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1.
Sci Rep ; 9(1): 15552, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31645631

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

2.
Cell Metab ; 30(4): 784-799.e5, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31474566

RESUMO

Fibrosis is the final common pathway leading to end-stage renal failure. By analyzing the kidneys of patients and animal models with fibrosis, we observed a significant mitochondrial defect, including the loss of the mitochondrial transcription factor A (TFAM) in kidney tubule cells. Here, we generated mice with tubule-specific deletion of TFAM (Ksp-Cre/Tfamflox/flox). While these mice developed severe mitochondrial loss and energetic deficit by 6 weeks of age, kidney fibrosis, immune cell infiltration, and progressive azotemia causing death were only observed around 12 weeks of age. In renal cells of TFAM KO (knockout) mice, aberrant packaging of the mitochondrial DNA (mtDNA) resulted in its cytosolic translocation, activation of the cytosolic cGAS-stimulator of interferon genes (STING) DNA sensing pathway, and thus cytokine expression and immune cell recruitment. Ablation of STING ameliorated kidney fibrosis in mouse models of chronic kidney disease, demonstrating how TFAM sequesters mtDNA to limit the inflammation leading to fibrosis.

3.
Kidney Int ; 96(4): 862-870, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31492507

RESUMO

A revolution in cellular measurement technology is underway. Whereas prior studies have been able to analyze only the averaged outputs from renal tissue, we now can accurately monitor genome-wide gene expression, regulation, function, cellular history, and cellular interactions in thousands of individual cells in a single experiment. These methods are key drivers in changing our previous morphotype-based organ and disease descriptions to unbiased genomic definitions and therefore improving our understanding of kidney development, homeostasis, and disease.

4.
Curr Diab Rep ; 19(10): 91, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31471761

RESUMO

PURPOSE OF THE REVIEW: Kidney disease is the major cause of morbidity and mortality in patients with diabetes. Poor glycemic control shows the strongest correlation with diabetic kidney disease (DKD) development. A period of poor glycemia increases kidney disease risk even after an extended period of improved glucose control-a phenomenon called metabolic memory. Changes in the epigenome have been proposed to mediate the metabolic memory effect, as epigenome editing enzymes are regulated by substrates of intermediate metabolism and changes in the epigenome can be maintained after cell division. RECENT FINDINGS: Epigenome-wide association studies (EWAS) have reported differentially methylated cytosines in blood and kidney samples of DKD subjects when compared with controls. Differentially methylated cytosines were enriched on regulatory regions and some correlated with gene expression. Methylation changes predicted the speed of kidney function decline. Site-specific methylome editing tools now can be used to interrogate the functional role of differentially methylated regions. Methylome changes can be detected in blood and kidneys of patients with DKD. Methylation changes can predict future kidney function changes. Future studies shall determine their role in disease development.

5.
Nat Commun ; 10(1): 3842, 2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31451708

RESUMO

Chronic kidney disease (CKD), defined by low estimated glomerular filtration rate (eGFR), contributes to global morbidity and mortality. Here we conduct a transethnic Genome-Wide Association Study of eGFR in 280,722 participants of the Million Veteran Program (MVP), with replication in 765,289 participants from the Chronic Kidney Disease Genetics (CKDGen) Consortium. We identify 82 previously unreported variants, confirm 54 loci, and report interesting findings including association of the sickle cell allele of betaglobin among non-Hispanic blacks. Our transcriptome-wide association study of kidney function in healthy kidney tissue identifies 36 previously unreported and nine known genes, and maps gene expression to renal cell types. In a Phenome-Wide Association Study in 192,868 MVP participants using a weighted genetic score we detect associations with CKD stages and complications and kidney stones. This investigation reinterprets the genetic architecture of kidney function to identify the gene, tissue, and anatomical context of renal homeostasis and the clinical consequences of dysregulation.

6.
Nat Commun ; 10(1): 2461, 2019 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-31165727

RESUMO

Epigenetic changes might provide the biological explanation for the long-lasting impact of metabolic alterations of diabetic kidney disease development. Here we examined cytosine methylation of human kidney tubules using Illumina Infinium 450 K arrays from 91 subjects with and without diabetes and varying degrees of kidney disease using a cross-sectional design. We identify cytosine methylation changes associated with kidney structural damage and build a model for kidney function decline. We find that the methylation levels of 65 probes are associated with the degree of kidney fibrosis at genome wide significance. In total 471 probes improve the model for kidney function decline. Methylation probes associated with kidney damage and functional decline enrich on kidney regulatory regions and associate with gene expression changes, including epidermal growth factor (EGF). Altogether, our work shows that kidney methylation differences can be detected in patients with diabetic kidney disease and improve kidney function decline models indicating that they are potentially functionally important.


Assuntos
Citosina/metabolismo , Metilação de DNA , Nefropatias Diabéticas/genética , Rim/metabolismo , Idoso , Estudos de Casos e Controles , Ilhas de CpG , Estudos Transversais , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Progressão da Doença , Epigênese Genética , Feminino , Fibrose , Regulação da Expressão Gênica , Taxa de Filtração Glomerular , Humanos , Rim/patologia , Masculino , Pessoa de Meia-Idade
7.
JCI Insight ; 4(11)2019 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-31167971

RESUMO

In patients with diabetes mellitus, poor metabolic control has a long-lasting impact on kidney disease development. Epigenetic changes, including cytosine methylation, have been proposed as potential mediators of the long-lasting effect of adverse metabolic events. Our understanding of the presence and contribution of methylation changes to disease development is limited because of the lack of comprehensive base-resolution methylome information of human kidney tissue samples and site-specific methylation editing. Base resolution, whole-genome bisulfite sequencing methylome maps of human diabetic kidney disease (DKD) tubule samples, and associated gene expression measured by RNA sequencing highlighted widespread methylation changes in DKD. Pathway analysis highlighted coordinated (methylation and gene expression) changes in immune signaling, including tumor necrosis factor alpha (TNF). Changes in TNF methylation correlated with kidney function decline. dCas9-Tet1-based lowering of the cytosine methylation level of the TNF differentially methylated region resulted in an increase in the TNF transcript level, indicating that methylation of this locus plays an important role in controlling TNF expression. Increasing the TNF level in diabetic mice increased disease severity, such as albuminuria. In summary, our results indicate widespread methylation differences in DKD kidneys and highlights epigenetic changes in the TNF locus and its contribution to the development of nephropathy in patients with diabetes mellitus.

8.
Sci Rep ; 9(1): 6693, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31040292

RESUMO

RAAS inhibition has been the standard treatment for CKD for years because it can reduce proteinuria and hence retard renal function decline, but the proteinuria reduction effect is still insufficient in many patients. Podocyte foot process and slit diaphragm are the final barrier to prevent serum proteins leak into urine, and podocyte foot process effacement is the common pathway of all proteinruic diseases. Cell structure are regulated by three evolutionarily conserved Rho GTPases, notably, Rac1 activation is sufficient and necessary for podocyte foot process effacement, however, Rac1 inhibition is not an option for kidney disease treatment because of its systemic side effects. Four-and-a-half LIM domains protein 2 (FHL2) is highly expressed in podocytes and has been implicated in regulating diverse biological functions. Here, we used micro-dissected human kidney samples, in vitro podocyte culture experiments, and a hypertension animal model to determine the possible role of FHL2 in hypertensive nephropathy. FHL2 was abundantly upregulated in hypertensive human glomeruli and animal kidney samples. Genetic deletion of the FHL2 did not alter normal renal structure or function but mitigated hypertension-induced podocyte foot process effacement and albuminuria. Mechanistically, angiotensin II-induced podocyte cytoskeleton reorganization via FAK-Rac1 axis, FHL2 binds with FAK and is an important mediator of Ang II induced Rac1 activation, thus, FHL2 inhibition can selectively block FAK-Rac1 axis in podocyte and prevent proteinuria. These results provide important insights into the mechanisms of podocyte foot process effacement and points out a promising strategy to treat kidney disease.

9.
J Clin Invest ; 129(6): 2192-2194, 2019 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-31063992

RESUMO

Acute kidney injury (AKI) is one of the most important risk factors for chronic and progressive kidney disease, leading to end-stage kidney failure. Tubule epithelial regeneration leads to the resolution of renal failure in AKI. Failure of tubule epithelial regeneration leads to concomitant hypoxia from loss of microcirculation, which serves as a critical factor leading to chronic kidney disease. In this issue of the JCI, Li et al. show that hypoxia activates the stress-responsive transcription factor FoxO3. Increased FoxO3 protein abundance leads to alterations in tubular epithelial autophagy and metabolism, highlighting an important mechanism causing permanent renal damage even after an acute injury.

10.
N Engl J Med ; 380(20): 1918-1928, 2019 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-31091373

RESUMO

BACKGROUND: In the context of kidney transplantation, genomic incompatibilities between donor and recipient may lead to allosensitization against new antigens. We hypothesized that recessive inheritance of gene-disrupting variants may represent a risk factor for allograft rejection. METHODS: We performed a two-stage genetic association study of kidney allograft rejection. In the first stage, we performed a recessive association screen of 50 common gene-intersecting deletion polymorphisms in a cohort of kidney transplant recipients. In the second stage, we replicated our findings in three independent cohorts of donor-recipient pairs. We defined genomic collision as a specific donor-recipient genotype combination in which a recipient who was homozygous for a gene-intersecting deletion received a transplant from a nonhomozygous donor. Identification of alloantibodies was performed with the use of protein arrays, enzyme-linked immunosorbent assays, and Western blot analyses. RESULTS: In the discovery cohort, which included 705 recipients, we found a significant association with allograft rejection at the LIMS1 locus represented by rs893403 (hazard ratio with the risk genotype vs. nonrisk genotypes, 1.84; 95% confidence interval [CI], 1.35 to 2.50; P = 9.8×10-5). This effect was replicated under the genomic-collision model in three independent cohorts involving a total of 2004 donor-recipient pairs (hazard ratio, 1.55; 95% CI, 1.25 to 1.93; P = 6.5×10-5). In the combined analysis (discovery cohort plus replication cohorts), the risk genotype was associated with a higher risk of rejection than the nonrisk genotype (hazard ratio, 1.63; 95% CI, 1.37 to 1.95; P = 4.7×10-8). We identified a specific antibody response against LIMS1, a kidney-expressed protein encoded within the collision locus. The response involved predominantly IgG2 and IgG3 antibody subclasses. CONCLUSIONS: We found that the LIMS1 locus appeared to encode a minor histocompatibility antigen. Genomic collision at this locus was associated with rejection of the kidney allograft and with production of anti-LIMS1 IgG2 and IgG3. (Funded by the Columbia University Transplant Center and others.).


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Variações do Número de Cópias de DNA , Rejeição de Enxerto/genética , Transplante de Rim , Proteínas com Domínio LIM/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Estudos de Coortes , Estudos de Associação Genética , Genótipo , Antígenos HLA/genética , Teste de Histocompatibilidade , Humanos , Imunoglobulina G/sangue , Proteínas com Domínio LIM/imunologia , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Polimorfismo de Nucleotídeo Único , Doadores de Tecidos
11.
Nat Med ; 25(5): 805-813, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31011203

RESUMO

Chronic inflammation is postulated to be involved in the development of end-stage renal disease in diabetes, but which specific circulating inflammatory proteins contribute to this risk remain unknown. To study this, we examined 194 circulating inflammatory proteins in subjects from three independent cohorts with type 1 and type 2 diabetes. In each cohort, we identified an extremely robust kidney risk inflammatory signature (KRIS), consisting of 17 proteins enriched in tumor necrosis factor-receptor superfamily members, that was associated with a 10-year risk of end-stage renal disease. All these proteins had a systemic, non-kidney source. Our prospective study findings provide strong evidence that KRIS proteins contribute to the inflammatory process underlying end-stage renal disease development in both types of diabetes. These proteins point to new therapeutic targets and new prognostic tests to identify subjects at risk of end-stage renal disease, as well as biomarkers to measure responses to treatment of diabetic kidney disease.


Assuntos
Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/etiologia , Falência Renal Crônica/sangue , Falência Renal Crônica/etiologia , Adulto , Idoso , Biomarcadores/sangue , Proteínas Sanguíneas/genética , Proteínas Sanguíneas/metabolismo , Estudos de Coortes , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/genética , Progressão da Doença , Feminino , Humanos , Mediadores da Inflamação/sangue , Falência Renal Crônica/genética , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Proteômica , Receptores do Fator de Necrose Tumoral/sangue , Receptores do Fator de Necrose Tumoral/genética , Fatores de Risco
12.
Curr Opin Nephrol Hypertens ; 28(3): 219-226, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30844884

RESUMO

PURPOSE OF REVIEW: Transcriptome analysis of human kidney samples provides an integrated output of genetic, physiological, or environmental inputs. This review summarizes recent findings including gene expression and genetic variation integration, bulk and single cell gene expression analysis, and describes how such studies have improved our understanding of kidney disease development. RECENT FINDINGS: Bulk or whole tissue analysis of patient kidney samples identified a large number of genes, whose levels correlate with kidney function and/or structural damage. These genes were enriched for metabolic and immune functions. Using expression quantitative trait analysis, genetic variations-driven gene expression can be identified. Recent developments in single cell sequencing defined cell-type-specific gene expression changes and highlighted specific cell types for disease development. SUMMARY: Recent advancement in whole tissue transcriptomics, specifically incorporating genotype information and single cell data have been powerful to identify kidney disease-associated genes, pathways, and cell types.

13.
J Am Soc Nephrol ; 30(4): 594-609, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30850438

RESUMO

BACKGROUND: Cytosine methylation of regulatory regions, such as promoters and enhancers, plays a key role in regulating gene expression, however, its role in kidney development has not been analyzed. METHODS: To identify functionally important epigenome-modifying enzymes and genome regions where methylation modifications are functionally important for kidney development, we performed genome-wide methylation analysis, expression profiling, and systematic genetic targeting of DNA methyltransferases (Dnmt1, Dnmt3a, and Dnmt3b) and Ten-eleven translocation methylcytosine hydroxylases (Tet2) in nephron progenitor cells (Six2 Cre) in mice. RESULTS: Genome-wide methylome analysis indicated dynamic changes on promoters and enhancers during development. Six2 Cre Dnmt3a f/f, Six2 Cre Dnmt3b f/f, and Six2 Cre Tet2 f/f mice showed no significant structural or functional renal abnormalities. In contrast, Six2 Cre Dnmt1 f/f mice died within 24 hours of birth, from a severe kidney developmental defect. Genome-wide methylation analysis indicated a marked loss of methylation of transposable elements. RNA sequencing detected endogenous retroviral transcripts. Expression of intracellular viral sensing pathways (RIG-I), early embryonic, nonrenal lineage genes and increased cell death contributed to the phenotype development. In podocytes, loss of Dnmt1, Dnmt3a, Dnmt3b, or Tet2 did not lead to functional or structural differences at baseline or after toxic injury. CONCLUSIONS: Genome-wide cytosine methylation and gene expression profiling showed that by silencing embryonic, nonrenal lineage genes and transposable elements, DNMT1-mediated cytosine methylation is essential for kidney development.

14.
J Clin Invest ; 130: 1612-1625, 2019 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-30702441

RESUMO

Although clear cell renal cell carcinoma (ccRCC) has been shown to result in widespread aberrant cytosine methylation and loss of 5-hydroxymethylcytosine (5hmC), the prognostic impact and therapeutic targeting of this epigenetic aberrancy has not been fully explored. Analysis of 576 primary ccRCC samples demonstrated that loss of 5hmC was strongly associated with aggressive clinicopathologic features and was an independent adverse prognostic factor. Loss of 5hmC also predicted reduced progression-free survival after resection of nonmetastatic disease. The loss of 5hmC in ccRCC was not due to mutational or transcriptional inactivation of ten eleven translocation (TET) enzymes, but to their functional inactivation by l-2-hydroxyglutarate (L2HG), which was overexpressed due to the deletion and underexpression of L2HG dehydrogenase (L2HGDH). Ascorbic acid (AA) reduced methylation and restored genome-wide 5hmC levels via TET activation. Fluorescence quenching of the recombinant TET-2 protein was unaffected by L2HG in the presence of AA. Pharmacologic AA treatment led to reduced growth of ccRCC in vitro and reduced tumor growth in vivo, with increased intratumoral 5hmC. These data demonstrate that reduced 5hmC is associated with reduced survival in ccRCC and provide a preclinical rationale for exploring the therapeutic potential of high-dose AA in ccRCC.

16.
Nat Commun ; 10(1): 380, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30670690

RESUMO

Knowledge of cell type composition in disease relevant tissues is an important step towards the identification of cellular targets of disease. We present MuSiC, a method that utilizes cell-type specific gene expression from single-cell RNA sequencing (RNA-seq) data to characterize cell type compositions from bulk RNA-seq data in complex tissues. By appropriate weighting of genes showing cross-subject and cross-cell consistency, MuSiC enables the transfer of cell type-specific gene expression information from one dataset to another. When applied to pancreatic islet and whole kidney expression data in human, mouse, and rats, MuSiC outperformed existing methods, especially for tissues with closely related cell types. MuSiC enables the characterization of cellular heterogeneity of complex tissues for understanding of disease mechanisms. As bulk tissue data are more easily accessible than single-cell RNA-seq, MuSiC allows the utilization of the vast amounts of disease relevant bulk tissue RNA-seq data for elucidating cell type contributions in disease.


Assuntos
Perfilação da Expressão Gênica/métodos , Expressão Gênica , Teste de Histocompatibilidade/métodos , Análise de Célula Única/métodos , Animais , Doença , Humanos , Ilhotas Pancreáticas/citologia , Rim/citologia , Camundongos , Modelos Teóricos , Ratos , Análise de Sequência de RNA/métodos
17.
PLoS Genet ; 15(1): e1007874, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30625149

RESUMO

Extensive cell-to-cell variation exists even among putatively identical cells, and there is great interest in understanding how the properties of transcription relate to this heterogeneity. Differential expression from the two gene copies in diploid cells could potentially contribute, yet our ability to measure from which gene copy individual RNAs originated remains limited, particularly in the context of tissues. Here, we demonstrate quantitative, single molecule allele-specific RNA FISH adapted for use on tissue sections, allowing us to determine the chromosome of origin of individual RNA molecules in formaldehyde-fixed tissues. We used this method to visualize the allele-specific expression of Xist and multiple autosomal genes in mouse kidney. By combining these data with mathematical modeling, we evaluated models for allele-specific heterogeneity, in particular demonstrating that apparent expression from only one of the alleles in single cells can arise as a consequence of low-level mRNA abundance and transcriptional bursting.


Assuntos
Desequilíbrio Alélico/genética , Hibridização in Situ Fluorescente/métodos , Rim/metabolismo , RNA Longo não Codificante/genética , Alelos , Animais , Regulação da Expressão Gênica no Desenvolvimento/genética , Camundongos , Especificidade de Órgãos , RNA Longo não Codificante/isolamento & purificação
18.
Nat Med ; 24(11): 1721-1731, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30275566

RESUMO

Chronic kidney disease (CKD), a condition in which the kidneys are unable to clear waste products, affects 700 million people globally. Genome-wide association studies (GWASs) have identified sequence variants for CKD; however, the biological basis of these GWAS results remains poorly understood. To address this issue, we created an expression quantitative trait loci (eQTL) atlas for the glomerular and tubular compartments of the human kidney. Through integrating the CKD GWAS with eQTL, single-cell RNA sequencing and regulatory region maps, we identified novel genes for CKD. Putative causal genes were enriched for proximal tubule expression and endolysosomal function, where DAB2, an adaptor protein in the TGF-ß pathway, formed a central node. Functional experiments confirmed that reducing Dab2 expression in renal tubules protected mice from CKD. In conclusion, compartment-specific eQTL analysis is an important avenue for the identification of novel genes and cellular pathways involved in CKD development and thus potential new opportunities for its treatment.

19.
PLoS Biol ; 16(9): e2005233, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30226866

RESUMO

While Notch signaling has been proposed to play a key role in fibrosis, the direct molecular pathways targeted by Notch signaling and the precise ligand and receptor pair that are responsible for kidney disease remain poorly defined. In this study, we found that JAG1 and NOTCH2 showed the strongest correlation with the degree of interstitial fibrosis in a genome-wide expression analysis of a large cohort of human kidney samples. Transcript analysis of mouse kidney disease models, including folic-acid (FA)-induced nephropathy, unilateral ureteral obstruction (UUO), or apolipoprotein L1 (APOL1)-associated kidney disease, indicated that Jag1 and Notch2 levels were higher in all analyzed kidney fibrosis models. Mice with tubule-specific deletion of Jag1 or Notch2 (Kspcre/Jag1flox/flox and Kspcre/Notch2flox/flox) had no kidney-specific alterations at baseline but showed protection from FA-induced kidney fibrosis. Tubule-specific genetic deletion of Notch1 and global knockout of Notch3 had no effect on fibrosis. In vitro chromatin immunoprecipitation experiments and genome-wide expression studies identified the mitochondrial transcription factor A (Tfam) as a direct Notch target. Re-expression of Tfam in tubule cells prevented Notch-induced metabolic and profibrotic reprogramming. Tubule-specific deletion of Tfam resulted in fibrosis. In summary, Jag1 and Notch2 play a key role in kidney fibrosis development by regulating Tfam expression and metabolic reprogramming.

20.
Diabetes ; 67(10): 1923-1931, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30237160

RESUMO

The American Diabetes Association convened a research symposium, "Epigenetics and Epigenomics: Implications for Diabetes and Obesity" on 17-19 November 2017. International experts in genetics, epigenetics, computational biology, and physiology discussed the current state of understanding of the relationships between genetics, epigenetics, and environment in diabetes and examined existing evidence for the role of epigenetic factors in regulating metabolism and the risk of diabetes and its complications. The authors summarize the presentations, which highlight how the complex interactions between genes and environment may in part be mediated through epigenetic changes and how information about nutritional and other environmental stimuli can be transmitted to the next generation. In addition, the authors present expert consensus on knowledge gaps and research recommendations for the field.


Assuntos
Diabetes Mellitus/genética , Epigênese Genética/genética , Epigenômica/métodos , Obesidade/genética , Metilação de DNA/genética , Humanos
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