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K Graf

Publications and source records attributed to K Graf.

At least 37 records · Page 2Linked to original sources
PubMed1999

Angiotensin II promotes integrin-mediated collagen gel contraction by adult rat cardiac fibroblasts.

Remodeling is a fundamental cardiac response to injury and involves cardiac fibroblast proliferation and extracellular matrix (ECM) production. Angiotensin II (Ang II) directly promotes these changes in cardiac fibroblasts and thus, plays critical roles in cardiac hypertrophy and wound healing. Osteopontin, fibronectin and laminin mRNA were detected in total RNA harvested from cultured adult rat cardiac fibroblasts. Immunocytochemistry staining of cultured adult rat cardiac fibroblasts grown on coverslips revealed the presence of beta 3 integrins on the surfaces of the cells. In the present study, we investigated the role of Ang II in a model of wound repair using floating collagen gels harboring adult rat cardiac fibroblasts, and we determined which members of the integrin family existed on these cells. The presence of either MPIIIB10, a monoclonal antibody against osteopontin (7.2 micrograms/ml) or RGD (arginine-glycine-aspartate) peptide (10(4) M) had no effect on gel contraction. Osteopontin itself induced gel contraction; however this effect was completely neutralized by MPIIIB10 (7.2 micrograms/ml, RGD peptide (10(4) M) and a monoclonal antibody against rat beta 3 integrin (25 micrograms/ml). We identified alpha v, beta 3 and beta 5 integrins on adult rat cardiac fibroblasts by fluorescence-activated cell sorting and confirmed that RGD peptide and an antibody against beta 3 integrin completely blocked osteopontin-induced gel contraction. These results suggest that Ang II promotes cardiac wound healing and remodeling processes by inducing expression of osteopontin and beta 3 integrin by cardiac fibroblasts.

Angiotensin II↗
PubMed1998

Mitogen-activated protein kinase activation mediates PDGF-directed migration of RPE cells.

Growth factor-directed migration is a critical component of the wound healing response although little is known about the signaling pathways involved. We examined the effect of inhibiting the mitogen-activated protein kinase (MAPK) pathway on platelet-derived growth factor (PDGF) and fibronectin-induced cell migration of human retinal pigment epithelial (RPE) cells. Using transwell cell-culture chambers, the effect of PDGF-BB (10-50 ng/ml) and fibronectin on components of migration was measured with or without the MAPK pathway inhibitor PD98059 (10-30 microM) MAPK activation of serum-starved cells by PDGF-BB was demonstrated by an immunoprecipitation/kinase assay and by immunohistochemistry using antibody specific for phosphorylated MAPK. PDGF-BB (10 ng/ml) stimulated MAPK activity in RPE (10 min) and its nuclear localization (1 h). PD98059 inhibited the activation of MAPK by PDGF-BB or serum. PDGF-BB stimulated RPE chemokinesis, chemotaxis, and haptotaxis; chemokinesis was additively increased and chemotaxis synergistically increased by the presence of a fibronectin substratum. PD98059 potently inhibited fibronectin-induced haptotaxis and PDGF-BB-induced chemotaxis but inhibited chemokinesis only at higher PDGF-BB (50 ng/ml) concentrations in the presence of fibronectin substratum. These results demonstrate that MAPK is critically involved in multiple components of RPE migration in vitro and suggest the potential of targeting MAPK to inhibit RPE migration in vivo.

Becaplermin↗
PubMed1998

Glucocorticoids and protein kinase C regulate neutral endopeptidase 24.11 in human vascular smooth muscle cells.

Neutral endopeptidase 24.11 (NEP) degrades vasoactive peptides, including natriuretic peptides, kinins, angiotensins, and endothelins. It contributes to the regulation of vascular tone and body fluid homeostasis. In the present study the expression of NEP was investigated in cultured human smooth muscle cells derived from umbilical veins (HSMC) and human coronary arteries (HCSMC). A constitutive NEP expression was found in growing and starved smooth muscle cells and was about 4 fold higher than in endothelial cells derived from umbilical veins. Treatment of smooth muscle cells with dexamethasone (0.01-0.1 microM Dex) and with the protein kinase C activator, phorbol myristate acetate (0.1 microM PMA), increased NEP mRNA by 3-4 fold and two fold, respectively. Dexamethasone (0.1 microM) and prednisolone (0.1 microM) increased protein concentrations of NEP and NEP-activity after 3 days and continued to increase at 5 days, whereas PMA induced maximal increase of NEP concentrations after 48 hours. The effect of dexamethasone was concentration-dependent and was completely abolished by cycloheximide (10 microM), a protein synthesis inhibitor. The effect of PMA on NEP protein was completely blocked by protein kinase C inhibitors, calphostin C and H7 (both 10 microM). NEP 24.11 is constitutively expressed in human smooth muscle cells from umbilical veins and coronary arteries and is upregulated by glucocorticoids and by protein kinase C activation in these cells.

Blotting, Northern↗
PubMed1998

Metacarpal index in short stature before and during growth hormone treatment.

AIMS: To assess the usefulness of the metacarpal index (MCI) as a radiographic measure of the proportions of the metacarpals in the differential diagnosis of short stature. To investigate the significance of the MCI in following the longitudinal growth and proportions of individual long bones during growth hormone stimulated catch up growth in children with short stature with and without growth hormone deficiency. SUBJECTS: 124 children, including 65 children with short stature caused by growth hormone deficiency, 13 with familial short stature, 29 with idiopathic short stature, and 17 with Ullrich-Turner syndrome. METHODS: Retrospective analysis of the MCI in five posterior-anterior radiographs of the left hand of all patients, which were performed sequentially for routine bone age determinations (Greulich and Pyle) before and during the first three years of growth hormone treatment. RESULTS: The MCI was similar in all patient groups, resembled that of healthy children, and correlated significantly with chronological age, bone age, and height before and during growth hormone treatment. Despite a remarkable growth hormone stimulated catch up growth, the MCI did not change significantly during growth hormone treatment. CONCLUSIONS: The role of the MCI is insignificant in the diagnosis of short stature, but the MCI can serve as an auxological measure of osseous proportions during longitudinal growth. Growth hormone treatment accelerates longitudinal growth without affecting the proportions of the long bones, indicating that growth hormone stimulated bone growth closely resembles spontaneous bone growth.

Body Height↗
PubMed1997

Inhibition of MAP kinase blocks insulin-mediated DNA synthesis and transcriptional activation of c-fos by Elk-1 in vascular smooth muscle cells.

Insulin-stimulated DNA synthesis, MAP kinase (MAPK) activity and c-fos expression in vascular smooth muscle cells (VSMCs) was blocked by the MAPK inhibitor PD 98059. Regulation of c-fos expression by the transcription factor Elk-1 at the serum response element (SRE) is dependent on its phosphorylation by MAPK. PD 98059 also suppressed insulin-induced Elk-1 transcriptional activity through the SRE. These data show that MAPK plays a critical role in both insulin-mediated growth and Elk-1-dependent induction of c-fos in VSMCs.

Animals↗
PubMed1997

Myocardial osteopontin expression is associated with left ventricular hypertrophy.

BACKGROUND: Osteopontin (OP) has been identified in cultured rat cardiac fibroblasts, where it contributes to angiotensin II (AII)-induced remodeling processes; in cultured cardiomyocytes; and in macrophages in cardiac tissues with inflammation. However, the presence of OP has not been reported in histological sections of myocardial tissue. In the present study, we investigated (1) the regulation of OP mRNA expression in cultured rat cardiomyocytes; (2) the localization of OP mRNA in neonatal and adult normal and hypertrophied rat hearts; and (3) the histology of OP expression in myocardial specimens from humans either with myocyte hypertrophy or with no pathological changes. METHODS AND RESULTS: Cultured neonatal cardiomyocytes expressed OP mRNA and were immunoreactive for OP. Endothelin-1 (ET-1) and norepinephrine (NE) increased both OP and atrial natriuretic peptide (ANP) mRNA levels twofold to threefold (P<.01). OP mRNA was prominent in ventricular tissue from neonatal and adult rats with renovascular hypertension and aortic banding, whereas barely detectable levels were observed in normal adult cardiac tissue. ANP and OP mRNA levels in normal and hypertrophied ventricles correlated (r2=.87, P<.001). OP immunoreactivity and mRNA transcripts were predominantly found in cardiomyocytes not associated with inflammatory cells in sections from neonatal and adult hypertrophied hearts. No staining was detectable in normal adult hearts. Human myocardium with extensive fibrosis and cardiomyocyte hypertrophy obtained from explanted hearts with either idiopathic (n=5) or ischemic cardiomyopathy (n=7) demonstrated substantial myocyte immunoreactivity for both OP and ANP in right and left ventricles that was not associated with leukocyte infiltration. In situ hybridization identified cardiomyocytes as the major source of OP mRNA transcripts in these hearts. In contrast, OP immunoreactivity was not detectable in four of five endomyocardial biopsies with normal histology. CONCLUSIONS: The present study provides the first evidence that cardiomyocytes are a prominent source of OP in vivo and suggests that induction of OP expression is strongly associated with ventricular hypertrophy.

Animals↗
PubMed1997

L-selectin-dependent leukocyte adhesion to microvascular but not to macrovascular endothelial cells of the human coronary system.

To characterize L-selectin-dependent cell adhesion to human vascular endothelium, human cardiac microvascular endothelial cells (HCMEC) and human coronary endothelial cells (HCEC) were isolated from explanted human hearts. The adhesion behavior of human (NALM-6) and mouse (300.19) pre-B cells transfected with cDNA encoding for human L-selectin was compared with that of the respective nontransfected cells in a flow chamber in vitro. More than 80% of the adhesion to tumor necrosis factor-alpha (TNF-alpha)-stimulated HCMEC at shear stresses >2 dyne/cm2 was L-selectin dependent and could be equally well blocked by an anti-L-selectin antibody or a L-selectin-IgG-chimera. No L-selectin dependent adhesion to HCEC could be shown. The L-selectin dependent adhesion to HCMEC was insensitive to neuraminidase, but greatly inhibited by addition of NaClO3, which inhibits posttranslational sulfation and remained elevated for at least 24 hours of stimulation. E-selectin dependent adhesion of HL60 cells to HCMEC was blocked by neuraminidase, but not by NaClO3 and returned to control levels within 18 hours of HCMEC stimulation. It is concluded that microvascular, but not macrovascular endothelial cells express TNF-alpha-inducible sulfated ligand(s) for L-selectin, which differ from known L-selectin ligands, because sialylation is not required. The prolonged time course of L-selectin dependent adhesion suggests a role in sustained leukocyte recruitment into inflammatory sites in vivo.

Animals↗
PubMed1997

Troglitazone inhibits angiotensin II-induced DNA synthesis and migration in vascular smooth muscle cells.

Angiotensin II (AII) plays a crucial role in controlling the proliferation and migration of vascular smooth muscle cells (VSMCs). The present study was undertaken to determine if troglitazone (Tro) has an effect on the G-protein coupled signaling through AII type I (AT-1) receptors in cultured rat aortic VSMCs. AII-induced MAP kinase activation was inhibited 67.9% by Tro. AII-induced DNA synthesis and migration was completely inhibited by Tro or by the AT-1 receptor blocker irbesartan. The present study demonstrates that troglitazone inhibits AII-induced DNA synthesis, migration and MAP kinase activation in VSMCs which are important molecular events for the development of neointimal hyperplasia and atherosclerosis.

Angiotensin II↗
PubMed1997

Protein kinase C-dependent regulation of the human AT1 promoter in vascular smooth muscle cells.

The expression level of angiotensin II (ANG II) type 1 receptors (AT1) determines the magnitude of ANG II signaling in vascular smooth muscle cells (VSMC). AT1 mRNA expression in cultured bovine VSMC increased twofold after 8 h of protein kinase C (PKC) activation with phorbol 12-myristate 13-acetate (PMA), whereas stimulation with forskolin did not alter the AT1 mRNA level. The expression of AT1 promoter/exon 1 [-513/+92 base pairs (bp)] luciferase constructs transfected into VSMC increased 2.4-fold with PMA stimulation. In-gel kinase assays demonstrated rapid phosphorylation of mitogen-activating protein kinases (MAPK) ERK1 and ERK2 by PMA. Electrophoretic gel mobility shift assays showed sequence-specific binding of nuclear proteins from PMA-activated VSMC, identified as activator protein 1 (AP-1) complex in competition assays, to a radiolabeled AT1-promoter fragment (-368/-399 bp). Recombinant AP-1 binds in a sequence-specific manner to the -386/-399-bp region. Site-specific mutagenesis destroying the AP-1 site, the adjacent polyoma enhancer activator 3 element, or both sites simultaneously indicated that both sites together are necessary and sufficient to control basal and PMA-induced activation of the human AT1 promoter in transfected VSMC. The capability of the phorbol ester PMA to activate the human AT1 promoter in VSMC via an AP-1 element suggests a prominent role for PKC/MAPK and Ets proteins in AT1 regulation.

Animals↗
PubMed1997

Mitogen-activated protein kinase activation is involved in platelet-derived growth factor-directed migration by vascular smooth muscle cells.

Migration of vascular smooth muscle cells (VSMCs) is a crucial response to vascular injury resulting in neointima formation and atherosclerosis. Platelet-derived growth factor (PDGF-BB) functions as a potent chemoattractant for VSMCs and enhances these pathologies in the vasculature. However, little is known about the intracellular pathways that mediate VSMC migration. In the present study, we investigated the role of mitogen-activated protein kinase (MAPK) activation in this function, since PDGF-BB as well as other growth factors activate this pathway. Using an in-gel kinase assay, we observed that PD 98059 an inhibitor of MEK that activates MAP kinase, inhibited PDGF-BB-induced activation of ERK-1 and ERK-2 in cultured rat aortic smooth muscle cells in a concentration-dependent manner. In contrast, PDGF-mediated activation of intracellular calcium release was not affected by PD 98059. The chemotactic response of both rat aortic smooth muscle cells (RASMCs) and human umbilical vein smooth muscle cells (HUSMCs) toward PDGF-BB (10 ng/mL) was significantly reduced by PD 98059 (10 mumol/L) to 41.7 +/- 7.1% in RASMCs (P < .01) and to 47.2 +/- 5.3% in HUSMCs (P < .01). Similar inhibition was seen at 30 mumol/L, less at 1 mumol/L. To further confirm the specificity of these results implicating the MAPK pathway, an antisense oligodeoxynucleotide (ODN) directed against the initiation translation site of rat ERK-1 and ERK-2 mRNA was used to suppress MAP kinase synthesis and function in rat VSMCs. Liposomal transfection with 0.4 mumol/L antisense ODN reduced ERK-1 and ERK-2 protein by 65% (P < .01) after 48 hours. The chemotactic response to PDGF-BB (10 ng/mL) was reduced by 75% (P < .01) in rat VSMCs transfected with the same antisense ODN concentration. Sense and scrambled control ODNs (0.4 mumol/L) did not affect ERK-1 and ERK-2 protein concentrations or chemotaxis of VSMCs induced by PDGF-BB. These experiments provide the first evidence that activation of MAPK is a critical event in PDGF-mediated signal transduction regulating VSMC migration.

Animals↗
PubMed1997

Angiotensin II-induced leukocyte adhesion on human coronary endothelial cells is mediated by E-selectin.

Clinical data suggest a link between the activation of the renin-angiotensin system and cardiovascular ischemic events. Leukocyte accumulation in the vessel wall is a hallmark of early atherosclerosis and plaque progression. E-Selectin, vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) are adhesion molecules participating in mediating interactions between leukocytes and endothelial cells and have been found to be expressed in athero-sclerotic plaques. We investigated whether angiotensin II, the effector of the renin-angiotensin system, influences the endothelial expression of E-selectin, VCAM-1, and ICAM-1. In coronary endothelial cells derived from explanted human hearts, angiotensin II (10(-11) to 10(-5) mol/L) induced a concentration-dependent increase in E-selectin expression. The effect was measured by cell ELISA and duplex reverse-transcription polymerase chain reaction (RT-PCR) and reached its maximum at 10(-7) mol/L. Angiotensin II induced only a small increase in E-selectin expression in cardiac microvascular endothelial cells. VCAM-1 and ICAM-1 were not affected by angiotensin II stimulation. In addition, the effect of angiotensin II-induced E-selectin expression on leukocyte adhesion was quantified under flow conditions. Angiotensin II (10(-7) mol/L) increased leukocyte adhesion significantly to 67% of the maximal effect by tumor necrosis factor-alpha at a wall shear stress of 2 dyne/cm2. This adhesion was found to be E-selectin dependent, as demonstrated by blocking antibodies. The AT1-receptor antagonist DUP 753 significantly reduced E-selectin-dependent adhesion, whereas the AT2-receptor antagonist PD 123177 had no inhibitory effect. In addition, only AT1-receptor, but not AT2-receptor, mRNA could be detected by RT-PCR in coronary endothelial cells. Therefore, it is suggested that AT1 receptors mediate the effects of angiotensin II on E-selectin expression and leukocyte adhesion on coronary endothelial cells.

Angiotensin II↗
PubMed1997

Angiotensin II promotes remodelling-related events in cardiac fibroblasts.

Remodelling is a fundamental cardiac response to injury, and involves cardiac fibroblast proliferation and extracellular matrix production. Angiotensin II (A II) directly promotes these changes in cardiac fibroblasts, and is thus a critical element in cardiac hypertrophy and a processor of wound healing. Osteopontin mRNA was readily detectable in total RNA harvested from cultured neonatal and adult cardiac fibroblasts. Immunocytochemical staining of cultured adult cardiac fibroblasts grown on coverslips revealed the presence of beta 3 integrin on the surfaces of the cells. In the present study, we investigated the role of A II in a model of wound healing using floating collagen gels harboring adult rat cardiac fibroblasts. The presence of a monoclonal antibody against osteopontin, MPIIIB10, at 7.2 micrograms/ml, or the arginine-glycine-aspartate (RGD) peptide (10(-4) M), had no effect on gel contraction. Osteopontin itself induced fibroblast gel contraction (79.1 +/- 3.8%). But this effect of osteopontin was completely neutralized by MPIIIB10 (7.2 micrograms/ml), RGD peptide (10(-4) M), and monoclonal antibody against rat beta 3 integrin (25 micrograms/ml). These results suggest that A II promotes cardiac wound healing and remodelling processes by inducing osteopontin and beta 3 integrin in cardiac fibroblasts.

Angiotensin II↗
PubMed1996

Osteopontin is produced by rat cardiac fibroblasts and mediates A(II)-induced DNA synthesis and collagen gel contraction.

Angiotensin II (AII) is a critical factor in cardiac remodeling which involves hypertrophy, fibroblast proliferation, and extracellular matrix production. However, little is known about the mechanism by which AII accelerates these responses. Osteopontin is an acidic phosphoprotein with RGD (arginine-glycine-aspartate) sequences that are involved in the vascular smooth muscle cell remodeling process. We identified the presence of osteopontin mRNA and protein in cultured rat cardiac fibroblasts and its prominent regulation by AII (10(-11) M). Osteopontin message levels were increased fourfold (P < 0.01) and protein fivefold (P < 0.05) at 24 h after addition of AII (10(-7) M). This response was inhibited by the AT1 receptor blocker, losartan. Osteopontin mRNA levels were increased in hypertrophied ventricles from animals with renovascular hypertension (1.6-fold, P < 0.05) and aortic banding (2.9-fold, P < 0.05). To examine the function of osteopontin, we determined its effects on (a) the ability of cardiac fibroblasts to contract three-dimensional collagen gels and (b) cardiac fibroblast growth. A monoclonal antibody against osteopontin partially blocked AII-induced three-dimensional collagen gel contraction by cardiac fibroblasts (64+/-4 vs. 86+/-5% in the presence of antibody, P < 0.05), while osteopontin itself promoted contraction of the gels by fibroblasts (71+/-5%, P < 0.05 compared with control). Either a monoclonal antibody against beta3 integrin which is a ligand for osteopontin or the RGD peptide blocked both AII and osteopontin-induced collagen gel contraction. Thus, the osteopontin RGD sequence binds to beta3 integrins on the fibroblast to promote fibroblast binding to collagen. All induced a threefold increase in DNA synthesis of cardiac fibroblasts, which was completely blocked by antibodies against osteopontin and beta3 integrin, or by RGD peptide, but not by controls. Thus, All-induced growth of cardiac fibroblasts also requires osteopontin engagement of the beta3 integrin. Taken together, these results provide the first evidence that osteopontin is a potentially important mediator of AII regulation of cardiac fibroblast behavior in the cardiac remodeling process.

Angiotensin II↗
PubMed1996

Troglitazone inhibits vascular smooth muscle cell growth and intimal hyperplasia.

Vascular smooth muscle cell (VSMC) proliferation and migration are responses to arterial injury that are highly important to the processes of restenosis and atherosclerosis. In the arterial balloon injury model in the rat, platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) are induced in the vessel wall and regulate these VSMC activities. Novel insulin sensitizing agents, thiazolidinediones, have been demonstrated to inhibit insulin and epidermal growth factor-induced growth of VSMCs. We hypothesized that these agents might also inhibit the effect of PDGF and bFGF on cultured VSMCs and intimal hyperplasia in vivo. Troglitazone (1 microM), a member of the thiazolidinedione class, produced a near complete inhibition of both bFGF-induced DNA synthesis as measured by bromodeoxyuridine incorporation (6.5+/-3.9 vs. 17.6+/-4.3% cells labeled, P < 0.05) and c-fos induction. This effect was associated with an inhibition (by 73+/-4%, P < 0.01) by troglitazone of the transactivation of the serum response element, which regulates c-fos expression. Inhibition of c-fos induction by troglitazone appeared to occur via a blockade of the MAP kinase pathway at a point downstream of MAP kinase activation by MAP kinase kinase. At this dose, troglitazone also inhibited PDGF-BB-directed migration of VSMC (by 70+/-6%, P < 0.01). These in vitro effects were operative in vivo. Quantitative image analysis revealed that troglitazone-treated rats had 62% (P < 0.001) less neointima/media area ratio 14 d after balloon injury of the aorta compared with injured rats that received no troglitazone. These results suggest troglitazone is a potent inhibitor of VSMC proliferation and migration and, thus, may be a useful agent to prevent restenosis and possibly atherosclerosis.

Animals↗
PubMed1996

Insulin and angiotensin II are additive in stimulating TGF-beta 1 and matrix mRNAs in mesangial cells.

Angiotensin II (Ang II) and insulin are implicated in the mesangial cell hypertrophy and excessive accumulation of mesangial matrix seen in glomerulosclerosis. Therefore, the effects of Ang II with and without insulin on mRNA levels of several important extracellular matrix genes and transforming growth factor beta-1 (TGF-beta 1) were examined. Ang II alone (1 microM) added to quiescent, murine mesangial cells in serum-free, insulin-free media slightly but not significantly increased TGF-beta 1, fibronectin, collagen I, collagen IV and laminin message levels. The slight elevations in message expression were reversed by losartan, suggesting that these modest effects are mediated by the AT-1 receptor. Ang II alone also had no significant effects on TGF-beta 1 and extracellular matrix message levels in quiescent rat mesangial cells. In contrast, significant increases in mRNA for collagen 1 (6-fold), collagen IV (4-fold), fibronectin 1 (4-fold) and TGF-beta 1 (2-fold) were seen with insulin alone (10(-6)M) in rat mesangial cells, and a dose-response effect could be demonstrated for insulin (10(-9) to 10(-6)M). Ang II plus insulin further significantly increased collagen I (9-fold), collagen IV (9-fold), fibronectin 1 (5-fold) and TGF-beta 1 (3-fold) message expression. These effects were partially reversed in the presence of losartan. The Northern analyses were supported by measurements of active and total TGF-beta 1 activity (pg/ml/ 5 x 10(6) cells): 1145 +/- 76 and 1960 +/- 199, serum free control; 1121 +/- 92 and 1932 +/- 214, Ang II (10(-6)M); 4589 +/- 103 (P < 0.001 vs. control) and 11071 +/- 1952 (P < 0.01 vs. control), insulin (10(-6)M); and 6881 +/- 183 (P < 0.001 vs. control) and 16626 +/- 1435 (P < 0.01 vs. control), insulin plus Ang II. These results suggest that insulin, itself, significantly increases TGF-beta 1 and extracellular matrix gene expression in rat mesangial cells. Ang II alone has modest effects, while Ang II and insulin have additive effects. To explain the mechanism of these additive effects, we investigated the action of Ang II on insulin signaling and the effect of insulin on Ang II AT1 receptor mRNA expression. Ang II did not enhance insulin-induced insulin receptor substrate-1 (IRS-1) phosporylation or phosphatidylinositol3 (PI-3) kinase activity, but did enhance insulin-induced mitogen activated protein (MAP) kinase activity. Insulin increased message levels of AT1 receptor by twofold. These results suggest that enhancement of MAP kinase activity and AT1 receptor regulation by insulin may contribute to the additive effects of insulin and Ang II in mesangial cells.

Angiotensin II↗