Ablation of Long Noncoding RNA Hoxb3os Exacerbates Cystogenesis in Mouse Polycystic Kidney Disease.

Significance Statement: Long noncoding RNAs (lncRNAs) are a class of nonprotein coding RNAs with pivotal functions in development and disease. They have emerged as an exciting new drug target category for many common conditions. However, the role of lncRNAs in autosomal dominant polycystic kidney disease (ADPKD) has been understudied.

Small hairpin inhibitory RNA delivery in the metanephric organ culture identifies long noncoding RNA as a modulator of cyst growth.

Autosomal dominant polycystic kidney disease (ADPKD) is a monogenic disorder characterized by the formation of kidney cysts that originate from the epithelial tubules of the nephron and primarily results from mutations in polycystin-1 () and polycystin-2 (). The metanephric organ culture (MOC) is an ex vivo system in which explanted embryonic kidneys undergo tubular differentiation and kidney development. MOC has been previously used to study polycystic kidney disease as treatment with 8-bromo-cAMP induces the formation of kidney cysts.

Interstitial microRNA miR-214 attenuates inflammation and polycystic kidney disease progression.

Renal cysts are the defining feature of autosomal dominant polycystic kidney disease (ADPKD); however, the substantial interstitial inflammation is an often-overlooked aspect of this disorder. Recent studies suggest that immune cells in the cyst microenvironment affect ADPKD progression. Here we report that microRNAs (miRNAs) are new molecular signals in this crosstalk.

Regulation of mTOR signaling by long non-coding RNA.

The mechanistic target of rapamycin (mTOR) is a major signaling hub that coordinates cellular and organismal responses, such as cell growth, proliferation, apoptosis, and metabolism. Dysregulation of mTOR signaling occurs in many human diseases, and there are significant ongoing efforts to pharmacologically target this pathway. Long noncoding RNAs (lncRNA), defined by a length > 200 nucleotides and absence of a long open-reading-frame, are a class of non-protein-coding RNAs.

Mechanism of Fibrosis in -Related Autosomal Dominant Tubulointerstitial Kidney Disease.

Background: Mutation of , the gene encoding transcription factor HNF-1, is one cause of autosomal dominant tubulointerstitial kidney disease, a syndrome characterized by tubular cysts, renal fibrosis, and progressive decline in renal function. HNF-1 has also been implicated in epithelial-mesenchymal transition (EMT) pathways, and sustained EMT is associated with tissue fibrosis. The mechanism whereby mutated leads to tubulointerstitial fibrosis is not known.

Long noncoding RNA is dysregulated in autosomal dominant polycystic kidney disease and regulates mTOR signaling.

Autosomal dominant polycystic kidney disease (ADPKD) is a debilitating disease that is characterized by the accumulation of numerous fluid-filled cysts in the kidney. ADPKD is primarily caused by mutations in two genes, and Long noncoding RNAs (lncRNA), defined by a length >200 nucleotides and absence of a long ORF, have recently emerged as epigenetic regulators of development and disease; however, their involvement in PKD has not been explored previously. Here, we performed deep RNA-Seq to identify lncRNAs that are dysregulated in two orthologous mouse models of ADPKD (kidney-specific and mutant mice).

Transcription factor HNF1β regulates expression of the calcium-sensing receptor in the thick ascending limb of the kidney.

Mutations in hepatocyte nuclear factor 1β (HNF1β) cause autosomal dominant tubulointerstitial kidney disease (ADTKD-HNF1β), and patients tend to develop renal cysts, maturity-onset diabetes of the young (MODY), and suffer from electrolyte disturbances, including hypomagnesemia, hypokalemia, and hypocalciuria. Previous HNF1β research focused on the renal distal convoluted tubule (DCT) to elucidate the ADTKD-HNF1β electrolyte phenotype, although 70% of Mg is reabsorbed in the thick ascending limb of Henle's loop (TAL). An important regulator of Mg reabsorption in the TAL is the calcium-sensing receptor (CaSR).

Loss of transcriptional activation of the potassium channel Kir5.1 by HNF1β drives autosomal dominant tubulointerstitial kidney disease.

Hepatocyte nuclear factor 1 homeobox B (HNF1β) is an essential transcription factor for the development and functioning of the kidney. Mutations in HNF1β cause autosomal dominant tubulointerstitial kidney disease characterized by renal cysts and maturity-onset diabetes of the young (MODY). Moreover, these patients suffer from a severe electrolyte phenotype consisting of hypomagnesemia and hypokalemia.

Hepatocyte Nuclear Factor-1 Regulates Urinary Concentration and Response to Hypertonicity.

The transcription factor hepatocyte nuclear factor-1 (HNF-1) is essential for normal kidney development and function. Inactivation of HNF-1 in mouse kidney tubules leads to early-onset cyst formation and postnatal lethality. Here, we used Pkhd1/Cre mice to delete HNF-1 specifically in renal collecting ducts (CDs).

microRNA-17 family promotes polycystic kidney disease progression through modulation of mitochondrial metabolism.

Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent genetic cause of renal failure. Here we identify miR-17 as a target for the treatment of ADPKD. We report that miR-17 is induced in kidney cysts of mouse and human ADPKD.

Transcription Factor Hepatocyte Nuclear Factor-1β Regulates Renal Cholesterol Metabolism.

HNF-1β is a tissue-specific transcription factor that is expressed in the kidney and other epithelial organs. Humans with mutations in HNF-1β develop kidney cysts, and HNF-1β regulates the transcription of several cystic disease genes. However, the complete spectrum of HNF-1β-regulated genes and pathways is not known.

MicroRNA-21 Aggravates Cyst Growth in a Model of Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD), one of the most common monogenetic disorders, is characterized by kidney failure caused by bilateral renal cyst growth. MicroRNAs (miRs) have been implicated in numerous diseases, but the role of these noncoding RNAs in ADPKD pathogenesis is still poorly defined. Here, we investigated the role of miR-21, an oncogenic miR, in kidney cyst growth.

Transcription Factor Hepatocyte Nuclear Factor-1β (HNF-1β) Regulates MicroRNA-200 Expression through a Long Noncoding RNA.

The transcription factor hepatocyte nuclear factor-1β (HNF-1β) regulates tissue-specific gene expression in the kidney and other epithelial organs. Mutations of HNF-1β produce kidney cysts, and previous studies have shown that HNF-1β regulates the transcription of cystic disease genes, including Pkd2 and Pkhd1. Here, we combined chromatin immunoprecipitation and next-generation sequencing (ChIP-Seq) with microarray analysis to identify microRNAs (miRNAs) that are directly regulated by HNF-1β in renal epithelial cells.

Tissue-specific regulation of the mouse Pkhd1 (ARPKD) gene promoter.

Autosomal recessive polycystic kidney disease, an inherited disorder characterized by the formation of cysts in renal collecting ducts and biliary dysgenesis, is caused by mutations of the polycystic kidney and hepatic disease 1 (PKHD1) gene. Expression of PKHD1 is tissue specific and developmentally regulated. Here, we show that a 2.

The MDM2-p53 pathway: multiple roles in kidney development.

The molecular basis of nephron progenitor cell renewal and differentiation into nascent epithelial nephrons is an area of intense investigation. Defects in these early stages of nephrogenesis lead to renal hypoplasia, and eventually hypertension and chronic kidney disease. Terminal nephron differentiation, the process by which renal epithelial precursor cells exit the cell cycle and acquire physiological functions is equally important.

A p53-Pax2 pathway in kidney development: implications for nephrogenesis.

Congenital reduction in nephron number (renal hypoplasia) is a predisposing factor for chronic kidney disease and hypertension. Despite identification of specific genes and pathways in nephrogenesis, determinants of final nephron endowment are poorly understood. Here, we report that mice with germ-line p53 deletion (p53(-/-)) manifest renal hypoplasia; the phenotype can be recapitulated by conditional deletion of p53 from renal progenitors in the cap mesenchyme (CM(p53-/-)).

Mechanisms of p53 activation and physiological relevance in the developing kidney.

The tumor suppressor protein p53 is a short-lived transcription factor due to Mdm2-mediated proteosomal degradation. In response to genotoxic stress, p53 is stabilized via posttranslational modifications which prevent Mdm2 binding. p53 activation results in cell cycle arrest and apoptosis.

Tight regulation of p53 activity by Mdm2 is required for ureteric bud growth and branching.

Mdm2 (Murine Double Minute-2) is required to control cellular p53 activity and protein levels. Mdm2 null embryos die of p53-mediated growth arrest and apoptosis at the peri-implantation stage. Thus, the absolute requirement for Mdm2 in organogenesis is unknown.

Bradykinin B2 receptor null mice harboring a Ser23-to-Ala substitution in the p53 gene are protected from renal dysgenesis.

A physiological cross talk operates between the tumor suppressor protein p53 and the bradykinin B2 receptor (BdkrB2) during renal organogenesis. Thus, although BdkrB2 is a target for p53-mediated transcriptional activation, BdkrB2 is required to restrict p53 proapoptotic activity. We previously demonstrated that BdkrB2(-/-) embryos exposed to gestational salt stress develop renal dysgenesis as a result of p53-mediated apoptosis of nephron progenitors and repression of the terminal differentiation program.

Resistance exercise effects on blood glutathione status and plasma protein carbonyls: influence of partial vascular occlusion.

Seven weight-trained males performed both light resistance with partial occlusion (LRO: 30% 1 RM) and moderate resistance (MR: 70% 1 RM) to failure to ascertain whether blood protein carbonyls (PC) and glutathione status was altered compared to partial occlusion (PO) in a counterbalanced fashion. PO was identical in duration to the LRO session and all sessions were on separate days. PC did not differ for the three conditions at PRE (0.

Transcriptional control of terminal nephron differentiation.

Terminal differentiation of epithelial cells into more specialized cell types is a critical step in organogenesis. Throughout the process of terminal differentiation, epithelial progenitors acquire or upregulate expression of renal function genes and cease to proliferate, while expression of embryonic genes is repressed. This exquisite coordination of gene expression is accomplished by signaling networks and transcription factors which couple the external environment with the new functional demands of the cell.

Effect of insertional mutations in the pueA and pueB genes encoding two polyurethanases in Pseudomonas chlororaphis contained within a gene cluster.

Aims: To better understand the role of PueA and PueB from Pseudomonas chlororaphis in polyurethane degradation, the present study was conducted to create insertional mutants in their respective genes.

Methods And Results: Growth kinetic studies showed that the pueA knockout mutant had a greater effect than the pueB knockout mutant. The pueA mutant had an 80% decrease in cell density from that of the wild type, while the pueB mutant had an 18% decrease in cell density.

Side-chain conformational restriction in template-competitive inhibitors of E. coli DNA polymerase I Klenow fragment: synthesis, structural characterization and inhibition activity.

Nucleotide triphosphate alpha-(4-azidophenyl)-1,N6-etheno-dATP 3 and its monophosphate 3m were synthesized by condensation of 2-halo-2-(4-azidophenyl)acetaldehyes with dATP and dAMP, respectively. Structure analysis shows that the azidophenyl side chain is attached to the alpha-position of the etheno ring (i.e.

Adiponectin responses to continuous and progressively intense intermittent exercise.

Purpose: Adiponectin is a recently discovered adipocyte protein that is lower in patients with coronary artery disease and in Type II diabetics who have insulin resistance. Regular exercise is known to be a preventative factor in the development of atherosclerosis and Type II diabetes. Acute exercise increases insulin sensitivity; however, it also increases beta-adrenergic and glucocorticoid activities that may suppress adiponectin expression.