Hepatocyte Growth Factor, but not Vascular Endothelial Growth Factor, Attenuates Angiotensin II–Induced Endothelial Progenitor Cell Senescence

Sanada, Fumihiro; Taniyama, Yoshiaki; Azuma, Junya; Iekushi, Kazuma; Dosaka, Norio; Yokoi, Taishi; Koibuchi, Nobutaka; Kusunoki, Hiroshi; Aizawa, Yoshifusa; Morishita, Ryuichi

doi:10.1161/hypertensionaha.108.120725

Cited by 55 publications

(49 citation statements)

References 33 publications

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“…These HGF-Tg mice showed a significant increase in the serum human HGF concentration of Ϸ3-fold as compared with control littermates. 7 As expected, HGF-Tg mice exhibited a much lower degree of renal injury, as assessed by diameter of the glomerulus, and glomerular injury index ( Figure 3A through 3C, PϽ0.01, respectively). Similarly, HGF-Tg mice exhibited significantly less renal fibrosis as compared with control ( Figure 3D and 3E, PϽ0.01).…”

Section: Overexpression Of Hgf Inhibited Renal Damage Induced By Ang supporting

confidence: 74%

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Hepatocyte Growth Factor Attenuates Transforming Growth Factor-β-Angiotensin II Crosstalk Through Inhibition of the PTEN/Akt Pathway

et al. 2011

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Abstract-Both angiotensin II (Ang II) and transforming growth factor (TGF)-␤1 are thought to be involved in the progression of chronic kidney disease. In contrast, hepatocyte growth factor (HGF) counteracts the actions of Ang II and TGF-␤1. Therefore, in this study, we investigated the molecular mechanisms of how HGF antagonizes the Ang II-TGF-␤ axis in renal cells. In cultured human mesangial cells, TGF-␤1 increased angiotensin type 1 receptor (AT 1 R) mRNA, mainly dependent on the Akt/phosphatidylinositol 3-kinase signaling pathway. Furthermore, TGF-␤1 decreased the expression and phosphatase activity of phosphatase and tensin homolog, deleted on chromosome 10 (PTEN), a negative regulator of the phosphatidylinositol 3-kinase/Akt pathway. These data revealed positive feedback of the Ang II-TGF-␤ pathway, because Ang II increased TGF-␤ expression. In contrast, HGF significantly attenuated the increase in AT 1 R gene expression, and inhibited the decrease in PTEN induced by TGF-␤1. Of importance, a PTEN-specific inhibitor significantly attenuated the reduction in TGF-␤1-induced AT 1 R expression by HGF. These data suggest that HGF attenuated TGF-␤1-induced AT 1 R expression through the PTEN/Akt pathway. To investigate this hypothesis, we performed in vivo experiments in mice with increased circulating levels of HGF produced by transgenically expressing HGF under control of a cardiac-specific transgene (HGF-Tg). In HGF-Tg mice, renal injury and fibrosis were significantly decreased, associated with reduction in AT 1 R expression and increase in PTEN after Ang II infusion, as compared with control mice. Moreover, these renal protective effects were abrogated by a neutralizing antibody against HGF. Thus, the present study demonstrated that HGF counteracts the vicious cycle of Ang II-TGF-␤1-AT 1 R, mediating the inhibition of PTEN.

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Section: Overexpression Of Hgf Inhibited Renal Damage Induced By Ang supporting

confidence: 74%

“…7 We administrated Ang II (0.7 mg/kg per day) by using osmotic minipump (DURECT Corporation, Cupertino, CA) to HGFtransgenic (Tg) mice and C57BL6N mice (littermates) aged 8 to 10 weeks for 4 weeks. Blood pressure was measured by tail-cuff plethysmography.…”

Section: In Vivo Experimentsmentioning

confidence: 99%

Hepatocyte Growth Factor Attenuates Transforming Growth Factor-β-Angiotensin II Crosstalk Through Inhibition of the PTEN/Akt Pathway

et al. 2011

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“…Transfection of the hepatocyte growth factor (HGF) gene enhances EPC function and improves EPC transplant efficiency for balloon-induced arterial injury in hypercholesterolemic rats (85). Interestingly, HGF also attenuates angiotensin IIinduced EPC senescence (73).…”

Section: Gene-mediated Treatment Of Epc Dysfunctionmentioning

confidence: 99%

Critical Role of the Nitric Oxide/Reactive Oxygen Species Balance in Endothelial Progenitor Dysfunction

Fleißner

Thum²

2011

Antioxidants & Redox Signaling

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Endothelial injury and dysfunction are critical events in the pathogenesis of cardiovascular disease. During these processes, an impaired balance of nitric oxide bioavailability and oxidative stress is mechanistically involved. Circulating angiogenic cells (including early and late outgrowth endothelial progenitor cells (EPC)) contribute to formation of new blood vessels, neovascularization, and homeostasis of the vasculature, and are highly sensitive for misbalance between NO and oxidative stress. We here review the role of the endothelial nitric oxide synthase and oxidative stress producing enzyme systems in EPC during cardiovascular disease. We also focus on the underlying molecular mechanisms and potential emerging drug-and gene-based therapeutic strategies to improve EPC function in cardiovascular diseased patients. Antioxid. Redox Signal. 15, 933-948.

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“…These hyperglycemia-dependent and -independent hemodynamic alterations have been implicated in the pathogenesis of microvascular and macrovascular complications associated with DM. ANG II is similarly associated with deleterious renal and systemic hemodynamic responses in animals and humans (4,(7)(8)(9)(10)(11). Advancing age may potentiate and exaggerate these systemic and renal hemodynamic consequences of hyperglycemia and the RAS (14).…”

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confidence: 99%

Age is a determinant of acute hemodynamic responses to hyperglycemia and angiotensin II in humans with uncomplicated type 1 diabetes mellitus

Cherney

Reich

Miller

et al. 2010

American Journal of Physiology-Regulatory, Integrative and Comp

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-Hyperglycemia is associated with hemodynamic changes in type 1 diabetes (DM), acting in part through renin-angiotensin system activation. Since aging is associated with vascular dysfunction in DM, we hypothesized that acute hemodynamic responses to clamped hyperglycemia and infused ANG II would be exaggerated in older adults compared with a group of adolescent/young adults with type 1 DM. Renal hemodynamic function, blood pressure, and arterial stiffness were assessed in adolescent/young adults (n ϭ 34; mean age: 18 Ϯ 3 yr) and older adults (n ϭ 32; mean age: 45 Ϯ 9 yr). Studies were performed during clamped euglycemia (4 -6 mmol/l) and hyperglycemia (9 -11 mmol/ l). Renal and systemic hemodynamic responses to ANG II were measured during clamped euglycemia in diabetic subjects. ANG II responses were also assessed in a cohort of non-DM subjects (n ϭ 97; mean age: 26; age range: 18 -40 yr). Older DM adults exhibited higher baseline blood pressure, arterial stiffness, and renal vascular resistance, and lower glomerular filtration rate (GFR) and effective renal plasma flow, compared with adolescent/young DM adults (P Ͻ 0.05). Clamped hyperglycemia was associated with exaggerated peripheral and renal hemodynamic responses uniquely in older DM adults; only GFR increased in adolescent/young DM adults. ANG II infusion also produced exaggerated vasoconstrictive responses in older DM adults vs. adolescent/young DM adults (P Ͻ 0.05). The independent effect of age on hemodynamic responses to hyperglycemia and ANG II was confirmed using multivariate regression analysis in DM subjects (P Ͻ 0.05), and results were still significant when participants were matched for DM duration. Age-related alterations in hemodynamic function and ANG II response were not observed in healthy non-DM control subjects. Acute hemodynamic responses to clamped hyperglycemia and ANG II were exaggerated in older subjects with type 1 DM, highlighting an important interaction between age and factors that contribute to the pathogenesis of acute vascular dysfunction in DM. renal hemodynamic function; systemic blood pressure; arterial stiffness HYPERGLYCEMIA PLAYS A CRITICAL role in the pathogenesis of renal and systemic vascular complications in type 1 diabetes mellitus (DM), in part by promoting many of the early, permissive hemodynamic changes characteristic of DM (1). In early type 1 DM, hyperglycemia is associated with reduced renal vascular resistance (RVR) and renal hyperfiltration, which may promote susceptibility to kidney injury mediated by intraglomerular hypertension (2). Hyperglycemia-mediated renin-angiotensin system (RAS) activation is also associated with renal hyperfiltration through arterial vasoconstriction (3). In older subjects with DM and clinical evidence of nephropathy, RVR is increased, which has also been associated with vascular injury and adverse renal outcomes (4, 5).In early, uncomplicated type 1 DM, vascular resistance in the systemic circulation is also low, resulting in systemic hyperperfusion; this vasodilated systemic phe...

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Hepatocyte Growth Factor, but not Vascular Endothelial Growth Factor, Attenuates Angiotensin II–Induced Endothelial Progenitor Cell Senescence

Cited by 55 publications

References 33 publications

Hepatocyte Growth Factor Attenuates Transforming Growth Factor-β-Angiotensin II Crosstalk Through Inhibition of the PTEN/Akt Pathway

Hepatocyte Growth Factor Attenuates Transforming Growth Factor-β-Angiotensin II Crosstalk Through Inhibition of the PTEN/Akt Pathway

Critical Role of the Nitric Oxide/Reactive Oxygen Species Balance in Endothelial Progenitor Dysfunction

Age is a determinant of acute hemodynamic responses to hyperglycemia and angiotensin II in humans with uncomplicated type 1 diabetes mellitus

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