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NDT Advance Access originally published online on April 4, 2007
Nephrology Dialysis Transplantation 2007 22(8):2133-2135; doi:10.1093/ndt/gfm178
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Prime time for polycystic kidney disease: does one shot of roscovitine bring the cure?*

E. Wolfgang Kuehn and Gerd Walz

Renal Division, University Hospital Freiburg, Hugstetter Strasse 55, 79104 Freiburg, Germany

Correspondence and offprint requests to: Gerd Walz, Renal Division, Hugstetter Strasse 55 79104 Freiburg, Germany. Email: gerd.walz{at}uniklinik-freiburg.de

Keywords: ADPKD; mTOR; polycystic kidney disease; roscovitine; therapy; vasopressin-2-receptor antagonists



   Introduction
Top
 Introduction
Subjects and methods
 Discussion and conclusion
 References
 
Autosomal dominant polycystic kidney disease (ADPKD), caused by either PKD1 or PKD2 mutations, relentlessly progresses to end-stage renal disease (ESRD) in more than half of the affected patients. Although the pathogenesis is still incompletely understood, several potential therapies are now emerging that promise to effectively prevent cyst formation and progression. In a lifelong disease, therapeutics with a long-lasting effect after a brief application appear particularly attractive. (R)-roscovitine, a protein kinase inhibitor with preferential selectivity for cyclin-dependent kinases (CDKs), may be just such a drug. A recent report demonstrates that roscovitine blocks cyst progression in two animal models of PKD, the jck (NEK8) and cpk (cystin) mouse. Roscovitine prevents phosphorylation of the retinoblastoma protein (Rb) through inhibition of CDKs, and normalizes the levels of several cyclins, thereby preventing cell proliferation. In addition, roscovitine ameliorates cyst progression, through inhibition of transcription and apoptosis. Perhaps most importantly, a 3-week course of therapy had a long-lasting beneficial effect on disease progression. In several clinical trials, roscovitine is reportedly well tolerated, adding yet another exciting approach to the list of putative therapies in ADPKD.



   Subjects and methods
Top
 Introduction
 Subjects and methods
Discussion and conclusion
 References
 
The pathogenesis of polycystic kidney disease
ADPKD and its much less common autosomal recessive siblings (e.g. ARPKD, nephronophthisis) were long considered untreatable hereditary defects. Over the last couple of years, several therapeutic approaches have surfaced that, in contrast to their predecessors, hold promise of a long-awaited cure [1]. ADPKD, caused by mutations of either PKD1 (polycystin-1) or PKD2 (polycystin-2), is characterized by progressive cyst formation leading to ESRD over the course of approximately five decades [2]. The pathogenesis of cyst formation has recently been linked to a ciliary defect. Deflection of the primary (non-motile) cilium that decorates most mammalian cells, causes an increase in intracellular calcium [3]. This calcium transient, which requires an intact polycystin-1/polycystin-2 complex and may be triggered by urine flow in vivo [4], appears to orient tubular cells along the anterior–posterior axis of the nephron [5,6]. Defective ciliary signalling results in confusion: rather than oriented divisions along the nephron, cells divide randomly and form cysts [7]. In ADPKD, <1% of all nephrons acquire a second somatic mutation that in combination with a germline mutation results in cystogenesis. Although mechanical compression, increased apoptosis of healthy tissue, and reactive fibrosis have been evoked to explain the progressive loss of renal function, why patients with ADPKD develop ESRD has remained largely elusive. This discrepancy may indicate that the pathogenesis of cyst formation and cyst progression differs, opening a window for therapeutic interventions.

Vasopressin-2-receptor antagonists and mTOR inhibitors
The cyst fluid contains several growth factors and hormones (e.g. antidiuretic hormone, ADH) that stimulate cyclic adenosine monophosphate (cAMP) accumulation and augment fluid secretion (Figure 1A). Many cyst cells express the vasopressin-2-receptor (V2R), and V2R antagonists, already tested in small clinical trials to increase water excretion in heart failure, showed spectacular effects in several animal models of PKD [8,9]. This benefit also holds up for the effects of rapamycin, an inhibitor of mTOR. Cells lining the cysts of human ADPKD kidneys, as well as several animal models, contain increased amounts of activated mTOR, a kinase that stimulates protein translation and cell growth in addition to many other actions (Figure 1B). The mTOR inhibitor rapamycin effectively blocks cyst progression, and exerts a dramatic effect on cyst and kidney growth [10–12]. These findings nurture the hope that therapeutics for ADPKD can be found that target the final common pathway of disease progression independently of the gene mutation that originally triggered the cyst formation.


Figure 1
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  		Fig. 1. Mode of drugs used to treat PKD. (A) Vasopressin-2-receptor antagonists. Binding of antidiuretic hormone (ADH) to the vasopressin-2-receptor results in G{alpha}s-dependent activation of adenylyl cyclase VI, production of cAMP, and cAMP-dependent chloride and fluid secretion. Vasopressin-2-receptor antagonists (V2RA) prevent ADH-mediated cAMP-stimulation and fluid secretion. (B) Inhibition of mTOR (mamalian target of rapamycin). The tuberous sclerosis complex (TSC), consisting of the gene products of TSC1 and TSC2 (hamartin, tuberin), is the central regulator of the small GTPase Rheb. Rheb regulates mTORC 1 (mTOR complex 1), which contains mTOR, raptor (regulatory associated protein of mTOR) and GßL (G protein ß-subunit-like protein) and mTORC 2, containing mTOR, GßL and rictor (rapamycin-independent companion of mTOR). Ciliary signalling and direct interaction of polycystins with the TSC complex appear to facilitate the negative effect of the TSC on Rheb, since the activity of mTOR is up-regulated in the cysts cells of patients with ADPKD [12]. Rapamycin inhibits mTORC1, resulting in decreased proliferation and increased apoptosis of cyst lining cells.

 
CDK inhibitors
With two excellent therapeutic options at hand, how did roscovitine make it into prime time? (R)-roscovitine is a potent Cdk2-cyclin E inhibitor, but also inhibits Cdk7, Cdk9, Cdk5 and other targets (Figure 2A). In their article, Bukanov et al. [13,14] treated jck (NEK8-mutant) mice with 50 and 150 mg/kg roscovitine for a total of 5 weeks, starting at 26 days of age. Both doses dramatically inhibited cyst and kidney growth, and the higher roscovitine dose also normalized BUN concentrations. Similar results were obtained in a second model of polycystic disease, the cpk (cystin-mutant) mouse [15]. Surprisingly, and perhaps most promising, 150 mg/kg/day roscovitine, given either for the first three weeks or every other week, were almost as effective as the continuous 5-week application. Although neither NEK8 nor cystin mutations have been found to cause human disease, the efficacy in both mouse models supports the hypothesis that CDK inhibitors target yet another essential component of the final common pathway of cyst progression. In a careful analysis, the authors detail the effects of roscovitine on cyst progression, and outline some of the mechanisms that appear to explain the dramatic effect of this drug in PKD (Figure 2B). R-roscovitine, through inhibition of Cdk2, prevents phosphorylation of Rb, and maintains the transcription factor E2F in an inactive state. Roscovitine normalizes phosphorylation of cyclin D1, and decreases the up-regulated levels of cyclin D2 and D3 by blocking ERK1/ERK2 activation [16]. Roscovitine also inhibits Cdk7 and Cdk9, thereby preventing the activation of RNA polymerase II (RNA pol II) and RNA pol II-dependent transcription. Down-regulation of the pro-apoptotic Cdk5-p25 in combination with the up-regulation of Bcl-2 and Bcl-xL appears to block apoptosis in the kidneys of roscovitine-treated jck mice.


Figure 2
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  		Fig. 2. Roscovitine in PKD. (A) Roscovitine. The (R)-sterioisomer of roscovitine (CYC202, Seliciclib; Cyclacel Ltd, Dundee, UK) is a small molecular weight compound of the 2,6,9-trisubstituted purine family; it binds to the ATP-binding pocket of cyclin-dependent kinases (CDKs). Roscovitine is fairly specific for CDKs, but also inhibits pyridoxal kinase, the enzyme responsible for activation of vitamin B6, and can prinicipally block other ATP-, GTP- or NAD-dependent protein kinases [16]. (B) Targets of roscovitine in PKD. (R)-Roscovitine is a potent Cdk2 inhibitor, preventing phosphorylation of the retinoblastoma protein (Rb). Roscovitine normalizes the phosphorylation level of cyclin D1, and inhibits D2 and D3 expression, in part through inhibition of the ERK1/ERK2 cascade [16]. Inhibition of Cdk7 and Cdk9, which phosphorylate and activate RNA polymerase II (RNA pol II), prevent RNA pol II-dependent transcription. Down-regulation of Cdk5-p25 and up-regulation of Bcl-2 and Bcl-xL expression may contribute to the anti-apoptotic effects observed in mouse models of PKD (modified from [14]).

 


   Discussion and conclusion
Top
 Introduction
 Subjects and methods
 Discussion and conclusion
References
 
Can ADPKD patients benefit from CDK inhibitors?
An intermittent or short-term therapy is appealing in a chronic disease that progresses over the course of five decades, and likely requires lifelong treatment. Other cancer drugs, for example taxol [17], previously entered centre court of polycystic kidney research, but did not translate into clinical trials, since the anticipated rate of side effects was considerable. What is so different about roscovitine? Similar to taxol, roscovitine is an anticancer drug that is currently being tested in several phase I/II clinical cancer trials. Although lower doses of the drug are surprisingly well tolerated [19], hyponatraemia and severe hypokalaemia, as well as acute renal failure with decreased renal blood flow on radioisotope imaging, were observed at higher doses [18]. These are worrying features in a therapy aimed to slow progression of ADPKD. Nevertheless, kinase inhibitors add to our armamentarium of novel therapeutic options to maintain renal function in patients with ADPKD.

Conflict of interest statement. None declared.



   Notes
 
*Comment on Bukanov NO, Smith LA, Klinger KW, Ledbetter SR, Ibraghimov-Beskrovnaya O. Long-lasting arrest of murine polycystic kidney disease with CDK inhibitor roscovitine. Nature 2006; 444: 949–952. Back



   References
Top
 Introduction
 Subjects and methods
 Discussion and conclusion
 References
 

  1. Walz G. Therapeutic approaches in autosomal dominant polycystic kidney disease (ADPKD): is there light at the end of the tunnel? Nephrol Dial Transplant (2006) 21:1752–1757.[Free Full Text]
  2. Wilson PD. Polycystic kidney disease. N Engl J Med (2004) 350:151–164.[Free Full Text]
  3. Praetorius HA, Spring KR. Bending the MDCK cell primary cilium increases intracellular calcium. J Membr Biol (2001) 184:71–79.[CrossRef][Web of Science][Medline]
  4. Nauli SM, Alenghat FJ, Luo Y, et al. Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat Genet (2003) 33:129–137.[CrossRef][Web of Science][Medline]
  5. Simons M, Gloy J, Ganner A, et al. Inversin, the gene product mutated in nephronophthisis type II, functions as a molecular switch between Wnt signaling pathways. Nat Genet (2005) 37:537–543.[CrossRef][Web of Science][Medline]
  6. Simons M, Walz G. Polycystic kidney disease: cell division without a c(l)ue? Kidney Int (2006) 70:854–864.[CrossRef][Web of Science][Medline]
  7. Fischer E, Legue E, Doyen A, et al. Defective planar cell polarity in polycystic kidney disease. Nat Genet (2006) 38:21–23.[CrossRef][Web of Science][Medline]
  8. Gattone VH II, Wang X, Harris PC, Torres VE. Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist. Nat Med (2003) 9:1323–1326.[CrossRef][Web of Science][Medline]
  9. Torres VE, Wang X, Qian Q, Somlo S, Harris PC, Gattone VH II. Effective treatment of an orthologous model of autosomal dominant polycystic kidney disease. Nat Med (2004) 10:363–364.[CrossRef][Web of Science][Medline]
  10. Tao Y, Kim J, Schrier RW, Edelstein CL. Rapamycin markedly slows disease progression in a rat model of polycystic kidney disease. J Am Soc Nephrol (2005) 16:46–51.[Abstract/Free Full Text]
  11. Wahl PR, Serra AL, Le Hir M, Molle KD, Hall MN, Wuthrich RP. Inhibition of mTOR with sirolimus slows disease progression in Han:SPRD rats with autosomal dominant polycystic kidney disease (ADPKD). Nephrol Dial Transplant (2006) 21:598–604.[Abstract/Free Full Text]
  12. Shillingford JM, Murcia NS, Larson CH, et al. The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease. Proc Natl Acad Sci USA (2006).
  13. Smith LA, Bukanov NO, Husson H, et al. Development of polycystic kidney disease in juvenile cystic kidney mice: insights into pathogenesis, ciliary abnormalities, and common features with human disease. J Am Soc Nephrol (2006) 17:2821–2831.[Abstract/Free Full Text]
  14. Bukanov NO, Smith LA, Klinger KW, Ledbetter SR, Ibraghimov-Beskrovnaya O. Long-lasting arrest of murine polycystic kidney disease with CDK inhibitor roscovitine. Nature (2006) 444:949–952.[CrossRef][Medline]
  15. Hou X, Mrug M, Yoder BK, et al. Cystin, a novel cilia-associated protein, is disrupted in the cpk mouse model of polycystic kidney disease. J Clin Invest (2002) 109:533–540.[CrossRef][Web of Science][Medline]
  16. Bach S, Knockaert M, Reinhardt J, et al. Roscovitine targets, protein kinases and pyridoxal kinase. J Biol Chem (2005) 280:31208–31219.[Abstract/Free Full Text]
  17. Woo DD, Miao SY, Pelayo JC, Woolf AS. Taxol inhibits progression of congenital polycystic kidney disease. Nature (1994) 368:750–753.[CrossRef][Medline]
  18. Benson C, White J, Bono JD, et al. A phase I trial of the selective oral cyclin-dependent kinase inhibitor seliciclib (CYC202; R-Roscovitine), administered twice daily for 7 days every 21 days. Br J Cancer (2006).
  19. de la Motte S, Gianella-Borradori A. Pharmacokinetic model of R-roscovitine and its metabolite in healthy male subjects. Int J Clin Pharmacol Ther (2004) 42:232–239.[Web of Science][Medline]
Received for publication: 14. 2.07
Accepted in revised form: 7. 3.07


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