Chiu, M.; (2007) Galactin-3 and the development of autosomal recessive polycystic kidney disease. Doctoral thesis , University of London.

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Abstract

Galectin-3 is a (3-galactoside-binding lectin implicated in renal collecting duct development and differentiation. Autosomal recessive polycystic kidney disease (ARPKD) affects 1 in 20,000 humans, and is characterised by cyst development from collecting ducts. Galectin-3 retards cystogenesis in at least 2 in vitro models. Hence, I hypothesised that endogenous galectin-3 may reduce cyst formation in vivo, and investigated this in the congenital polycystic kidney mouse (cpk), a well-characterised ARPKD model. Widespread galectin-3 expression was detected in cpk cyst epithelia in a distinct distribution compared to other developmental markers and renal galectins, and also in other cystic mice and human PKD, raising the possibility that galectin-3 may be a common part of a 'cystogenic' pathway. Next, I investigated whether reduced galectin-3 accelerated cyst formation in vivo using cpk and galectin-3 mutants to generate double cpk/galectin-3 mutants. Initial results on a mixed genetic background demonstrated large variability, but still significantly increased cysts in mice lacking galectin-3. I then backcrossed onto a pure 129Sv background but offspring developed unexpected increased mortality and pancreatic cysts, which confounded this experiment. Hence, we imported different galectin-3 mutants to reassess on the C57BL/6j background: cyst formation was less rapid than mixed/129Sv, but significantly more cortical cysts were again observed in galectin-3 null mutants. I detected galectin-3 in the primary cilium and centrosomes both in vivo and in vitro in normal and cystic samples for the first time. At least some of the galectin-3 appears on the outside of the cilia and paclitaxel, a therapy that retards PKD in cpk mice, caused increased extracellular galectin-3, a location where the lectin might interact with cilia. Preliminary experiments were also performed to investigate ciliary function using atomic force microscopy. These data raise the possibility that galectin-3 may act as a 'natural' brake on cystogenesis in cpk mice, perhaps via ciliary roles.

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