RETRACTION: STAT3 Regulates Steady-State Expression of Synaptopodin in Cultured Mouse Podocytes

Abstract

The transcription factor signal transducer and activator of transcription-3 (STAT3) is activated by proinflammatory cytokines and circulating factors in many cell types. Synaptopodin (Synpo) is a cytoskeleton regulatory protein expressed in podocyte foot processes that regulates the dynamics of actin filaments and the stability of small GTPases. Here we show that inhibition of STAT3 signaling using the small-molecule inhibitor benzo [b]thiophene, 6-nitro-,1,1-dioxide (Stattic), or by STAT3 knockdown by small interfering RNA, caused a decrease in Synpo mRNA and protein in an immortalized mouse podocyte cell line. This loss of Synpo, which occurred in 30-80 minutes, was also seen after treatment with the translational inhibitor cycloheximide. The loss of Synpo protein after Stattic or cycloheximide treatment did not occur when podocytes were simultaneously exposed to 1-[N-[(L-3-transcarboxyoxirane-2-carbonyl)-L-leucyl]amino]-4-guanidinobutane (E-64), an inhibitor of thiol proteases such as cathepsin L. Treatment with interleukin-6 (IL-6) increased tyrosine phosphorylation of STAT3 and evoked a parallel increase in Synpo levels in podocytes. The stimulatory effect of IL-6 on Synpo was completely inhibited by pretreatment with Stattic. By contrast, 30-60-minute exposure to angiotensin II (Ang II) inhibited STAT3 signaling and concurrently reduced Synpo protein levels. The Ang II-evoked loss of Synpo was prevented by E-64 but not by inhibition of calcineurin or blockade of transient receptor potential cation channels. Inhibition of STAT3 by Stattic caused marked changes in the distribution of podocyte actin filaments, and caused a nearly complete suppression of the migration of these cells in wound assays, consistent with the loss of Synpo. Stattic treatment also caused loss of RhoA protein.

Protein Kinase A/CREB Signaling Prevents Adriamycin-Induced Podocyte Apoptosis via Upregulation of Mitochondrial Respiratory Chain Complexes

“…Podocytes play an essential role in the maintenance of the integrity of the glomerular filtration membrane, and injury to this membrane occurs in many glomerular diseases (30). Increasing evidence indicates that intracellular signaling pathways are involved in changes in the biological function of podocytes under different stimuli (31,32). Our results indicated that PKA signaling might increase mitochondrial oxidative phosphorylation and reduce ROS generation, thus preventing podocyte injury.…”

Chronic cathepsin inhibition by E-64 in Dahl salt-sensitive rats

“…The proteinuria we observed in the SS rats fed a HS diet was expected to be attenuated by E‐64 treatment. In cultured podocytes, E‐64 was recently reported to block an Ang II‐induced, STAT3 mediated loss of the cytoskeleton regulatory protein synaptopodin (Abkhezr and Dryer ). The absence of attenuated albuminuria suggests that cysteine Caths are not involved in the development of SS hypertension‐associated proteinuria.…”