8 Effect Of Inhibitors Of Pi-plc G I Ras Map Kinasmentioning

confidence: 99%

Mechanism of Angiotensin II-mediated Regulation of Fibronectin Gene in Rat Vascular Smooth Muscle Cells

Tamura

Nyui²,

Tamura

et al. 1998

Journal of Biological Chemistry

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Hemodynamic and endocrine factors are among the most important factors implicated in the physiology and pathophysiology of the vascular wall. Arterial hypertension evokes structural and functional changes of the vascular wall (1, 2). Modifications of the extracellular matrix, including fibronectin (FN) 1 and collagen, have been previously reported in vessel walls of hypertensive animals (3-5). Activation and qualitative changes in the extracellular matrix participate in vascular wall remodeling and in the pathogenesis of atherosclerosis. Vascular remodeling in hypertension may be an adaptive response to increased transmural pressure (6 -9). Mechanical stress seems to play a direct role in vascular remodeling, since mechanical stretch is able to increase protein synthesis by vascular smooth muscle cells (VSMCs) (10). However, neuronal and humoral factors may be critical in hypertension-induced remodeling of vascular wall. Especially, several in vivo studies have reported that hypertension activates the vascular renin-angiotensin system (RAS) including angiotensin-converting enzyme (ACE) (11), and infusion of pressor and subpressor doses of angiotensin II (Ang II) increases aortic FN mRNA in both hypertensive and normotensive animals (12, 13). Ang II evokes diverse physiological response including arterial vasoconstriction to elevate blood pressure in vivo (14) and increases production of collagen with a growth-promoting effect on VSMCs in vitro (15). Pharmacological evidence has defined at least two subtypes of Ang II receptors, Ang II type 1 (AT1) receptor and Ang II type 2 (AT2) receptor. Previous results of molecular cloning have revealed that both receptor subtypes belong to the superfamily of G protein-coupled receptors with seven transmembrane helices (16 -19). According to the recent results of in vitro studies, Ang II initially activates a phosphatidylinositol-specific phospholipase C (PI-PLC) via its binding to AT1 receptor on the surface of VSMCs, leading to the generation of inositol triphosphate and diacylglycerol (20), which are involved in intracellular Ca 2ϩ mobilization (21) and protein kinase C (PKC) activation (22), respectively. In VSMCs, Ang II also induces a rapid increase in expression of the growth-associated nuclear protooncogenes and stimulates tyrosine phosphorylation of multiple substrates (23, 24). These findings, taken together with relatively abundant expression of AT1 receptor in vascular wall and VSMCs, indicate that Ang II plays an important role in vascular remodeling via an AT1 receptor pathway. Thus, investigation of the mechanism of Ang II-induced regulation of extracellular matrix and tissue RAS in VSMCs is essential in elucidating the mechanism of vascular remodeling and the pathogenesis of atherosclerosis.In the present study, we examined the effects of Ang II on gene expression of extracellular matrix components (FN and

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Protein kinase C signals thromboxane induced increases in fibronectin synthesis and TGF-β bioactivity in mesangial cells

Cited by 83 publications

References 44 publications

Des-Arg10-kallidin Engagement of the B1 Receptor Stimulates Type I Collagen Synthesis via Stabilization of Connective Tissue Growth Factor mRNA

Des-Arg10-kallidin Engagement of the B1 Receptor Stimulates Type I Collagen Synthesis via Stabilization of Connective Tissue Growth Factor mRNA

Tranilast Prevents the Progression of Experimental Diabetic Nephropathy through Suppression of Enhanced Extracellular Matrix Gene Expression

Mechanism of Angiotensin II-mediated Regulation of Fibronectin Gene in Rat Vascular Smooth Muscle Cells

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