Abstract
Previous studies have shown that the transcription factor signal transducer and activator of transcription-3 (STAT3) in podocytes plays an important role in progression of HIV nephropathy and in collapsing forms of glomerulonephritis. Here, we have observed that application of 100 nM angiotensin II (Ang II) to cultured podocytes for 6–24 hours causes a marked increase in the phosphorylation of STAT3 on tyrosine Y705 but has no effect on phosphorylation at serine S727. By contrast, Ang II treatment of short periods (20–60 minutes) caused a small but consistent suppression of tyrosine phosphylation of STAT3. A similar biphasic effect was seen after treatment with the diacylglycerol analog 1-oleoyl-2-acetyl-sn-glycerol (OAG), an agent that causes activation of Ca2+-permeable canonical transient receptor potential-6 (TRPC6) channels in podocytes. The stimulatory effects of Ang II on STAT3 phosphorylation were abolished by small-interfering RNA knockdown of TRPC6 and also by inhibitors of the Ca2+-dependent downstream enzymes calcineurin and Ca2+-calmodulin-dependent protein kinase II. The stimulatory effects of Ang II appear to be mediated by secretion and accumulation of an unknown factor into the surrounding medium, as they are no longer detected when medium is replaced every 2 hours even if Ang II is continuously present. By contrast, the inhibitory effect of Ang II on STAT3 phosphorylation persists with frequent medium changes. Experiments with neutralizing and inhibitory antibodies suggest that the STAT3 stimulatory factor secreted from podocytes is not interleukin-6, but also suggest that this factor exerts its actions through a receptor system that requires glycoprotein 130.
Footnotes
- Received February 28, 2014.
- Accepted May 9, 2014.
This work was supported in part by an M. James Scherbenske award from the American Society of Nephrology (to S.E.D.), and by a contract from Pfizer, Inc. (to S.E.D.). The corresponding author had full control over the conduct of these experiments and controlled the decision to publish.
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- Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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