Abstract
Protein kinase A (PKA) regulates morphogenetic responses to bone morphogenetic proteins (BMPs) during embryogenesis. However, the mechanisms by which PKA regulates BMP function are unknown. During kidney development, BMP-2 and high doses of BMP-7 inhibit branching morphogenesis, whereas low doses of BMP-7 are stimulatory (Piscione, T. D., Yager, T. D., Gupta, I. R., Grinfeld, B., Pei, Y., Attisano, L., Wrana, J. L., and Rosenblum, N. D. (1997) Am. J. Physiol. 273, F961-F975). We examined the interactions between PKA and these BMPs in embryonic kidney explants and in the mouse inner medullary collecting duct-3 model of collecting duct morphogenesis. H-89, an inhibitor of PKA, stimulated branching morphogenesis and enhanced the stimulatory effect of low doses of BMP-7 on tubule formation. Furthermore, H-89 rescued the inhibition of tubulogenesis by BMP-2 (or high doses of BMP-7) by attenuating BMP-2-induced collecting duct apoptosis. In contrast, 8-bromo-cAMP, an activator of PKA, inhibited tubule formation and attenuated the stimulatory effects of low doses of BMP-7. To determine mechanisms underlying the interdependence of BMP signaling and PKA activity, we examined the effect of PKA on the known signaling events in the BMP-2-dependent Smad1 signaling pathway and the effect of BMP-2 on PKA activity. PKA did not induce endogenous Smad1 phosphorylation, Smad1-Smad4 complex formation, or Smad1 nuclear translocation. In contrast, BMP-2 increased endogenous PKA activity and induced phosphorylation of the PKA effector, cAMP-response element-binding protein, in a PKA-dependent manner. We conclude that BMP-2 induces activation of PKA and that PKA regulates the effects of BMPs on collecting duct morphogenesis without activating the known signaling events in the BMP-2-dependent Smad1 signaling pathway.
Highlights
Branching morphogenesis, defined as growth and branching of epithelial tubules during embryonic development, arises in the kidney through reciprocal mesenchymal-epithelial tissue interactions between the mesenchymal metanephric blastema and the epithelial ureteric bud [1]
To determine whether the dependence of inhibitory bone morphogenetic proteins (BMPs) on Protein kinase A (PKA) is mediated by regulation of the PKA signaling pathway by BMPs, we demonstrated that BMP-2 increases endogenous PKA activity and induces phosphorylation of its downstream effector, cAMP-response element-binding protein (CREB)
We show that PKA directly controls renal branching morphogenesis and, within this context, modifies the morphogenetic effects of stimulatory and inhibitory BMPs, and hepatocyte growth factor (HGF)
Summary
Branching morphogenesis, defined as growth and branching of epithelial tubules during embryonic development, arises in the kidney through reciprocal mesenchymal-epithelial tissue interactions between the mesenchymal metanephric blastema and the epithelial ureteric bud (and its derivative collecting ducts) [1]. Protein kinase A (PKA), an intracellular kinase, has been implicated in the control of morphogenesis in diverse nonrenal tissues including the central nervous system [5, 6], the eye [7], and the limb [8, 9] Within these tissues, PKA interacts with growth factor signaling pathways to regulate morphogenetic responses to BMPs [7,8,9]. Using embryonic renal explants and an in vitro cell culture model of tubulogenesis, we demonstrate that inhibition of PKA rescues ureteric buds or collecting ducts from the inhibitory effects of BMPs by decreasing tubular cell apoptosis Consistent with these effects, activation of PKA abrogates the stimulatory effects of low dose BMP-7. Our results show that PKA acts via a pathway parallel to ligand-induced Smad to inhibit renal branching morphogenesis and that PKA activity is positively regulated by BMP-2
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