Kidney International, Vol. 57 (2000), pp. 1770–1771

EDITORIAL

Polycystin: From structure to function

Autosomal dominant polycystic kidney disease ceptor tyrosine kinase inhibitors failed to block cAMP-(ADPKD) is a multisystem disease characterized by the mediated proliferation of tubular cells from ADPKDprogressive development of numerous fluid-filled cysts patients. These studies indicate that cAMP agonists stim-in the kidney, leading to chronic renal failure. Predomi- ulate PKA-mediated activation of ERK, at a locus distalnant tubular epithelial cell abnormalities associated with to receptor tyrosine kinase in ADPKD cells, but not inADPKD include abnormal maturation, excessive prolif- NHK cells.eration, and fluid secretion. Since polycystin 1 and poly- The basis for this fundamental difference in the prolif-cystin 2 have been cloned, more recent studies have erative response of ADPKD and NHK cells to cAMPfocused on defining the mechanism through which struc- agonists, and how this difference may be related to struc-tural alterations in these genes give rise to the tubular tural alterations in the polycystin molecules raises a num-epithelial cell abnormalities characteristic of ADPKD. ber of questions that need to be addressed by furtherPolycystin 1 has 9 to 11 transmembrane domains, a large study:amino terminal extracellular tail that appears to be in- (1) Is the cAMP-PKA pathway abnormally activatedvolved in cell-cell and cell-matrix interactions, and a in ADPKD? To demonstrate that the proliferative re-cytoplasmic carboxy terminus that contains a number of sponse of ADPKD cells to cAMP agonists is relevant tomotifs that may interact with the cytoskeleton and play our understanding of the pathophysiology of polycystican important role in intracellular signaling [1]. In vitro kidney disease, it will be necessary to show that theexpression studies have shown that the cytoplasmic do- cAMP-PKA pathway is indeed activated. There is somemain of polycystin 1 contains sites that are phosphory- indirect evidence in support of this activation. In thelated by protein kinase A and c-src [2] and may be in- murine pcy/pcy model of PKD, cystogenesis is associatedvolved in the protein kinase C a dependent and c-Jun with a progressive increase in renal cAMP content [5].N-terminal kinase dependent activation of transcription Cysts from human ADPKD patients contain micromolarfactors, including AP-1 [3]. concentrations of ATP and metabolites of ATP, presum-

Despite these advances, the mechanisms underlying ably released from cyst lining epithelial cells [6]. In the-excessive tubular epithelial cell proliferation in ADPKD ory, this concentration of ATP is sufficient to activate renalhave not been defined. In this issue of Kidney Interna- epithelial cell purinergic receptors, increasing secretion oftional, Yamaguchi and colleagues provide evidence that fluid into the cyst lumen. However, further studies arecyclic AMP (cAMP) may play a critical role as a second needed to determine whether intracellular activation ofmessenger in a signaling pathway leading to tubular epi- the cAMP-PKA pathway occurs in ADPKD.thelial cell proliferation and fluid secretion in ADPKD (2) If the cAMP-PKA pathway is indeed activated in[4]. In tubular epithelial cells derived from normal hu- ADPKD, how does this relate to structural abnormalitiesman kidney (NHK), agonists of the cAMP signaling sys- in the polycystin 1 and/or polycystin 2 gene products?tem block basal and growth factor-mediated activation of Cystogenic epithelium in ADPKD is often described asthe extracellular signal-regulated protein kinase (ERK) having a “fetal-like” phenotype, characterized by persis-pathway and inhibit proliferation. In contrast, Yama- tent expression of genes expressed during embryogene-guchi et al report that agonists of the cAMP signaling sis, by an increased rate of proliferation, and by abnormalsystem stimulate proliferation of tubular epithelial cells polarity of ion transporters and growth factor receptors.derived from patients with ADPKD. The stimulatory ef- It is certainly possible that structural abnormalities infect of cAMP on proliferation of ADPKD cells was associ- the polycystin molecules give rise to a wide variety ofated with activation of the ERK-pathway. Both protein defects in cell-cell and/or cell-matrix interactions duringkinase A (PKA) inhibitors and MEK (mitogen-activated, embryogenesis, and may thereby alter the pattern ofERK-activating kinase) inhibitors blocked the prolifera- gene expression associated with normal tubular epithe-tive response of ADPKD cells to cAMP. However, re- lial cell growth and development. The precise mechanism

by which these developmental alterations lead to in-creased cAMP-PKA signaling needs to be defined. An-Key words: ADPKD, cAMP, transcription factors, normal human

kidney. other possibility is that structural defects in and/or aber-rant expression of polycystin in tubular epithelial cells 2000 by the International Society of Nephrology

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Editorial 1771

gives rise to alterations in intracellular cAMP metabo- The studies by Yamaguchi et al provide indirect evi-dence that polycystin may play a key role in the organiza-lism in ADPKD. Intracellular cyclic nucleotide levels

are largely regulated through catabolic pathways medi- tion and integration of signals that regulate a variety ofprocesses, including proliferation and secretion. Studiesated by a large family of phosphodiesterases (PDEs) [7].

Even partial inhibition of PDEs may give rise to a many- to determine whether components of the cAMP-PKAsignaling pathway directly interact with polycystin andfold increase in cAMP-PKA signaling. Recent studies,

using PDE isoform-specific inhibitors, have demonstrated to determine how these interactions may be altered mayprovide important insights into the pathophysiology ofthat mesangial cells contain functionally compartmental-

ized pools of cAMP that regulate disparate cellular func- ADPKD. These studies may provide the basis for tar-geting the cAMP-PKA pathway through “signal trans-tions, including mitogenesis and reactive oxygen species

generation. Activation of the cAMP-PKA pathway in duction pharmacotherapy” to inhibit tubular epithelialcell mitogenesis and secretion, thereby retarding the rateADPKD may therefore be secondary to a deficiency

in PDE production and/or compartmentalization. Even of cystogenesis in patients with ADPKD.though it may be possible to relate deficiencies in PDE

Joseph P. Grandeproduction and/or localization to structural abnormali-Rochester, Minnesota, USAties in polycystin, it will be more difficult to explain the

fundamental difference in cAMP-PKA mitogenic signal-ACKNOWLEDGMENTing between ADPKD cells and NHK cells, as observed

This work is dedicated to the memory of Dr. Thomas Dousa, myby Yamaguchi and colleagues, on this basis.friend and colleague, who has contributed greatly to our understanding(3) Are targets of the cAMP-PKA signaling pathway of signaling mechanisms underlying renal pathophysiologic states.

different in ADPKD versus NHK cells? In many cell types,Correspondence to Joseph P. Grande, M.D., Ph.D., Mayo Clinic,activation of growth factor receptors by ligand triggers

200 First Street SW, Guggenheim Building 501, Rochester, Minnesota,activation of the low molecular weight G protein Ras, 55905, USA.with subsequent activation of Raf-1, followed by MEK-1 E-mail: grande.joseph@mayo.eduand ERK. In mesangial cells and many other cell types,cAMP-mediated PKA activation apparently leads to REFERENCESphosphorylation of Raf-1 at an inhibitory site, preventing 1. Hughes J, Ward C, Peral B, Aspinwall R, Clark K, San Millanthe activation of MEK-1 [8]. Dr. Yamaguchi and col- J: The polycystic kidney disease (PKD1) gene encodes a novel

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