Skip to main content

Main menu

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • Article Collections
    • JASN Podcasts
    • Archives
    • Saved Searches
    • ASN Meeting Abstracts
  • Authors
    • Submit a Manuscript
    • Author Resources
  • Editorial Team
  • Subscriptions
  • More
    • About JASN
    • Alerts
    • Advertising
    • Editorial Fellowship Team
    • Feedback
    • Reprints
    • Impact Factor
    • Editorial Fellowship Application Process
  • ASN Kidney News
  • Other
    • CJASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology

User menu

  • Subscribe
  • My alerts
  • Log in
  • Log out
  • My Cart

Search

  • Advanced search
American Society of Nephrology
  • Other
    • CJASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology
  • Subscribe
  • My alerts
  • Log in
  • Log out
  • My Cart
Advertisement
American Society of Nephrology

Advanced Search

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • Article Collections
    • JASN Podcasts
    • Archives
    • Saved Searches
    • ASN Meeting Abstracts
  • Authors
    • Submit a Manuscript
    • Author Resources
  • Editorial Team
  • Subscriptions
  • More
    • About JASN
    • Alerts
    • Advertising
    • Editorial Fellowship Team
    • Feedback
    • Reprints
    • Impact Factor
    • Editorial Fellowship Application Process
  • ASN Kidney News
  • Follow JASN on Twitter
  • Visit ASN on Facebook
  • Follow JASN on RSS
  • Community Forum
Editorials
You have accessRestricted Access

Regulating Renal Drug Elimination?

Florian Lang
JASN June 2005, 16 (6) 1535-1536; DOI: https://doi.org/10.1681/ASN.2005030311
Florian Lang
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Info & Metrics
  • View PDF
Loading

Among the clinically highly relevant functions of the kidney is the elimination of xenobiotics, including drugs. In the past years a wide variety of transport systems have been identified serving renal transport of organic cations and anions (1–4). The operation of several of those transport proteins and the partially poor substrate selectivity allows the kidneys to efficiently eliminate a multitude of xenobiotics (1,3,4). Needless to say, altered function of the transporters is expected to modify plasma levels of the drugs and thus their efficacy and side effects. Nephrologists know well that acute or chronic renal failure affects the appropriate dosage of a wide variety of drugs (5). Compelling evidence suggests, however, that renal elimination of certain drugs could be compromised in a seemingly normal kidney.

In recent years polymorphisms of genes encoding proteins involved in the metabolism and subsequent renal and/or extrarenal elimination of xenobiotics have been shown to correlate with drug sensitivity (3,4). Gain of function of an organic cation transporter (OCT) relevant for drug elimination will decrease plasma levels and may prevent appropriate therapeutic effects at standard dosage. A loss-of-function polymorphism may lead to increased toxicity in affected individuals.

The article by Ciarimboli et al. (6) sheds new light on a further possible cause of deranged drug elimination, i.e., altered regulation of the carrier. The authors demonstrate that activation of protein kinase C (PKC) leads to strong stimulation of the organic cation transporter rOCT1 expressed in human embryonic kidney cells. In a laudable molecular analysis they identify the putative phosphorylation sites within the carrier molecule. Moreover, they provide evidence that PKC does not only increase the maximal transport rate but that it alters the relative selectivity of the carrier. Those observations could imply that the effect of PKC activation may not uniformly modify all substrates of the carrier. In prior studies (7,8) the authors provided evidence that cation transporter isoforms do not only differ in substrate affinities but also in regulation. The article in this issue of JASN is not only of high theoretical interest but may also disclose novel potential mechanisms causing deranged drug elimination.

First, stimulation of PKC and similar kinases may affect renal drug elimination. For instance, marked upregulation of PKC has been observed in diabetic nephropathy (9–16) which could in theory interfere with drug elimination. Moreover, gain-of-function or loss-of-function mutations of PKC related kinases may affect the regulation of the carriers and thus drug elimination. Polymorphisms of different PKC isoforms have been described and associated with diverse diseases (17–20). A common gain-of-function gene variant has been identified for the serum and glucocorticoid inducible kinase SGK1 (21), which is similarly upregulated in diabetic nephropathy (22) and regulates a wide variety of transport mechanisms (23,24). It would be interesting to explore whether any of those polymorphisms is associated with altered drug elimination. Finally, polymorphisms affecting the carrier phosphorylation sites may affect the in vivo regulation of the otherwise intact carrier and thus again modify drug excretion.

At this time, the role of dysregulated carriers in deranged drug excretion is a matter of speculation, and experimental efforts are required explore the role of kinases in the excretion of xenobiotics. We are only beginning to appreciate that a seemingly normal kidney may differ in function and regulation of specific channels and carriers and that renal drug elimination may be sensitive to altered function or regulation of distinct carriers involved in the renal elimination of xenobiotics. Much has to be learned before the present knowledge can be translated into drug safety. But the article by Ciarimboli et al. (6) should encourage researchers to correlate polymorphisms of genes encoding transport-regulating kinases with drug elimination.

Footnotes

  • Published online ahead of print. Publication date available at www.jasn.org.

  • © 2005 American Society of Nephrology

References

  1. ↵
    Koepsell H, Schmitt BM, Gorboulev V: Organic cation transporters. Rev Physiol Biochem Pharmacol 150 : 36 –90, 2003
    OpenUrlPubMed
  2. Lee W, Kim RB: Transporters and renal drug elimination. Annu Rev Pharmacol Toxicol 44 : 137 –166, 2004
    OpenUrlCrossRefPubMed
  3. ↵
    Marzolini C, Tirona RG, Kim RB: Pharmacogenomics of the OATP and OAT families. Pharmacogenomics 5 : 273 –282, 2004
    OpenUrlCrossRefPubMed
  4. ↵
    Schwab M, Eichelbaum M, Fromm MF: Genetic polymorphisms of the human MDR1 drug transporter. AnnuRev Pharmacol Toxicol 43 : 285 –307, 2003
    OpenUrlCrossRefPubMed
  5. ↵
    Cutler RE, Forland SC: Pharmacokinetics of drugs and the effects of renal failure. In: Textbook of Nephrology, edited by Massry SG, Glassock RJ, Philadelphia, Lippincott Williams & Wilkins, 2001
  6. ↵
    Ciarimboli G, Koepsell H, Iordanova M, Gorboulev V, Durner B, Lang D, Edemir B, Schröter R, Van Le T, Schlatter E: Individual PKC-phosphorylation sites in organic cation transposter 1 determine substrate selectivity and transport regulation. J Am Soc Nephrol 16 : 1562 –1570, 2005
    OpenUrlAbstract/FREE Full Text
  7. ↵
    Ciarimboli G, Schlatter E: Regulation of organic cation transport. Pflugers Arch 449 : 423 –441, 2005
    OpenUrlCrossRefPubMed
  8. ↵
    Pietig G, Mehrens T, Hirsch JR, Cetinkaya I, Piechota H, Schlatter E: Properties and regulation of organic cation transport in freshly isolated human proximal tubules. J Biol Chem 276 : 33741 –33746, 2001
    OpenUrlAbstract/FREE Full Text
  9. ↵
    Awazu M, Ishikura K, Hida M, Hoshiya M: Mechanisms of mitogen-activated protein kinase activation in experimental diabetes. J Am Soc Nephrol 10 : 738 –745, 1999
    OpenUrlAbstract/FREE Full Text
  10. Ceol M, Gambaro G, Sauer U, Baggio B, Anglani F, Forino M, Facchin S, Bordin L, Weigert C, Nerlich A, Schleicher ED: Glycosaminoglycan therapy prevents TGF-beta1 overexpression and pathologic changes in renal tissue of long-term diabetic rats. J Am Soc Nephrol 11 : 2324 –2336, 2000
    OpenUrlAbstract/FREE Full Text
  11. Ha H, Yu MR, Choi YJ, Kitamura M, Lee HB: Role of high glucose-induced nuclear factor-kappaB activation in monocyte chemoattractant protein-1 expression by mesangial cells. J Am Soc Nephrol 13 : 894 –902, 2002
    OpenUrlAbstract/FREE Full Text
  12. Hayashida T, Schnaper HW: High ambient glucose enhances sensitivity to TGF-beta1 via extracellular signal–regulated kinase and protein kinase Cdelta activities in human mesangial cells. J Am Soc Nephrol 15 : 2032 –2041, 2004
    OpenUrlAbstract/FREE Full Text
  13. Lee GT, Ha H, Jung M, Li H, Hong SW, Cha BS, Lee HC, Cho YD: Delayed treatment with lithospermate B attenuates experimental diabetic renal injury. J Am Soc Nephrol 14 : 709 –720, 2003
    OpenUrlAbstract/FREE Full Text
  14. Lee HB, Yu MR, Yang Y, Jiang Z, Ha H: Reactive oxygen species-regulated signaling pathways in diabetic nephropathy. J Am Soc Nephrol 14 : S241 –S245, 2003
    OpenUrlAbstract/FREE Full Text
  15. Menne J, Park JK, Boehne M, Elger M, Lindschau C, Kirsch T, Meier M, Gueler F, Fiebeler A, Bahlmann FH, Leitges M, Haller H: Diminished loss of proteoglycans and lack of albuminuria in protein kinase C-alpha-deficient diabetic mice. Diabetes 53 : 2101 –2109, 2004
    OpenUrlAbstract/FREE Full Text
  16. ↵
    Yoo CW, Song CY, Kim BC, Hong HK, Lee HS: Glycated albumin induces superoxide generation in mesangial cells. Cell Physiol Biochem 14 : 361 –368, 2004
    OpenUrlPubMed
  17. ↵
    Chen DH, Brkanac Z, Verlinde CL, Tan XJ, Bylenok L, Nochlin D, Matsushita M, Lipe H, Wolff J, Fernandez M, Cimino PJ, Bird TD, Raskind WH: Missense mutations in the regulatory domain of PKC gamma: A new mechanism for dominant nonepisodic cerebellar ataxia. Am J Hum Genet 72 : 839 –849, 2003
    OpenUrlCrossRefPubMed
  18. Ikeda Y, Suehiro T, Osaki F, Tsuzura S, Kumon Y, Hashimoto K: Polymorphisms in the 5′-upstream region of the PKCbeta gene in Japanese patients with type 2 diabetes. Diabet Med 21 : 1113 –1120, 2004
    OpenUrlCrossRefPubMed
  19. Knauf JA, Ward LS, Nikiforov YE, Nikiforova M, Puxeddu E, Medvedovic M, Liron T, Mochly-Rosen D, Fagin JA: Isozyme-specific abnormalities of PKC in thyroid cancer: Evidence for post-transcriptional changes in PKC epsilon. J Clin Endocrinol Metab 87 : 2150 –2159, 2002
    OpenUrlCrossRefPubMed
  20. ↵
    Kofler K, Erdel M, Utermann G, Baier G: Molecular genetics and structural genomics of the human protein kinase C gene module. Genome Biol 3 : RESEARCH0014, 2002
  21. ↵
    Busjahn A, Aydin A, Uhlmann R, Krasko C, Bahring S, Szelestei T, Feng Y, Dahm S, Sharma AM, Luft FC, Lang F: Serum- and glucocorticoid-regulated kinase (SGK1) gene and blood pressure. Hypertension 40 : 256 –260, 2002
    OpenUrlAbstract/FREE Full Text
  22. ↵
    Lang F, Klingel K, Wagner CA, Stegen C, Warntges S, Friedrich B, Lanzendorfer M, Melzig J, Moschen I, Steuer S, Waldegger S, Sauter M, Paulmichl M, Gerke V, Risler T, Gamba G, Capasso G, Kandolf R, Hebert SC, Massry SG, Broer S: Deranged transcriptional regulation of cell-volume-sensitive kinase hSGK in diabetic nephropathy. Proc Natl Acad Sci U S A 97 : 8157 –8162, 2000
    OpenUrlAbstract/FREE Full Text
  23. ↵
    Lang F, Henke G, Embark HM, Waldegger S, Palmada M, Bohmer C, Vallon V: Regulation of channels by the serum and glucocorticoid-inducible kinase—Implications for transport, excitability and cell proliferation. Cell Physiol Biochem 13 : 41 –50, 2003
    OpenUrlCrossRefPubMed
  24. ↵
    Pearce D: SGK1 regulation of epithelial sodium transport. Cell Physiol Biochem 13 : 13 –20, 2003
    OpenUrlCrossRefPubMed
PreviousNext
Back to top

In this issue

Journal of the American Society of Nephrology: 16 (6)
Journal of the American Society of Nephrology
Vol. 16, Issue 6
1 Jun 2005
  • Table of Contents
  • Index by author
View Selected Citations (0)
Print
Download PDF
Sign up for Alerts
Email Article
Thank you for your help in sharing the high-quality science in JASN.
Enter multiple addresses on separate lines or separate them with commas.
Regulating Renal Drug Elimination?
(Your Name) has sent you a message from American Society of Nephrology
(Your Name) thought you would like to see the American Society of Nephrology web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Regulating Renal Drug Elimination?
Florian Lang
JASN Jun 2005, 16 (6) 1535-1536; DOI: 10.1681/ASN.2005030311

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Request Permissions
Share
Regulating Renal Drug Elimination?
Florian Lang
JASN Jun 2005, 16 (6) 1535-1536; DOI: 10.1681/ASN.2005030311
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like

Jump to section

  • Article
    • Footnotes
    • References
  • Info & Metrics
  • View PDF

More in this TOC Section

  • Me Or Your Own Eyes: RNA-Seq and the Kidney
  • Promoting Equity in Eligibility for Registration on the Kidney Transplantation Waiting List: Looking beyond eGFRcr
  • Glomerular Exostosin Deposits in Membranous Lupus Nephritis—a Dialogue
Show more Editorials

Cited By...

  • Pharmacology behind Common Drug Nephrotoxicities
  • Onco-Nephrology: Renal Toxicities of Chemotherapeutic Agents
  • Renal Vulnerability to Drug Toxicity
  • Google Scholar

Similar Articles

Related Articles

  • No related articles found.
  • PubMed
  • Google Scholar

Articles

  • Current Issue
  • Early Access
  • Subject Collections
  • Article Archive
  • ASN Annual Meeting Abstracts

Information for Authors

  • Submit a Manuscript
  • Author Resources
  • Editorial Fellowship Program
  • ASN Journal Policies
  • Reuse/Reprint Policy

About

  • JASN
  • ASN
  • ASN Journals
  • ASN Kidney News

Journal Information

  • About JASN
  • JASN Email Alerts
  • JASN Key Impact Information
  • JASN Podcasts
  • JASN RSS Feeds
  • Editorial Board

More Information

  • Advertise
  • ASN Podcasts
  • ASN Publications
  • Become an ASN Member
  • Feedback
  • Follow on Twitter
  • Password/Email Address Changes
  • Subscribe

© 2021 American Society of Nephrology

Print ISSN - 1046-6673 Online ISSN - 1533-3450

Powered by HighWire