Normally cAMP’s role in the renal epthilum is to inhibit the Ras/Raf-1/MEK/ERK pathway at Raf-1 causing inhibition of cell proliferation. In contrast, cAMP has been shown to stimulate ?-Raf (via cSrc–dependent phosphorylation)
and to activate the MEK/ERK pathway in ARPKD cells, leading to increased cell proliferation (65,66,67,68,69).
Therefore, cAMP can act to stimulate or inhibit proliferation depending on intracellular conditions. This phenotypic shift in response to cAMP appears to involve cross talk between cAMP and Ca2+ and the cSrc signaling in response to ?-Raf, a kinase upstream
of the MEK/ERK pathway (57,70).
In normal cells, ?-Raf is repressed by Akt (protein kinase B), a Ca2+-dependent kinase, preventing cAMP activation of ERK and cell proliferation. In PKD epithelia from either ARPKD or ADPKD kidneys, low Ca2+ levels and cSrc-dependent phosphorylation of ?-Raf
result in an increased expression of cAMP and a switch in cAMP from an antiproliferative signaling molecule to a promitogenic stimulus that both activates the MEK/ERK pathway and promotes cellular proliferation and secretion (57,70).
The switch in cAMP from an antimitogenic to a mitogenic stimulus has been shown to be directly correlated with intracellular Ca2i (68).
Pharmacological elevation of Ca2+ increases phospho-Akt levels, whereas Ca2+ channel blockers decrease phospho-Akt (69).
This observation that the reduction of intracellular Ca2i in M-1 or normal human kidney cells with calcium channel blockers replicates the abnormal proliferative response of PKD cells to cAMP establishes a link among the PKD proliferative phenotype, reduction
in Ca2+i, and cAMP activity (70).
Evidence for the role of Ca2+i-mediated proliferation has been further strengthened by studies showing that the elevation of Ca2+i levels in ADPKD-cultured and ARPKD-cultured cells increases Akt activity and blocks cAMP-dependent
?-Raf and ERK activation (69). The study has
also demonstrated that increases in Ca2+i restore the normal antimitogenic response to cAMP in renal cells derived from human ADPKD or ARPKD kidneys.
These data suggest that the PKD proteins (PC1, PC2, and fibrocystin) play a role in maintaining Ca2+ homeostasis. Mutations in any of the PKD proteins may lead to reduced Ca2+i and activate the cAMP mitogenic pathway