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1.
Minerva Urol Nefrol ; 65(1): 61-8, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23538311

ABSTRACT

Autosomal dominant polycystic kidney disease (ADPKD) represents the most prevalent inherited kidney disease, and an important contributor to renal and systemic morbidity. Almost 20 years after the discovery of the Pkd-1 and Pkd-2 genes, the exact molecular mechanisms of polycystic kidney disease pathogenesis still remain elusive. In the absence of a specific therapy for polycystic kidney disease, patients are treated for chronic kidney disease symptoms, like hypertension, anemia, hyperparathyroidism and pain. Intensive research on ADPKD and a variety of related complex cystic kidney disease syndromes revealed a network of intracellular signaling pathways that depend on ciliary function and include calcium- and cAMP-dependent mechanisms. Furthermore, proliferative and tissue patterning responses to mTOR, STAT, CDK and wnt signaling play an important role in various aspects of cystogenesis and represent further targets for therapy. Only a limited amount of clinical evidence from randomized controlled trials is currently available to evaluate treatment options. This includes ongoing trials of the vasopressin receptor-2 antagonist tolvaptan, as well as a set of studies that fail to show a clear therapeutic benefit of everolimus or sirolimus in PKD progression. Future research will involve the evaluation of small molecule inhibitors of growth factor receptor-, CDK- and STAT-pathways, as well as the characterization of novel biomarkers of disease progression and therapeutic response.


Subject(s)
Polycystic Kidney, Autosomal Dominant , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Disease Progression , Humans , Intracellular Signaling Peptides and Proteins/physiology , Kidney Failure, Chronic/etiology , Kidney Failure, Chronic/prevention & control , Polycystic Kidney, Autosomal Dominant/drug therapy , Polycystic Kidney, Autosomal Dominant/epidemiology , Polycystic Kidney, Autosomal Dominant/genetics , Polycystic Kidney, Autosomal Dominant/metabolism , Prevalence , Protein Kinase Inhibitors/therapeutic use , Randomized Controlled Trials as Topic , Signal Transduction/drug effects , TRPP Cation Channels/genetics , TRPP Cation Channels/physiology
2.
Exp Cell Res ; 269(1): 42-53, 2001 Sep 10.
Article in English | MEDLINE | ID: mdl-11525638

ABSTRACT

Angiogenesis research has focused on receptors and ligands mediating endothelial cell proliferation and migration. Little is known about the molecular mechanisms that are involved in converting endothelial cells from a proliferative to a differentiated state. Microvascular differentiation gene 1 (Mdg1) has been isolated from differentiating microvascular endothelial cells that had been cultured in collagen type I gels (3D culture). In adult human tissue Mdg1 is expressed in endothelial and epithelial cells. Sequence analysis of the full-length cDNA revealed that the N-terminal region of the putative Mdg1-protein exhibits a high sequence similarity to the J-domain of Hsp40 chaperones. We show that this region functions as a bona fide J-domain as it can replace the J-domain of Escherichia coli DnaJ-protein. Mdg1 is also upregulated in primary endothelial and mesangial cells when subjected to various stress stimuli. GFP-Mdg1 fusion constructs showed the Mdg1-protein to be localized within the cytoplasm under control conditions. Stress induces the translocation of Mdg1 into the nucleus, where it accumulates in nucleoli. Costaining with Hdj1, Hdj2, Hsp70, and Hsc70 revealed that Mdg1 colocalizes with Hsp70 and Hdj1 in control and stressed HeLa cells. These data suggest that Mdg1 is involved in the control of cell cycle arrest taking place during terminal cell differentiation and under stress conditions.


Subject(s)
Cell Differentiation/physiology , Endothelium, Vascular/physiopathology , Heat-Shock Proteins/genetics , Heat-Shock Proteins/metabolism , Molecular Chaperones/genetics , Neovascularization, Physiologic/physiology , Up-Regulation/genetics , Amino Acid Sequence/physiology , Base Sequence/physiology , Carrier Proteins/metabolism , Cell Compartmentation/physiology , Cell Division/physiology , Cell Nucleolus/metabolism , Cells, Cultured/metabolism , DNA, Complementary/metabolism , Endothelium, Vascular/metabolism , Escherichia coli Proteins , Gene Expression Regulation/physiology , HSC70 Heat-Shock Proteins , HSP40 Heat-Shock Proteins , HSP70 Heat-Shock Proteins/metabolism , Heat-Shock Proteins/chemistry , Immunohistochemistry , Membrane Proteins , Molecular Chaperones/metabolism , Molecular Sequence Data , Protein Structure, Tertiary/physiology , RNA, Messenger/metabolism , Wound Healing/physiology
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