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1 Department of Medicine, Yale University School of Medicine, New Haven, CT, USA
2 Probiodrug AG, Halle (Saale), Germany
* To whom correspondence should be addressed. E-mail: peter.aronson{at}yale.edu.
We have recently reported that NHE3 exists in multimeric complexes with dipeptidyl peptidase IV (DPPIV) in renal brush border membranes. To examine the possible role of DPPIV in modulating NHE3 activity, we evaluated whether specific competitive inhibitors that bind to the active site of DPPIV affect NHE3 activity in the OKP line of proximal tubule cells. The DPPIV inhibitors diprotin A and P32/98 significantly reduced NHE3 activity whereas the inactive isomer P34/98 had no effect. DPPIV inhibitors did not reduce the activity of another brush border transport process, Na/Pi cotransport. Effects of DPPIV inhibitors on NHE3 activity were not associated with detectable changes in amount or apparent molecular weight of NHE3 or in NHE3 surface expression. To investigate the signaling mechanisms involved in modulation of NHE3 activity by DPPIV, we used inhibitors of protein kinase pathways known to regulate NHE3. While the PKA inhibitor H89 failed to block the effect of DPPIV, the tyrosine kinase inhibitor genistein alone caused a decrement in NHE3 activity very similar in magnitude to that caused by P32/98. We also found that the effects of genistein and P32/98 on NHE3 activity were not additive. In contrast, forskolin/IBMX and P32/98 had additive inhibitory effects on NHE3 activity. These findings suggested that the effect of DPPIV inhibitors to reduce NHE3 activity results from inhibition of a tyrosine kinase signaling pathway rather than by activation of PKA. We conclude that DPPIV plays an unexpected role in modulating Na+-H+ exchange mediated by NHE3 in proximal tubule cells.
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