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Reduction of advanced liver fibrosis by short‐term targeted delivery of an angiotensin receptor blocker to hepatic stellate cells in rats
Author(s) -
Moreno Montserrat,
Gonzalo Teresa,
Kok Robbert J.,
SanchoBru Pau,
van Beuge Marike,
Swart Josine,
Prakash Jai,
Temming Kai,
Fondevila Constantino,
Beljaars Leonie,
Lacombe Marie,
van der Hoeven Paul,
Arroyo Vicente,
Poelstra Klaas,
Brenner David A.,
Ginès Pere,
Bataller Ramón
Publication year - 2010
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.23419
Subject(s) - losartan , hepatic stellate cell , angiotensin ii , fibrosis , sirius red , medicine , angiotensin ii receptor type 1 , angiotensin receptor , endocrinology , pharmacology , receptor
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 platinum‐based linker to develop a conjugate of the AT1 receptor blocker losartan and the HSC‐selective 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 α‐actin [α‐SMA]) and collagen deposition (Sirius red and hydroxyproline content) were measured. Hepatic expression of procollagen α2(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–α‐SMA. Losartan‐M6PHSA, but not oral losartan, reduced collagen deposition, accumulation of myofibroblasts, inflammation and procollagen α2(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. (H EPATOLOGY 2010.)