Browsing by Subject "Polycystic Kidney Diseases"
Now showing 1 - 8 of 8
- Results Per Page
- Sort Options
Item Autosomal dominant polycystic kidney disease(1990-05-24) Stone, Dennis K.Item Autosomal dominant polycystic kidney disease (ADPKD)(2001-07-26) Igarashi, PeterItem New mechanisms and therapeutic approaches in polycystic kidney disease(2012-07-06) Patel, VishalItem Polycystic kidney disease(2008-05-02) Igarashi, PeterItem [Southwestern News](2003-03-31) Siem, Staishy BostickItem Targeting Glutamine Metabolism in Kidney Development and Polycystic Kidney Disease(2018-07-30) Flowers, Ebony Michelle; Zhu, Hao; Abrams, John M.; Cobb, Melanie H.; DeBerardinis, Ralph J.; Carroll, Thomas J.Polycystic kidney disease is a hereditary disorder characterized by the progressive manifestation of numerous fluid-filled sacs, known as cysts, within the renal epithelia. The enlargement of the cysts causes the gradual replacement of normal kidney parenchyma which leads to impairment of renal function, and ultimately, renal failure. While the primary causes of PKD are genetic mutations in one of the polycystins that encode the PKD1 and PKD2 proteins, the age of onset and severity of PKD cases greatly varies, suggesting other genes/processes are involved. Lkb1 is a serine-threonine kinase involved in the regulation of several molecular processes including cellular polarity, autophagy, mTOR signaling, and energetic stress response, all of which are dysregulated in PKD. We generated mice lacking Lkb1 in developing kidney epithelia to establish which of these processes contributed to cyst formation and progression in the absence of Lkb1. Surprisingly, Lkb1 mutant mice showed no defects in renal tubule development or maintenance. However, later studies revealed the co-ablation Lkb1 along with Tsc1, a gene known to play a role in human PKD, within the developing renal epithelia prompted a drastic acceleration in the timing, number, and size of cyst formation. We utilized in vitro cell culture coupled with ex vivo culture of embryonic kidneys with defined media allowed us to determine which metabolic pathways were affected by the deficit of Lkb1. Our results revealed that Lkb1 mutant cells and embryonic kidneys require glutamine for growth while wild-type cells and kidneys did not. Subsequent studies demonstrated that Pkd1 embryonic kidneys phenocopied Lkb1 mutant kidneys in respect to their reliance on glutamine for growth. Further investigation into defining which metabolic enzymes/pathways are regulated in normal kidney development and how the absence of Lkb1 or Pkd1 alters these metabolic processes will allow us to gain a greater understanding of the role of metabolism in PKD and potentially lead to t the development of therapeutics to reduce cyst number and/or size.Item Understanding HNF-1β through Identification of Interacting Proteins and Target Genes in the Kidney(2010-11-02) Choi, Yun-Hee; Igarashi, PeterHepatocyte nuclear factor-1Beta (HNF-1Beta) is a POU/homeodomain-containing transcription factor that regulates tissue-specific gene expression in the liver, kidney, pancreas, and other epithelial organs. During kidney development, HNF-1Beta is expressed in renal collecting ducts and all segments of the nephron. Mutation of HNF-1Beta causes maturity-onset diabetes of the young type 5 (MODY5) and kidney developmental anomalies including renal agenesis, hypoplasia, and cysts. Here, I studied interacting proteins and target genes to understand the function of HNF-1Beta in the kidney. Yeast two-hybrid screening was performed to identify binding partners of HNF-1Beta in the kidney. Zyxin and LPP were isolated as putative interacting proteins. The LIM-containing proteins, Zyxin and LPP, are focal adhesion proteins that shuttle between the cytoplasm and nucleus and play a role in the architectural organization of cells. Both Zyxin and LPP interact with HNF-1Beta and stimulate the transcriptional activity of HNF-1Beta in mIMCD3 renal epithelial cells. Epidermal growth factor (EGF), which plays a role in the progression of polycystic kidney disease, induces translocation of zyxin into the nucleus. These studies identify a novel pathway by which signals may be transmitted from the cell surface to regulate the activity of a nuclear transcription factor that is essential for epithelial differentiation in the kidney. Chromatin immunoprecipitaion and DNA chip analysis (ChIP-chip) were performed to identify direct target genes of HNF-1Beta in the kidney. Phosphodiesterase 4C (PDE4C) was identified as an HNF-1Beta target gene. PDE4C belongs to the phosphodiesterase superfamily of enzymes that control the intracellular concentration of cyclic adenosine monophosphate (cAMP) by catalyzing its hydrolysis. cAMP may play a role in cystogenesis by stimulating fluid secretion and cell proliferation. PDE4C is transcriptionally activated by HNF-1Beta and regulates cAMP levels in mIMCD3 renal epithelial cells. Antibody staining showed that PDE4C is localized in the primary cilium and there interacts with a protein complex containing AKAP150, adenylyl cyclase 5/6 (AC5/6), protein kinase A (PKA), and polycystin-2 (PKD2). These results identify a cAMP-regulating protein complex that is localized in the primary cilium and is disrupted in PKD.