Member Of Nuclear Receptor Superfamily Research Articles

Retinoids, Stilbenes and Vitis Vinifera modulate VDR-RXR cross-talk in HT22 mouse hippocampus neuron: an approach towards prevention of neuronal dysfunction in brain inflammation (54.20)

Abstract The vitamin D receptor (VDR) belongs to a member of nuclear hormone receptor superfamily. The present study delineated a mechanism of VDR mode of action in prevention of neuronal dysfunction and damage in central nervous system. The in vitro treatment of HT 22 mouse hippocampus neuron with RXR agonist retinoic acid was found to modulate VDR. The stilbenes and vitis vinifera were also found to influence VDR in HT22 cells. Moreover, treatment of HT22 cells with retinoic acid rich carrot extract was found to attenuate paraquat induced damage of HT 22 cells. A study has been initiated to determine mode of action of the compounds and to evaluate mechanism of VDR-RXR interactive signals in attenuation of neuronal dysfunction in hippocampus in dementia and seizures. Acknowledgement. I (SDG) acknowledge Eileen McFadden and Christopher Riley for their support in research. The HT 22 cells were provided by Dr Mark S Kindy (MUSC). I am thankful to Dr Sebastiano Gattoni- Celli (MD) for his suggestions.We are thankful to the MUSC research endeavors.

PPAR-γ Agonists in Polycystic Kidney Disease with Frequent Development of Cardiovascular Disorders

Autosomal dominant polycystic kidney disease (ADPKD) is the most common of the monogenic disorders and is characterized by bilateral renal cysts; cysts in other organs including liver, pancreas, spleen, testis and ovary; vascular abnormalities including intracranial aneurysms and subarachnoid hemorrhage; and cardiac disorders such as left ventricular hypertrophy (LVH), mitral valve regurgitation, mitral valve prolapse and aortic regurgitation. Autosomal recessive polycystic kidney disease (ARPKD) is an early-onset multisystem disorder characterized by polycysts divided from the renal collecting ducts, congenital hepatic fibrosis, and ductal plate malformation complicated by pulmonary hyperplasia and systemic hypertension. In these polycystic kidney diseases (PKD), progressive enlargement of the cysts results from the aberrant proliferation of tubule epithelial cells and trans-epithelial fluid secretion leading to extensive nephron loss and interstitial fibrosis. Peroxisome proliferator-activated receptor-γ (PPAR-γ), a member of the liganddependent nuclear receptor superfamily, is expressed in a variety of tissues, including kidneys and liver, and plays important roles in cell proliferation, fibrosis, and inflammation. PPAR-γ agonists ameliorate polycystic kidney, polycystic liver and cardiac defects through β-catenin, c-Myc, CFTR, MCP-1, S6, ERK, and TGF-β signaling pathways in animal models of PKD. In this review, we describe the possible therapeutic value of PPAR-γ agonists in the treatment of renal and hepatic manifestations, and cardiac defects in progressive PKD.

PPAR-γ Agonists in Polycystic Kidney Disease with Frequent Development of Cardiovascular Disorders

Autosomal dominant polycystic kidney disease (ADPKD) is the most common of the monogenic disorders and is characterized by bilateral renal cysts; cysts in other organs including liver, pancreas, spleen, testis and ovary; vascular abnormalities including intracranial aneurysms and subarachnoid hemorrhage; and cardiac disorders such as left ventricular hypertrophy (LVH), mitral valve regurgitation, mitral valve prolapse and aortic regurgitation. Autosomal recessive polycystic kidney disease (ARPKD) is an early-onset multisystem disorder characterized by polycysts divided from the renal collecting ducts, congenital hepatic fibrosis, and ductal plate malformation complicated by pulmonary hyperplasia and systemic hypertension. In these polycystic kidney diseases (PKD), progressive enlargement of the cysts results from the aberrant proliferation of tubule epithelial cells and trans-epithelial fluid secretion leading to extensive nephron loss and interstitial fibrosis. Peroxisome proliferator-activated receptor-γ (PPAR-γ), a member of the ligand-dependent nuclear receptor superfamily, is expressed in a variety of tissues, including kidneys and liver, and plays important roles in cell proliferation, fibrosis, and inflammation. PPAR-γ agonists ameliorate polycystic kidney, polycystic liver and cardiac defects through β-catenin, c-Myc, CFTR, MCP-1, S6, ERK, and TGF-β signaling pathways in animal models of PKD. In this review, we describe the possible therapeutic value of PPAR-γ agonists in the treatment of renal and hepatic manifestations, and cardiac defects in progressive PKD.

Abstract 950: Orphan nuclear receptor DAX1 exhibits suppressive effect on prostate cancer cell growth

Abstract The nuclear receptor superfamily comprises a large group of transcriptional factors involved broadly in many physiological functions including control of embryonic development and cellular homeostasis. In general, nuclear receptors can bind to specific DNA regulatory elements (REs) as homo- or heterodimers. DAX1 (Dosage sensitive sex reversal (DSS), adrenal hypoplasia congenita (AHC) critical region, on chromosome X, gene 1, NR0B1) is a unique ligand-independent orphan nuclear receptor, which lacks the conventional DNA-binding domain (DBD) and in some cases it functions as a coregulatory protein inhibiting the transcriptional activity of other nuclear receptors by forming heterodimers. Previous studies show that DAX1 may play an essential role in establishment and maintenance of the steroidogenic axis of development, maintenance of murine embryonic stem cell pluripotency and cancer development including ovarian, breast and endometrial cancers. A recent report identified the inverse correlation of immunoreactivity of DAX1 with Gleason score of prostate cancer. In a preliminary investigation of expression patterns of members of nuclear receptor superfamily in a panel of immortalized prostatic epithelial cell and prostate cancer cell lines by semi-quantitative and real-time PCR, we observed that DAX1 displayed a variable expression pattern with low or undetectable levels in most tested immortalized prostatic epithelial cell lines and prostate cancer cell lines (including the classical LNCaP and PC-3) but high levels in some prostate cancer cells (VCaP, DuCaP, RC-58T and DU145) and also an in vitro model of transformed immortalized human prostatic epithelial cells BPH-1CAFTD. In order to elucidate the possible functional roles of DAX1 in the prostate cancer cell growth regulation, we generated DAX1-stable expression clones in two prostate cancer cell lines, LNCaP and PC-3, which expressed low endogenous DAX1 levels, by retroviral transduction for in vitro growth characterization. Our results showed that overexpression of DAX1 in LNCaP and PC-3 cells suppressed their in vitro cell proliferation, single-cell colony formation and anchorage-independent growth capacity in soft agar. Moreover, luciferase reporter gene assay showed that DAX1 suppressed the ERRα-induced transactivation of VEGFA. Our results suggested that DAX1 might perform a suppressive growth regulatory role in prostate cancer cells. (Lin Jia is supported by a RGC Hong Kong-PhD Fellowship Scheme) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 950. doi:1538-7445.AM2012-950

Hepatocarcinogenesis in FXR−/− Mice Mimics Human HCC Progression That Operates through HNF1α Regulation of FXR Expression

Farnesoid X receptor (FXR) (nuclear receptor subfamily 1, group H, member 4) is a member of nuclear hormone receptor superfamily, which plays essential roles in metabolism of bile acids, lipid, and glucose. We previously showed spontaneously hepatocarcinogenesis in aged FXR(-/-) mice, but its relevance to human hepatocellular carcinoma (HCC) is unclear. Here, we report a systematical analysis of hepatocarcinogenesis in FXR(-/-) mice and FXR expression in human liver cancer. In this study, liver tissues obtained from FXR(-/-) and wild-type mice at different ages were compared by microarray gene profiling, histological staining, chemical analysis, and quantitative real-time PCR. Primary hepatic stellate cells and primary hepatocytes isolated from FXR(-/-) and wild-type mice were also analyzed and compared. The results showed that the altered genes in FXR(-/-) livers were mainly related to metabolism, inflammation, and fibrosis, which suggest that hepatocarcinogenesis in FXR(-/-) mice recapitulated the progression of human liver cancer. Indeed, FXR expression in human HCC was down-regulated compared with normal liver tissues. Furthermore, the proinflammatory cytokines, which were up-regulated in human HCC microenvironment, decreased FXR expression by inhibiting the transactivity of hepatic nuclear factor 1α on FXR gene promoter. Our study thereby demonstrates that the down-regulation of FXR has an important role in human hepatocarcinogenesis and FXR(-/-) mice provide a unique animal model for HCC study.

Sesquiterpene lactones from Tithonia diversifolia act as peroxisome proliferator-activated receptor agonists

Tithonia diversifolia is a well-known traditional Chinese medicine treating diabetes, hepatitis, and hepatocarcinoma but its molecular mechanism is not fully understood. Peroxisome proliferator-activated receptors (PPARs) α and γ are members of nuclear receptor superfamily. Their agonists are prescribed as antihyperlipidemic and antihyperglycemic drugs now. In this study, sesquiterpene lactones, tirotundin and tagitinin A, were isolated from T. diversifolia and evaluated for their activity against PPARs by the transient transfection reporter assay. Tirotundin and tagitinin A transactivated PPARγ dependent promoters including PPRE (PPARγ response element), SHP, and ABCA1 gene promoters in dose-dependent manner. Furthermore, the fluorescence polarization competitive binding assay showed that tirotundin (IC50=27μM) and tagitinin A (IC50=55μM) enhanced PPARγ transactivation activity by directly binding to PPARγ ligand binding domain. Additionally, they stimulated the transactivation of PPARα dependent SULT2A1 gene promoter by 2.3-fold of vehicle effect at 10μM. These results highly indicated that tirotundin and tagitinin A are the active components of T. diversifolia to exert anti-diabetic effect through PPARγ pathway. Moreover, these sesquiterpene lactones behaved as PPARα/γ dual agonists so they might be useful as the potential herbal treatment for diabetes.

Liver X Receptor Modulation of Gene Expression Leading to Proluteolytic Effects in Primate Luteal Cells1

The expressions of genes involved in cholesterol efflux increase, whereas those involved in extracellular cholesterol uptake decrease, during spontaneous functional regression of the primate corpus luteum (CL). This may result from liver x receptor (LXR) alpha (official symbol NR1H3) and/or beta (official symbol NR1H2) control of luteal gene transcription, because these nuclear receptor superfamily members are key regulators of cellular cholesterol homeostasis. Therefore, studies were conducted to assess endogenous LXR ligands in the primate CL through the luteal phase, and to determine the effect of synthetic or natural LXR ligands on cholesterol efflux and uptake in functional primate luteal cells. Using high-performance liquid chromatography tandem mass spectrometry, three LXR ligands were identified and quantified in the rhesus macaque CL, including 22R-hydroxycholesterol (22ROH), 27-hydroxycholesterol (27OH), and desmosterol. Levels of 22ROH paralleled serum progesterone concentrations, whereas mean levels of 27OH tended to be higher following the loss of progesterone synthesis. Desmosterol was present throughout the luteal phase. Functional macaque luteal cells treated with the synthetic LXR agonist T0901317 or physiologically relevant concentrations of the endogenous luteal ligands 22ROH, 27OH, and desmosterol had increased expression of various known LXR target genes and greater cholesterol efflux. Additionally, T0901317 reduced low-density lipoprotein receptor protein and extracellular low-density lipoprotein uptake, whereas 27OH decreased low-density lipoprotein receptor protein, most likely via a posttranslational mechanism. Collectively, these data support the hypothesis that LXR activation causes increased cholesterol efflux and decreased extracellular cholesterol uptake. In theory, these effects could deplete the primate CL of cholesterol needed for steroidogenesis, ultimately contributing to functional regression.

Cardiomyocyte-expressed farnesoid-X-receptor is a novel apoptosis mediator and contributes to myocardial ischaemia/reperfusion injury

Emerging evidence indicates that nuclear receptors play a critical regulatory role in cardiovascular physiology/pathology. Recently, farnesoid-X-receptor (FXR), a member of the metabolic nuclear receptor superfamily, has been demonstrated to be expressed in vascular cells, with important roles in vascular physiology/pathology. However, the potential cardiac function of FXR remains unclear. We investigated the cardiac expression and biological function of FXR. Farnesoid-X-receptor was detected in both isolated neonatal rat cardiac myocytes and fibroblasts. Natural and synthetic FXR agonists upregulated cardiac FXR expression, stimulated myocyte apoptosis, and reduced myocyte viability dose- and time-dependently. Mechanistic studies demonstrated that FXR agonists disrupted mitochondria, characterized by mitochondrial permeability transition pores activation, mitochondrial potential dissipation, cytochrome c release, and both caspase-9 and -3 activation. Such mitochondrial apoptotic responses were abolished by siRNA-mediated silencing of endogenous FXR or pharmacological inhibition of mitochondrial death signalling. Furthermore, low levels of FXR were detected in the adult mouse heart, with significant (∼2.0-fold) upregulation after myocardial ischaemia/reperfusion (MI/R). Pharmacological inhibition or genetic ablation of FXR significantly reduced myocardial apoptosis by 29.0-53.4%, decreased infarct size by 23.4-49.7%, and improved cardiac function in ischaemic/reperfused myocardium. These results demonstrate that nuclear receptor FXR acts as a novel functional receptor in cardiac tissue, regulates apoptosis in cardiomyocytes, and contributes to MI/R injury.

Farnesoid X receptor expression is reduced in human hepatocellular carcinoma

Farnesoid X receptor (FXR, NR1H4) is a member of nuclear hormone receptor superfamily. Previously studies showed that FXR−/− mice spontaneously developed liver tumors when they aged, however, the relevance of which to human hepatocellular carcinoma (HCC) is unclear. The aim of this study is to observe whether FXR expression is also downregulated in HCC and discuss the mechanism of the reduced FXR expression in HCC. Expression of FXR and small heterodimer partner (SHP) was measured by real-time PCR and immunohistochemical technique. Effect of pro-inflammatory cytokines on expression of FXR and its promoter activity were determined in primary hepatocytes or HepG2 and Huh7 cell lines. Our results showed that expression of FXR and its target gene SHP in human HCC was strongly downregulated compared to the normal liver tissues. In addition, pro-inflammatory cytokines were able to decrease FXR expression by inhibiting the FXR promoter activity. In conclusion this work demonstrates FXR expression is strongly downregulated in human HCC, which may be caused by decreased FXR promoter activity, suggesting a potential role of FXR in human HCC development.

Fibrates: Therapeutic potential for diabetic nephropathy?

Despite intensive glucose-lowering treatment and advanced therapies for cardiovascular risk factors, such as hypertension and dyslipidaemia, diabetes mellitus with its macro- and microvascular complications remains a major health problem. Especially diabetic nephropathy is a leading cause of morbidity and mortality, and its prevalence is increasing. Peroxisome proliferator-activated receptor-α (PPAR-α), a member of a large nuclear receptor superfamily, is expressed in several tissues including the kidney. Recently, experimental data have suggested that PPAR-α activation plays a pivotal role in the regulation of fatty acid oxidation, lipid metabolism, inflammatory and vascular responses, and might regulate various metabolic and intracellular signalling pathways that lead to diabetic microvascular complications. This review examines the role of PPAR-α activation in diabetic nephropathy and summarises data from experimental and clinical studies on the emerging therapeutic potential of fibrates in diabetic nephropathy.

Targeting PPARγSignaling Cascade for the Prevention and Treatment of Prostate Cancer

The peroxisome proliferator-activated receptor-gamma (PPARγ) is a member of the hormone-activated nuclear receptor superfamily. PPARγ can be activated by a diverse group of agents, such as endogenous polyunsaturated fatty acids, 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), and thiazolidinedione (TZD) drugs. PPARγ induces antiproliferative, antiangiogenic, and prodifferentiation pathways in several tissue types, thus making it a highly useful target for downregulation of carcinogenesis. These TZD-derived novel therapeutic agents, alone or in combination with other anticancer drugs, have translational relevance in fostering effective strategies for cancer treatment. TZDs have been proven for antitumor activity in a wide variety of experimental cancer models, both in vitro and in vivo, by affecting the cell cycle, inducing cell differentiation and apoptosis, as well as by inhibiting tumor angiogenesis. Angiogenesis inhibition mechanisms of TZDs include direct inhibition of endothelial cell proliferation and migration, as well as reduction in tumor cell vascular endothelial growth factor production. In prostate cancer, PPARγ ligands such as troglitazone and 15d-PGJ2 have also shown to inhibit tumor growth. This paper will focus on current discoveries in PPARγ activation, targeting prostate carcinogenesis as well as the role of PPARγ as a possible anticancer therapeutic option. Here, we review PPARγ as an antitumor agent and summarize the antineoplastic effects of PPARγ agonists in prostate cancer.

Expression of Estrogen Receptor Alpha36 in the Hamster Ovary and Its Possible Regulation by Gonadotropins and Steroid Hormones.

In the ovary, estrogen signaling is of utmost importance that is carried out by the estrogen receptor, member of nuclear receptor superfamily. In reproductive females, estrogen plays an essential role in the reproductive cyclicity and other ovarian functions. Here we report the expression of estrogen receptor α36 (ERα36), a splice variant of the estrogen receptor α (ERα), in the hamster ovary throughout the estrous cycle, and its possible regulation by follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol-17β (E) and progesterone (P). Hamster ovaries were collected from Day 1 (estrus, D1) though Day 4 (proestrus, D4) morning and D4 afternoon, and the expression pattern of ERα36 protein was examined by immunofluorescence and Western immunoblotting. Immunoblot data indicated that ERα36 expression declined by D4:0900h through D4:1600h compared to other days of the estrous cycle. Immunofluorescence results revealed that ERα36 was expressed in the plasma membrane of both follicular and interstitial cells in the ovary with highest level of expression in the granulosa cells; however, the immunostaining declined by D4:0900h through D4:1600h. No staining was observed in the cell nuclei. To determine the role of individual reproductive hormones on ovarian ERα36 expression, hypophysectomized hamsters were treated with FSH, LH, E or P on postoperative day 10. Immunoblot data revealed a significant decline in ERα36 protein in hypophysectomized hamsters compared to intact hamster on D1. FSH-treatment upregulated the receptor protein level to that of D1 hamsters. LH-treatment showed a similar increase. In contrast, a combined treatment of FSH and LH failed to raise the receptor protein level to that of the either hormone alone. E or P treatment upregulated ERα36 protein level, but P effect was stronger. Nevertheless, the increase in ERα36 expression was much less than that was induced by FSH and LH. No increase was observed after a combined treatment of E and P. The data were validated by immunofluorescence localization. These results indicate that the ERα splice variant, ERα36, is translated into protein in ovarian follicular cells, but the receptor protein is mostly localized in the plasma membrane in contrast to the classic ERα, which is located in the nucleus. Further, the induction of ERα mRNA splicing and the translation of the truncated receptor mRNA seems to be regulated by gonadotropins, such FSH or LH. Ovarian steroids may have a different regulatory role on ERα36 expression. Therefore, ERα36 may play a unique regulatory role in estrogen signaling during ovarian follicular development. (poster)

Dynamic nature of transcriptional regulation of nuclear receptor target genes in the context of chromatin organization.

Many members of the nuclear receptor (NR) superfamily are expressed in the skin making them a highly interesting subject of dermato-endocrine research. Natural and synthetic NR ligands are used for the treatment of various skin disorders. We discuss here the impact of the dynamic nature of chromatin organization, i.e., the spatio-temporal changes of chromatin region of NR target genes. This dynamics is triggered by environmental changes, of which for NRs the exposure with their ligands is most critical. For an understanding of skin disorders, which involve the actions of NRs, this means that the parameter time should be carefully considered in context of other factors that may influence the chromatin organization, and by this the responsiveness, of key NR target genes.

Ancient friends, revisited: New aspects on the important role of nuclear receptor signalling for skin physiology and for the treatment of skin diseases.

Many members of the nuclear receptor (NR) superfamily are strongly expressed in human skin, making them a highly interesting target of dermato-endocrine research. Consequently, an increasing number...

Inflammatory control on lifestyle-related diseases and bone metabolism

Recent findings suggest that chronic inflammation is involved in lifestyle related diseases and osteoporosis. Members of nuclear receptor superfamily have regulatory effects on inflammatory processes and cytokine responses which contribute to prevention and treatment of above diseases. Here, recent studies are described that these nuclear receptors have regulatory roles called transrepression in chronic inflammatory diseases through their interactions with transcription factors and cell-signaling systems.

Lymphoid Enhancer-binding Factor-1 (LEF1) Interacts with the DNA-binding Domain of the Vitamin D Receptor

Ligand-independent actions of the vitamin D receptor (VDR) are required for normal post-morphogenic hair cycles; however, the molecular mechanisms by which the VDR exerts these actions are not clear. Previous studies demonstrated impaired regulation of the canonical Wnt signaling pathway in primary keratinocytes lacking the VDR. To identify the key effector of canonical Wnt signaling that interacts with the VDR, GST pulldown studies were performed. A novel interaction between the VDR and LEF1 (lymphoid enhancer-binding factor-1) that is independent of β-catenin was identified. This interaction is dependent upon sequences within the N-terminal region of the VDR, a domain required for VDR-DNA interactions and normal hair cycling in mice. Mutation of specific residues within the N-terminal region of the VDR not only abrogated interactions between the VDR and LEF1 but also impaired the ability of the VDR to enhance Wnt signaling in vdr(-/-) primary keratinocytes. Thus, this study demonstrates a novel interaction between the VDR and LEF1 that is mediated by the DNA-binding domain of the VDR and that is required for normal canonical Wnt signaling in keratinocytes.

Arginine and Glutamate-rich 1 (ARGLU1) Interacts with Mediator Subunit 1 (MED1) and Is Required for Estrogen Receptor-mediated Gene Transcription and Breast Cancer Cell Growth

Estrogen receptor is a nuclear receptor superfamily member of transcriptional activators that regulate gene expression by recruiting diverese transcriptional coregulators. The Mediator complex is a central transcriptional coactivator complex that acts as a bridge between transcriptional activators and RNA polymerase II. MED1 (Mediator subunit 1) is the key Mediator subunit that directly interacts with estrogen receptor to mediate its functions both in vitro and in vivo. Interestingly, our previous biochemical analyses indicated that MED1 exists only in a subpopulation of the Mediator complex that is enriched with a number of distinct Mediator subunits and RNA polymerase II. Here, we report ARGLU1 as a MED1/Mediator-associated protein. We found that ARGLU1 (arginine and glutamate rich 1) not only colocalizes with MED1 in the nucleus, but also directly interacts with a far C-terminal region of MED1. Reporter assays indicate that ARGLU1 is able to cooperate with MED1 to regulate estrogen receptor-mediated gene transcription. Importantly, ARGLU1 is recruited, in a ligand-dependent manner, to endogenous estrogen receptor target gene promoters and is required for their expression. Furthermore, by ChIP-reChIP assay, we confirm that ARGLU1 and MED1 colocalize on the same estrogen receptor target gene promoter upon estrogen induction. Moreover, we found that depletion of ARGLU1 significantly impairs the growth, as well as anchorage-dependent and -independent colony formation of breast cancer cells. Taken together, these results establish ARGLU1 as a new MED1-interacting protein required for estrogen-dependent gene transcription and breast cancer cell growth.

Is the Hospital Course in Hypertriglyceridemia-Induced Pancreatitis (HIP) Different From That of Gallstone Pancreatitis (GSP)?

Cryptochinones A–D are tetrahydroflavanones isolated from the leaves of Cryptocarya chinensis, an evergreen tree whose extracts are believed to have a variety of health benefits. The origin of their possible bioactivity is unclear. The farnesoid X receptor (FXR) is a member of nuclear receptor superfamily that has been widely targeted for developing treatments for chronic liver disease and for hyperglycemia. We studied whether cryptochinones A–D, which are structurally similar to known FXR ligands, may act at this target. Indeed, in mammalian one-hybrid and transient transfection reporter assays, cryptochinones A–D transactivated FXR to modulate promoter action including GAL4, SHP, CYP7A1, and PLTP promoters in dose-dependent manner, while they exhibited similar agonistic activity as chenodeoxycholic acid (CDCA), an endogenous FXR agonist. Through molecular modeling docking studies we evaluated their ability to bind to the FXR ligand binding pocket. Our results indicate that cryptochinones A–D can behave as FXR agonists.

PPAR-γ agonist ameliorates kidney and liver disease in an orthologous rat model of human autosomal recessive polycystic kidney disease

In autosomal recessive polycystic kidney disease (ARPKD), progressive enlargement of fluid-filled cysts is due to aberrant proliferation of tubule epithelial cells and transepithelial fluid secretion leading to extensive nephron loss and interstitial fibrosis. Congenital hepatic fibrosis associated with biliary cysts/dilatations is the most common extrarenal manifestation in ARPKD and can lead to massive liver enlargement. Peroxisome proliferator-activated receptor γ (PPAR-γ), a member of the ligand-dependent nuclear receptor superfamily, is expressed in a variety of tissues, including the kidneys and liver, and plays important roles in cell proliferation, fibrosis, and inflammation. In the current study, we determined that pioglitazone (PIO), a PPAR-γ agonist, decreases polycystic kidney and liver disease progression in the polycystic kidney rat, an orthologous model of human ARPKD. Daily treatment with 10 mg/kg PIO for 16 wk decreased kidney weight (% of body weight), renal cystic area, serum urea nitrogen, and the number of Ki67-, pERK1/2-, and pS6-positive cells in the kidney. There was also a decrease in liver weight (% of body weight), liver cystic area, fibrotic index, and the number of Ki67-, pERK1/2-, pERK5-, and TGF-β-positive cells in the liver. Taken together, these data suggest that PIO inhibits the progression of polycystic kidney and liver disease in a model of human ARPKD by inhibiting cell proliferation and fibrosis. These findings suggest that PPAR-γ agonists may have therapeutic value in the treatment of the renal and hepatic manifestations of ARPKD.

SF-1 gene mutation and gonad development

Orphan nuclear receptor steroidogenic factor 1 (SF-1) is a member of the nuclear receptor superfamily. It regulates the expression of multiple genes involved in adrenal and gonadal development,steroidogenesis,and reproductive function. Twenty five different mutations have been described and their clinical features are various. Detection of SF-1 gene may be contribute to the etiological diagnosis for 46, XY disorder of sex development patients. Key words: SF-1 ; Gene mutation; Gonadal development