High glucose increases Cdk5 activity in podocytes via transforming growth factor-β1 signaling pathway.
Podocytes are highly specialized and terminally differentiated glomerular cells that play a vital role in the development and progression of diabetic nephropathy (DN). Cyclin-dependent kinase 5 (Cdk5), who is an atypical but essential member of the Cdk family of proline-directed serine/threonine kinases, has been shown as a key regulator of podocyte differentiation, proliferation and morphology. Our previous studies demonstrated that the expression of Cdk5 was significantly increased in podocytes of diabetic rats, and was closely related with podocyte injury of DN. However, the mechanisms of how expression and activity of Cdk5 are regulated under the high glucose environment have not yet been fully elucidated. In this study, we showed that high glucose up-regulated the expression of Cdk5 and its co-activator p35 with a concomitant increase in Cdk5 kinase activity in conditionally immortalized mouse podocytes in vitro. When exposed to 30 mM glucose, transforming growth factor-β1 (TGF-β1) was activated. Most importantly, we found that SB431542, the Tgfbr1 inhibitor, significantly decreased the expression of Cdk5 and p35 and Cdk5 kinase activity in high glucose-treated podocytes. Moreover, high glucose increased the expression of early growth response-1 (Egr-1) via TGF-β1-ERK1/2 pathway in podocytes and inhibition of Egr-1 by siRNA decreased p35 expression and Cdk5 kinase activity. Furthermore, inhibition of Cdk5 kinase activity effectively alleviated podocyte apoptosis induced by high glucose or TGF-β1. Thus, the TGF-β1-ERK1/2-Egr-1 signaling pathway may regulate the p35 expression and Cdk5 kinase activity in high glucose-treated podocytes, which contributes to podocyte injury of DN.
Department of Diagnostics, Hebei Medical University, Shijiazhuang 050017, China.
Yue
Y
Zhang
Department of Pathology, Hebei Medical University, Shijiazhuang 050017, China.
Hongbo
H
Li
Department of Pathology, Hebei Medical University, Shijiazhuang 050017, China.
Jun
J
Hao
Department of Neurology, the Second Hospital of Hebei Medical University, Shijiazhuang 050000, China.
Yi
Y
Zhou
Department of Pathology, Hebei Medical University, Shijiazhuang 050017, China. Electronic address: lwei929@126.com.
Wei
W
Liu
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001549:Benzamides / Q000494:pharmacology; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D004149:Dioxoles / Q000494:pharmacology; D051766:Early Growth Response Protein 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism*; D051379:Mice; D010770:Phosphotransferases / Q000235:genetics / Q000378:metabolism; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011687:Purines / Q000494:pharmacology; D051381:Rats; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D000077546:Roscovitine; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D015854:Up-Regulation
C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; C492236:Cdk5r1 protein, mouse; D004149:Dioxoles; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D047428:Protein Kinase Inhibitors; D011687:Purines; D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000077546:Roscovitine; D010770:Phosphotransferases; D051360:Cyclin-Dependent Kinase 5; D017346:Protein Serine-Threonine Kinases; C495906:Cdk5 protein, mouse; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625842:Tgfbr1 protein, mouse; C000625843:Tgfbr1 protein, rat; D005947:Glucose
Cdk5; Diabetic nephropathy; High glucose; Podocyte; TGF-β1