Systems biology of polycystic kidney disease: a critical review

Menezes, Luís F.; Germino, Gregory G.

doi:10.1002/wsbm.1289

Cited by 19 publications

(14 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This comparison will be the subject of a future communication. Other evaluations of gene expression data have relied on murine cell lines or RNA isolated from newly formed cysts from conditional knockout models, and results from these studies identify similar themes for aberrant signaling such as immune defense, cell structure and motility, cellular proliferation, apoptosis, and metabolic control [59–62]. These are GSEA findings that are also observed in our study suggesting that a subset of findings observed in our cell lines are generalizable.…”

Section: Discussionsupporting

confidence: 75%

Transcriptome analysis reveals manifold mechanisms of cyst development in ADPKD

et al. 2016

View full text Add to dashboard Cite

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) causes progressive loss of renal function in adults as a consequence of the accumulation of cysts. ADPKD is the most common genetic cause of end-stage renal disease. Mutations in polycystin-1 occur in 87% of cases of ADPKD and mutations in polycystin-2 are found in 12% of ADPKD patients. The complexity of ADPKD has hampered efforts to identify the mechanisms underlying its pathogenesis. No current FDA (Federal Drug Administration)-approved therapies ameliorate ADPKD progression.ResultsWe used the de Almeida laboratory’s sensitive new transcriptogram method for whole-genome gene expression data analysis to analyze microarray data from cell lines developed from cell isolates of normal kidney and of both non-cystic nephrons and cysts from the kidney of a patient with ADPKD. We compared results obtained using standard Ingenuity Volcano plot analysis, Gene Set Enrichment Analysis (GSEA) and transcriptogram analysis. Transcriptogram analysis confirmed the findings of Ingenuity, GSEA, and published analysis of ADPKD kidney data and also identified multiple new expression changes in KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways related to cell growth, cell death, genetic information processing, nucleotide metabolism, signal transduction, immune response, response to stimulus, cellular processes, ion homeostasis and transport and cofactors, vitamins, amino acids, energy, carbohydrates, drugs, lipids, and glycans. Transcriptogram analysis also provides significance metrics which allow us to prioritize further study of these pathways.ConclusionsTranscriptogram analysis identifies novel pathways altered in ADPKD, providing new avenues to identify both ADPKD’s mechanisms of pathogenesis and pharmaceutical targets to ameliorate the progression of the disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s40246-016-0095-x) contains supplementary material, which is available to authorized users.

show abstract

Section: Discussionsupporting

confidence: 75%

Transcriptome analysis reveals manifold mechanisms of cyst development in ADPKD

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Second, it is necessary to exploit novel molecular genetic techniques to pinpoint the molecular mechanisms known to cause common kidney diseases (7,8). This is because kidney pathologies are lumped together by their temporal patterns (acute or chronic) or by their target structure (glomerular vs tubular), which obscures the underlying kidney biology and prevents targeted precision medicine.…”

mentioning

confidence: 99%

Comprehensive single cell RNAseq analysis of the kidney reveals novel cell types and unexpected cell plasticity

Park

Shrestha

Qiu

et al. 2017

Preprint

View full text Add to dashboard Cite

Abstract:A key limitations to understand kidney function and disease development has been that specific cell types responsible for specific homeostatic kidney function or disease phenotypes have not been defined at the molecular level.To fill this gap, we characterized 57,979 cells from healthy mouse kidneys using unbiased single-cell RNA sequencing. We show that genetic mutations that present with similar phenotypes mostly affect genes that are expressed in a single unique differentiated cell type. On the other hand, we found unexpected cell plasticity of epithelial cells in the final segment of the kidney (collecting duct) that is responsible for final composition of the urine. Using All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

show abstract

“…E‐F). Thus, gender might influence cystogenesis in the ADPKD kidney, with female gender being a protective factor both in the animal model and in ADPKD patients .…”

Section: Resultsmentioning

confidence: 99%

Rapamycin treatment dose‐dependently improves the cystic kidney in a new ADPKD mouse model via the mTORC1 and cell‐cycle‐associated CDK1/cyclin axis

Fan

et al. 2017

J Cellular Molecular Medi

View full text Add to dashboard Cite

Although translational research into autosomal dominant polycystic kidney disease (ADPKD) and its pathogenesis has made considerable progress, there is presently lack of standardized animal model for preclinical trials. In this study, we developed an orthologous mouse model of human ADPKD by cross‐mating Pkd2 conditional‐knockout mice (Pkd2 f3) to Cre transgenic mice in which Cre is driven by a spectrum of kidney‐related promoters. By systematically characterizing the mouse model, we found that Pkd2 f3/f3 mice with a Cre transgene driven by the mouse villin‐1 promoter (Vil‐Cre;Pkd2 f3/f3) develop overt cysts in the kidney, liver and pancreas and die of end‐stage renal disease (ESRD) at 4–6 months of age. To determine whether these Vil‐Cre;Pkd2 f3/f3 mice were suitable for preclinical trials, we treated the mice with the high‐dose mammalian target of rapamycin (mTOR) inhibitor rapamycin. High‐dose rapamycin significantly increased the lifespan, lowered the cystic index and kidney/body weight ratio and improved renal function in Vil‐Cre;Pkd2 f3/f3 mice in a time‐ and dose‐dependent manner. In addition, we further found that rapamycin arrested aberrant epithelial‐cell proliferation in the ADPKD kidney by down‐regulating the cell‐cycle‐associated cyclin‐dependent kinase 1 (CDK1) and cyclins, namely cyclin A, cyclin B, cyclin D1 and cyclin E, demonstrating a direct link between mTOR signalling changes and the polycystin‐2 dysfunction in cystogenesis. Our newly developed ADPKD model provides a practical platform for translating in vivo preclinical results into ADPKD therapies. The newly defined molecular mechanism by which rapamycin suppresses proliferation via inhibiting abnormally elevated CDK1 and cyclins offers clues to new molecular targets for ADPKD treatment.

show abstract

Systems biology of polycystic kidney disease: a critical review

Cited by 19 publications

References 60 publications

Transcriptome analysis reveals manifold mechanisms of cyst development in ADPKD

Transcriptome analysis reveals manifold mechanisms of cyst development in ADPKD

Comprehensive single cell RNAseq analysis of the kidney reveals novel cell types and unexpected cell plasticity

Rapamycin treatment dose‐dependently improves the cystic kidney in a new ADPKD mouse model via the mTORC1 and cell‐cycle‐associated CDK1/cyclin axis

Contact Info

Product

Resources

About