Reduction of advanced liver fibrosis by short-term targeted delivery of an angiotensin receptor blocker to hepatic stellate cells in rats

Montserrat Moreno, Teresa Gonzalo, Robbert J. Kok, Pau Sancho-Bru, Marike Van Beuge, Josine Swart, Jai Prakash, Kai Temming, Constantino Fondevila, Leonie Beljaars, Marie Lacombe, Paul Van Der Hoeven, Vicente Arroyo, Klaas Poelstra, David A. Brenner, Pere Giǹes, Raḿon Bataller*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    108 Citations (Scopus)

    Abstract

    There is no effective therapy for advanced liver fibrosis. Angiotensin type 1 (AT1) receptor blockers attenuate liver fibrogenesis, yet their efficacy in reversing advanced fibrosis is unknown. We investigated whether the specific delivery of an AT1 receptor blocker to activated hepatic stellate cells (HSCs) reduces established liver fibrosis. We used a platinumbased linker to develop a conjugate of the AT1 receptor blocker losartan and the HSCselective drug carrier mannose-6-phosphate modified human serum albumin (losartan-M6PHSA). An average of seven losartan molecules were successfully coupled to M6PHSA. Rats with advanced liver fibrosis due to prolonged bile duct ligation or carbon tetrachloride administration were treated with daily doses of saline, losartan-M6PHSA, M6PHSA or oral losartan during 3 days. Computer-based morphometric quantification of inflammatory cells (CD43), myofibroblasts (smooth muscle-actin [-SMA]) and collagen deposition (Sirius red and hydroxyproline content) were measured. Hepatic expression of procollagen 2(I) and genes involved in fibrogenesis was assessed by quantitative polymerase chain reaction. Losartan-M6PHSA accumulated in the fibrotic livers and colocalized with HSCs, as assessed by immunostaining of anti-HSA and anti--SMA. Losartan-M6PHSA, but not oral losartan, reduced collagen deposition, accumulation of myofibroblasts, inflammation and procollagen 2(I) gene expression. Losartan-M6PHSA did not affect metalloproteinase type 2 and 9 activity and did not cause apoptosis of activated HSCs. Conclusion: Short-term treatment with HSC-targeted losartan markedly reduces advanced liver fibrosis. This approach may provide a novel means to treat chronic liver diseases.

    Original languageEnglish
    Pages (from-to)942-952
    Number of pages11
    JournalHepatology
    Volume51
    Issue number3
    DOIs
    Publication statusPublished - 1 Mar 2010

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