Elsevier

The Lancet

Volume 355, Issue 9205, 26 February 2000, Pages 741-744
The Lancet

Hypothesis
Prenylation inhibitors in renal disease

https://doi.org/10.1016/S0140-6736(99)08347-6Get rights and content

Summary

Members of the superfamily of Ras GTPase signalling proteins (monomeric G proteins) require post-translational carboxy-terminal prenylation to function. Prenylation is the covalent attachment of a hydrophobic prenyl group (either farnesyl or geranylgeranyl), which localises the GTPase to cell membranes. Ras proteins exert substantial control on cell proliferation and gene-transcription events, and prenylation inhibitors are now included in clinical trials for cancer. Many renal diseases are highly proliferative and are driven by a range of profibrotic cytokines. We hypothesise that inhibition of prenylation could be of substantial therapeutic benefit in such diseases, providing greater selectivity against abnormal cytokine-driven proliferation and fibrogenesis than current treatments available to nephrologists.

Section snippets

Cell proliferation and renal disease

Many renal diseases are characterised by excessive cellular proliferation, such as proliferation of epithelial cells and macrophages in crescentic glomerulonephritis and proliferation of mesangial cells in IgA nephropathy.1 Fibroblast proliferation is important in the progression of tubulointerstitial scarring, which seems to be a final common pathway for renal failure in a wide range of primary conditions.2 Proliferation of vascular-smoothmuscle cells is a typical feature of ischaemic

Ras superfamily of GTPases and prenylation

The Ras superfamily of proteins plays a crucial part in cell differentiation, proliferation, apoptosis, and regulation of transcription of many genes involved in inflammation and fibrogenesis.6, 7 Within this superfamily the two individual families of GTPases of most importance are the Ras family itself and the Rho family: oncogenic Ras mutations have been implicated in up to 30% of human cancers,8 and Rho proteins have a key role in maintaining cytoskeletal structure as well as regulating

Statins, prenylation, and renal disease

Indirect evidence linking prenylation to renal disease comes from the use of statins in vitro and in vivo. Lovastatin inhibits the activation of the transcription factor nuclear factor KB in human renal mesangial cells and this effect is reversed by the addition of mevalonate or farnesyl pyrophosphate.12 Prenylation blockade is therefore an important mechanism by which statins exert an antiproliferative effect. A wide array of genes are under the control of nuclear factor KB, including many

Prenylation inhibitors and their specific targets

The discovery that some mutated Ras proteins are solely dependent on farnesylation for prenylation has led to the use of farnesyl transferase as a target for anticancer therapy. In vivo work has shown that farnesyl-transferase inhibitors inhibit tumour growth in nude mouse xenografts24 and can cause tumour regression in oncogenic mice.25 Farnesyl-transferase inhibitors preferentially inhibit growth in transformed rather than normal cells and remarkably seem to have low toxicity in normal cells,

Testing the hypothesis and future therapeutic strategies

The idea that prenylation inhibitors are of potential use in the treatment of renal disease requires further testing in animals with proliferative and fibrotic renal disease. These could include the use of anti-Thy-1·1 glomerulonephritis and nephrotoxic serum nephritis as well as ischaemic nephropathy and ureteric obstruction. The main endpoints would include outcome for renal function and proteinuria, as well as histological assessment of glomerular damage, interstitial fibrosis, and

References (32)

  • SM Sebti et al.

    A novel approach to cancer chemotherapy

    Pharmacol Ther

    (1997)
  • DJ Augeri et al.

    Potent and orally bioavailable noncysteine-containing inhibitors of protein farnesyltransferase

    Bioorg Med Chem Lett

    (1999)
  • J Lanoix et al.

    Dysregulation of cellular proliferation and apoptosis mediates human autosomal dominant polycystic kidney disease (ADPKD)

    Oncogene

    (1996)
  • RJ Johnson

    Cytokines, growth factors and renal injury: where do we go now?

    Kidney Int

    (1997)
  • MS Boguski et al.

    Proteins regulating Ras and its relatives

    Nature

    (1993)
  • A Hall

    Rho GTPases and the actin cytoskeleton

    Science

    (1998)
  • Cited by (52)

    • Statins inhibit aminoglycoside accumulation and cytotoxicity to renal proximal tubule cells

      2010, Biochemical Pharmacology
      Citation Excerpt :

      Since statins have a relatively safe clinical profile, they represent a possible strategy for the prevention of nephrotoxicity in man through the blockade of AG uptake and accumulation. Statins can also prevent other forms of renal injury through their inhibition of protein prenylation [22]. In this in vitro study, we have therefore tested the hypothesis that through the pharmacological inhibition of HMG-CoA reductase, statins can inhibit the receptor-mediated endocytosis of AGs into cultured renal proximal tubule cells and the resultant cytotoxicity.

    • The management of CKD: A look into the future

      2007, Kidney International
      Citation Excerpt :

      A number of inhibitors targeting this pathway are already in use in oncology,36 these drugs may be promising therapeutics in progressive CKD. Statins also attenuate fibrogenesis in a number of in vivo models such as nephrotoxic nephritis,39 and there is a body of evidence to suggest that these effects are mediated by the inhibition of Ras signaling (by depleting prenylation substrates) rather than by cholesterol reduction.40 Clinical trials are underway to assess full potential of statins in the management of progressive CKD.

    • Fibroblast Differentiation in Wound Healing and Fibrosis

      2007, International Review of Cytology
    • The inhibition of human mesangial cell proliferation by S-trans, trans-farnesylthiosalicylic acid

      2005, Kidney International
      Citation Excerpt :

      Targeting Ras with FTS appears to be a promising therapeutic development. A number of other strategies that can target Ras may also be of clinical value in proliferative renal disease[30]. These include the use of statins, which inhibit the prenylation of Ras and Rho GTPases, as well as newer compounds that target signals upstream or downstream of Ras.

    View all citing articles on Scopus
    View full text