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This Article Full Text Full Text (PDF) All Versions of this Article: fj.08-109488v1 22/10/3469    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Venkatesan, B. Articles by Choudhury, G. G. PubMed PubMed Citation Articles by Venkatesan, B. Articles by Choudhury, G. G.

Resveratrol inhibits PDGF receptor mitogenic signaling in mesangial cells: role of PTP1B

Balachandar Venkatesan^*, Nandini Ghosh-Choudhury^,||, Falguni Das^*, Lenin Mahimainathan^*, Amrita Kamat^*,, Balakuntalam S. Kasinath^*,,||, Hanna E. Abboud^*,,|| and Goutam Ghosh Choudhury^*,,,||,1

^* Department of Medicine,

Department of Pathology, and

O'Brien Kidney Research Center, University of Texas Health Science Center, San Antonio, Texas, USA; and

Geriatric Research, Education, and Clinical Center,

^|| South Texas Veterans Health Care System, San Antonio, Texas, USA

¹Correspondence: Department of Medicine, Mail Code 7882, 7703 Floyd Curl Dr., San Antonio, TX, 78229-3900, USA. E-mail: choudhuryg{at}uthscsa.edu

Mesangioproliferative glomerulonephritis is associated with overactive PDGF receptor signal transduction. We show that the phytoalexin resveratrol dose dependently inhibits PDGF-induced DNA synthesis in mesangial cells with an IC₅₀ of 10 µM without inducing apoptosis. Remarkably, the increased SIRT1 deacetylase activity induced by resveratrol was not necessary for this inhibitory effect. Resveratrol significantly blocked PDGF-stimulated c-Src and Akt kinase activation, resulting in reduced cyclin D1 expression and attenuated pRb phosphorylation and cyclin-dependent kinase-2 (CDK2) activity. Furthermore, resveratrol inhibited PDGFR phosphorylation at the PI 3 kinase and Grb-2 binding sites tyrosine-751 and tyrosine-716, respectively. This deficiency in PDGFR phosphorylation resulted in significant inhibition of PI 3 kinase and Erk1/2 MAPK activity. Interestingly, resveratrol increased the activity of protein tyrosine phosphatase PTP1B, which dephosphorylates PDGF-stimulated phosphorylation at tyrosine-751 and tyrosine-716 on PDGFR with concomitant reduction in Akt and Erk1/2 kinase activity. PTP1B significantly inhibited PDGF-induced DNA synthesis without inducing apoptosis. These results for the first time provide evidence that the stilbene resveratrol targets PTP1B to inhibit PDGFR mitogenic signaling.—Venkatesan, B., Ghosh-Choudhury, N., Das, F., Mahimainathan, L., Kamat, A., Kasinath, B. S., Abboud, H. E., Choudhury, G. G. Resveratrol inhibits PDGF receptor mitogenic signaling in mesangial cells: role of PTP1B.

Key Words: SIRT1 • Akt kinase • CDK2