Kidney Institute - Faculty
Department of Internal Medicine, Division of Nephrology & Hypertension
The primary focus of my research is to understand the molecular pathogenesis of autosomal dominant polycystic kidney diseases (ADPKD) and to translate these findings for ADPKD treatment. To this end, my lab has two emphasis areas of research:
1. TNF-alpha signaling and apoptosis signaling in ADPKD. In the past we found that a tumor necrosis factor-α–mediated pathway promoting cyst and treatment of Pkd2+/- mice with the TNF-α inhibitor etanercept prevented cyst formation. This study uncovered the connection among TNF-α signaling, polycystins and cystogenesis. (Li et al., Nature Medicine, 2008). Recently, we found that a second mitochondria-derived activator of caspase (Smac)-mimetic, induces TNFα-dependent cystic renal epithelial cell death specifically, leading to the removal of cystic epithelial cells from renal tissues, thus, preventing cyst formation. Our current study helps to clarify the role of apoptosis in the regulation of cyst size and in a larger sense may open a new approach to target renal cysts and prevent their endless expansion by the administration of Smac-mimetics, which encourages a paradigm shift from current efforts that focus on normalizing cell function in cystic epithelial cells to directly targeting these cells for removal.
2. Epigenetics and ADPKD. We have conducted extensive research on the function of histone deacetylases (HDACs) and histone methyltransferases (HMTs) in ADPKD. In the past, we found that: i) Polycystin-dependent fluid flow sensing targets histone deacetylase 5 to prevent the development of renal cysts (Xia et al., Development, 2010); ii) Inhibition of histone deacetylases targets the transcription regulator Id2 to attenuate cystic epithelial cell proliferation (Fan et al., Kidney International, 2012); iii) HDAC6 regulates epidermal growth factor receptor (EGFR) endocytic trafficking and degradation in renal epithelial cells (Liu et al., Plos One. 2013). We are now focusing on: i) Vitamin B3 prevents cyst formation through Sirt1 mediated cyst epithelial cell proliferation and apoptosis; ii) SIRT2 regulates ciliogenesis and contributes to loss of polycystin-1 mediated abnormal centrosome amplification; iii) Aberrant histone and/or protein methylation, which is regulated by heat shock protein 90, and/or DNA methylation of CpG island containing promoters leads to permanent silencing of genes in both physiological and pathological contexts in cystic epithelial cells.
Zhou X, Fan LX, Sweeney, WE, Denu Avner ED, Li X. Vitamin B3 delays cyst formation through targeting SIRT1 mediated cyst epithelial cell proliferation and apoptosis. J Clin Invest. 2013. In Press.
Liu W, Fan LX, Zhou X, Sweeney WE Jr., Avner ED, Li X. HDAC6 regulates epidermal growth factor receptor (EGFR) endocytic trafficking and degradation in renal epithelial cells. PLoS One. 7:e49418, 2012. (In Press) PMID: 23152903. PMCID: 3496684.
Fan LX, Li X, Magenheimer BS, Calvet JP, Li X. Inhibition of histone deacetylases targets the transcription regulator Id2 to attenuate cystic epithelial cell proliferation. Kidney Int. 81:76-85, 2012. PMID: 21900881. PMCID: PMC3409467.
Li X. Epigenetics and autosomal dominant polycystic kidney disease. Biochim Biophys Acta. 1812:1213–1218, 2011. PMCID: PMC3413450.
Xia S, Li X, Johnson T, Seidel C, Wallace DP, and Li R. Polycystin-dependent fluid flow sensing targets histone deacetylase 5 to prevent the development of renal cysts. Development. 137:1075-84, 2010. PMID: 20181743. PMCID: PMC2835323.
Li X, Magenheimer BS, Xia S, Johnson T, Wallace DP, Calvet JP, Li R. A tumor necrosis factor-alpha-mediated epigenetic switch promoting autosomal dominant polycystic kidney disease. Nat Med. 14:863-8, 2008. PMID: 18552856. PMCID: PMC3359869.
Xiaogang Li, Ph.D.
Kidney Institute - Faculty