Kidney omics in hypertension: from statistical associations to biological mechanisms and clinical applications
- Tomaszewski, Maciej, Morris, Andrew, Howson, Joanna, Franceschini, Nora, Eales, James, Xu, Xiaoguang, Dikalov, Sergey, Guzik, Tomasz, Humphreys, Benjamin, Harrap, Stephen, Charchar, Fadi
- Authors: Tomaszewski, Maciej , Morris, Andrew , Howson, Joanna , Franceschini, Nora , Eales, James , Xu, Xiaoguang , Dikalov, Sergey , Guzik, Tomasz , Humphreys, Benjamin , Harrap, Stephen , Charchar, Fadi
- Date: 2022
- Type: Text , Journal article , Review
- Relation: Kidney International Vol. 102, no. 3 (2022), p. 492-505
- Full Text:
- Reviewed:
- Description: Hypertension is a major cardiovascular disease risk factor and contributor to premature death globally. Family-based investigations confirmed a significant heritable component of blood pressure (BP), whereas genome-wide association studies revealed >1000 common and rare genetic variants associated with BP and/or hypertension. The kidney is not only an organ of key relevance to BP regulation and the development of hypertension, but it also acts as the tissue mediator of genetic predisposition to hypertension. The identity of kidney genes, pathways, and related mechanisms underlying the genetic associations with BP has started to emerge through integration of genomics with kidney transcriptomics, epigenomics, and other omics as well as through applications of causal inference, such as Mendelian randomization. Single-cell methods further enabled mapping of BP-associated kidney genes to cell types, and in conjunction with other omics, started to illuminate the biological mechanisms underpinning associations of BP-associated genetic variants and kidney genes. Polygenic risk scores derived from genome-wide association studies and refined on kidney omics hold the promise of enhanced diagnostic prediction, whereas kidney omics-informed drug discovery is likely to contribute new therapeutic opportunities for hypertension and hypertension-mediated kidney damage. © 2022 International Society of Nephrology
- Authors: Tomaszewski, Maciej , Morris, Andrew , Howson, Joanna , Franceschini, Nora , Eales, James , Xu, Xiaoguang , Dikalov, Sergey , Guzik, Tomasz , Humphreys, Benjamin , Harrap, Stephen , Charchar, Fadi
- Date: 2022
- Type: Text , Journal article , Review
- Relation: Kidney International Vol. 102, no. 3 (2022), p. 492-505
- Full Text:
- Reviewed:
- Description: Hypertension is a major cardiovascular disease risk factor and contributor to premature death globally. Family-based investigations confirmed a significant heritable component of blood pressure (BP), whereas genome-wide association studies revealed >1000 common and rare genetic variants associated with BP and/or hypertension. The kidney is not only an organ of key relevance to BP regulation and the development of hypertension, but it also acts as the tissue mediator of genetic predisposition to hypertension. The identity of kidney genes, pathways, and related mechanisms underlying the genetic associations with BP has started to emerge through integration of genomics with kidney transcriptomics, epigenomics, and other omics as well as through applications of causal inference, such as Mendelian randomization. Single-cell methods further enabled mapping of BP-associated kidney genes to cell types, and in conjunction with other omics, started to illuminate the biological mechanisms underpinning associations of BP-associated genetic variants and kidney genes. Polygenic risk scores derived from genome-wide association studies and refined on kidney omics hold the promise of enhanced diagnostic prediction, whereas kidney omics-informed drug discovery is likely to contribute new therapeutic opportunities for hypertension and hypertension-mediated kidney damage. © 2022 International Society of Nephrology
Hypertension and renin-angiotensin system blockers are not associated with expression of angiotensin-converting enzyme 2 (ACE2) in the kidney
- Jiang, Xiao, Eales, James, Scannali, David, Prestes, Priscilla, Charchar, Fadi
- Authors: Jiang, Xiao , Eales, James , Scannali, David , Prestes, Priscilla , Charchar, Fadi
- Date: 2020
- Type: Text , Journal article
- Relation: European Heart Journal Vol. 41, no. 48 (2020), p. 4580-4588
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- Description: Aims Angiotensin-converting enzyme 2 (ACE2) is the cellular entry point for severe acute respiratory syndrome coronavirus (SARS-CoV-2) - the cause of coronavirus disease 2019 (COVID-19). However, the effect of renin-angiotensin system (RAS)-inhibition on ACE2 expression in human tissues of key relevance to blood pressure regulation and COVID-19 infection has not previously been reported. Methods and results We examined how hypertension, its major metabolic co-phenotypes, and antihypertensive medications relate to ACE2 renal expression using information from up to 436 patients whose kidney transcriptomes were characterized by RNA-sequencing. We further validated some of the key observations in other human tissues and/or a controlled experimental model. Our data reveal increasing expression of ACE2 with age in both human lungs and the kidney. We show no association between renal expression of ACE2 and either hypertension or common types of RAS inhibiting drugs. We demonstrate that renal abundance of ACE2 is positively associated with a biochemical index of kidney function and show a strong enrichment for genes responsible for kidney health and disease in ACE2 coexpression analysis. Conclusion Our results indicate that neither hypertension nor antihypertensive treatment is likely to alter the expression of the key entry receptor for SARS-CoV-2 in the human kidney. Our data further suggest that in the absence of SARS-CoV-2 infection, kidney ACE2 is most likely nephro-protective but the age-related increase in its expression within lungs and kidneys may be relevant to the risk of SARS-CoV-2 infection. © The Author(s) 2020. *Please note that there are multiple authors for this article therefore only the name of the first 5 including Federation University Australia affiliates “James Eales", "Priscilla Prestes" and "Fadi Charchar” are provided in this record**
- Authors: Jiang, Xiao , Eales, James , Scannali, David , Prestes, Priscilla , Charchar, Fadi
- Date: 2020
- Type: Text , Journal article
- Relation: European Heart Journal Vol. 41, no. 48 (2020), p. 4580-4588
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- Reviewed:
- Description: Aims Angiotensin-converting enzyme 2 (ACE2) is the cellular entry point for severe acute respiratory syndrome coronavirus (SARS-CoV-2) - the cause of coronavirus disease 2019 (COVID-19). However, the effect of renin-angiotensin system (RAS)-inhibition on ACE2 expression in human tissues of key relevance to blood pressure regulation and COVID-19 infection has not previously been reported. Methods and results We examined how hypertension, its major metabolic co-phenotypes, and antihypertensive medications relate to ACE2 renal expression using information from up to 436 patients whose kidney transcriptomes were characterized by RNA-sequencing. We further validated some of the key observations in other human tissues and/or a controlled experimental model. Our data reveal increasing expression of ACE2 with age in both human lungs and the kidney. We show no association between renal expression of ACE2 and either hypertension or common types of RAS inhibiting drugs. We demonstrate that renal abundance of ACE2 is positively associated with a biochemical index of kidney function and show a strong enrichment for genes responsible for kidney health and disease in ACE2 coexpression analysis. Conclusion Our results indicate that neither hypertension nor antihypertensive treatment is likely to alter the expression of the key entry receptor for SARS-CoV-2 in the human kidney. Our data further suggest that in the absence of SARS-CoV-2 infection, kidney ACE2 is most likely nephro-protective but the age-related increase in its expression within lungs and kidneys may be relevant to the risk of SARS-CoV-2 infection. © The Author(s) 2020. *Please note that there are multiple authors for this article therefore only the name of the first 5 including Federation University Australia affiliates “James Eales", "Priscilla Prestes" and "Fadi Charchar” are provided in this record**
Uncovering genetic mechanisms of kidney aging through transcriptomics, genomics, and epigenomics
- Rowland, Joshua, Akbarov, Artur, Eales, James, Xu, Xiaoguang, Dormer, John, Guo, Hui, Denniff, Matthew, Jiang, Xiao, Ranjzad, Parisa, Nazgiewicz, Alicja, Prestes, Priscilla, Antczak, Andrzej, Szulinska, Monika, Wise, Ingrid, Zukowska-Szczechowska, Ewa, Bogdanski, Pawel, Woolf, Adrian, Samani, Nilesh, Charchar, Fadi, Tomaszewski, Maciej
- Authors: Rowland, Joshua , Akbarov, Artur , Eales, James , Xu, Xiaoguang , Dormer, John , Guo, Hui , Denniff, Matthew , Jiang, Xiao , Ranjzad, Parisa , Nazgiewicz, Alicja , Prestes, Priscilla , Antczak, Andrzej , Szulinska, Monika , Wise, Ingrid , Zukowska-Szczechowska, Ewa , Bogdanski, Pawel , Woolf, Adrian , Samani, Nilesh , Charchar, Fadi , Tomaszewski, Maciej
- Date: 2019
- Type: Text , Journal article
- Relation: Kidney International Vol. 95, no. 3 (2019), p. 624-635
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- Reviewed:
- Description: Nephrons scar and involute during aging, increasing the risk of chronic kidney disease. Little is known, however, about genetic mechanisms of kidney aging. We sought to define the signatures of age on the renal transcriptome using 563 human kidneys. The initial discovery analysis of 260 kidney transcriptomes from the TRANScriptome of renaL humAn TissuE Study (TRANSLATE) and the Cancer Genome Atlas identified 37 age-associated genes. For 19 of those genes, the association with age was replicated in 303 kidney transcriptomes from the Nephroseq resource. Surveying 42 nonrenal tissues from the Genotype–Tissue Expression project revealed that, for approximately a fifth of the replicated genes, the association with age was kidney-specific. Seventy-three percent of the replicated genes were associated with functional or histological parameters of age-related decline in kidney health, including glomerular filtration rate, glomerulosclerosis, interstitial fibrosis, tubular atrophy, and arterial narrowing. Common genetic variants in four of the age-related genes, namely LYG1, PPP1R3C, LTF and TSPYL5, correlated with the trajectory of age-related changes in their renal expression. Integrative analysis of genomic, epigenomic, and transcriptomic information revealed that the observed age-related decline in renal TSPYL5 expression was determined both genetically and epigenetically. Thus, this study revealed robust molecular signatures of the aging kidney and new regulatory mechanisms of age-related change in the kidney transcriptome.
- Authors: Rowland, Joshua , Akbarov, Artur , Eales, James , Xu, Xiaoguang , Dormer, John , Guo, Hui , Denniff, Matthew , Jiang, Xiao , Ranjzad, Parisa , Nazgiewicz, Alicja , Prestes, Priscilla , Antczak, Andrzej , Szulinska, Monika , Wise, Ingrid , Zukowska-Szczechowska, Ewa , Bogdanski, Pawel , Woolf, Adrian , Samani, Nilesh , Charchar, Fadi , Tomaszewski, Maciej
- Date: 2019
- Type: Text , Journal article
- Relation: Kidney International Vol. 95, no. 3 (2019), p. 624-635
- Full Text:
- Reviewed:
- Description: Nephrons scar and involute during aging, increasing the risk of chronic kidney disease. Little is known, however, about genetic mechanisms of kidney aging. We sought to define the signatures of age on the renal transcriptome using 563 human kidneys. The initial discovery analysis of 260 kidney transcriptomes from the TRANScriptome of renaL humAn TissuE Study (TRANSLATE) and the Cancer Genome Atlas identified 37 age-associated genes. For 19 of those genes, the association with age was replicated in 303 kidney transcriptomes from the Nephroseq resource. Surveying 42 nonrenal tissues from the Genotype–Tissue Expression project revealed that, for approximately a fifth of the replicated genes, the association with age was kidney-specific. Seventy-three percent of the replicated genes were associated with functional or histological parameters of age-related decline in kidney health, including glomerular filtration rate, glomerulosclerosis, interstitial fibrosis, tubular atrophy, and arterial narrowing. Common genetic variants in four of the age-related genes, namely LYG1, PPP1R3C, LTF and TSPYL5, correlated with the trajectory of age-related changes in their renal expression. Integrative analysis of genomic, epigenomic, and transcriptomic information revealed that the observed age-related decline in renal TSPYL5 expression was determined both genetically and epigenetically. Thus, this study revealed robust molecular signatures of the aging kidney and new regulatory mechanisms of age-related change in the kidney transcriptome.
Epigenetic modifications in essential hypertension
- Authors: Wise, Ingrid
- Date: 2018
- Type: Text , Thesis , PhD
- Full Text:
- Description: Background: Hypertension (HTN) is a complex, multifactorial, quantitative trait under polygenic control that affects more than one billion people globally. Despite advances in our understanding of the pathophysiology of HTN and the implementation of more effective treatment and prevention strategies, HTN remains one of the world’s great public health problems. The accepted inference from genome-wide association studies (GWAS) is that the genetic code lays the foundation for transcriptomic changes and in turn physiological change. On the other side of the coin, environmental factors (smoking, diet, chemical exposure) can in turn affect DNA itself in genes relevant to blood pressure (BP). Variation in epigenetic forms of modification may thus explain additional phenotypic variation in BP and provide new clues to the physiological processes influencing its regulation. DNA methylation is one of these epigenetic mechanisms responsible for changes to gene expression, activated by interaction with environmental triggers. DNA methylation is a reversible epigenetic modifier of specific dinucleotide sites called CpGs, which consists of a transfer of a methyl group derived from S-adenosyl-L-methionine to position five of a cytosine ring, forming 5mC. Pathophysiologically, the kidney is known as the key organ of BP regulation and one of the most important contributors to HTN. According to the hypothesis put forward by Guyton, over 40 years ago, the control of BP in the steady-state and longer-term is critically dependent on renal mechanisms. In fact, almost all monogenic forms of HTN are driven by rare mutations in genes involved in salt handling in the distal nephron. It is therefore crucial to understand kidney DNA methylation changes that may drive gene expression in kidney and lead to HTN. Hypothesis: The central hypothesis underpinning this PhD thesis is that alterations in kidney specific DNA methylation plays a fundamental role in modulating gene expression changes involved in the regulation of BP and pathophysiology of EH. Aims: This PhD thesis focuses on characterising the role of DNA methylation in the hypertensive kidney using array and RNA-sequencing methods. Three major aims are addressed: • Aim 1: To characterise blood and kidney global DNA methylation dynamics and its functional role in the hypertensive population (Chapter 3). • Aim 2: To determine the role of genome-wide, loci specific DNA methylation in the hypertensive human kidney (Chapter 4). • Aim 3: To understand the relationship between DNA methylation and differential expression of genes associated with BP and HTN in the human kidney (Chapter 5). Results: In Aim 1 global DNA methylation changes were characterised in peripheral blood leukocyte and kidney DNA of the hypertensive (HT) population using he ELISA method. We found no association between HTN diagnosis and global methylation percentage in either peripheral blood leukocytes or kidney DNA. However, a negative correlation was found between global methylation and diastolic blood pressure (DBP), yet this relationship was not evident after adjustment for the effect of antihypertensive medication. Furthermore, we investigated the sensitivity of ELISA-based global methylation detection by calculating the percentage of global methylation in kidney using array based methods; the results were similar, demonstrating no association between HTN diagnosis and median kidney methylation
- Description: Doctor of Philosophy
- Authors: Wise, Ingrid
- Date: 2018
- Type: Text , Thesis , PhD
- Full Text:
- Description: Background: Hypertension (HTN) is a complex, multifactorial, quantitative trait under polygenic control that affects more than one billion people globally. Despite advances in our understanding of the pathophysiology of HTN and the implementation of more effective treatment and prevention strategies, HTN remains one of the world’s great public health problems. The accepted inference from genome-wide association studies (GWAS) is that the genetic code lays the foundation for transcriptomic changes and in turn physiological change. On the other side of the coin, environmental factors (smoking, diet, chemical exposure) can in turn affect DNA itself in genes relevant to blood pressure (BP). Variation in epigenetic forms of modification may thus explain additional phenotypic variation in BP and provide new clues to the physiological processes influencing its regulation. DNA methylation is one of these epigenetic mechanisms responsible for changes to gene expression, activated by interaction with environmental triggers. DNA methylation is a reversible epigenetic modifier of specific dinucleotide sites called CpGs, which consists of a transfer of a methyl group derived from S-adenosyl-L-methionine to position five of a cytosine ring, forming 5mC. Pathophysiologically, the kidney is known as the key organ of BP regulation and one of the most important contributors to HTN. According to the hypothesis put forward by Guyton, over 40 years ago, the control of BP in the steady-state and longer-term is critically dependent on renal mechanisms. In fact, almost all monogenic forms of HTN are driven by rare mutations in genes involved in salt handling in the distal nephron. It is therefore crucial to understand kidney DNA methylation changes that may drive gene expression in kidney and lead to HTN. Hypothesis: The central hypothesis underpinning this PhD thesis is that alterations in kidney specific DNA methylation plays a fundamental role in modulating gene expression changes involved in the regulation of BP and pathophysiology of EH. Aims: This PhD thesis focuses on characterising the role of DNA methylation in the hypertensive kidney using array and RNA-sequencing methods. Three major aims are addressed: • Aim 1: To characterise blood and kidney global DNA methylation dynamics and its functional role in the hypertensive population (Chapter 3). • Aim 2: To determine the role of genome-wide, loci specific DNA methylation in the hypertensive human kidney (Chapter 4). • Aim 3: To understand the relationship between DNA methylation and differential expression of genes associated with BP and HTN in the human kidney (Chapter 5). Results: In Aim 1 global DNA methylation changes were characterised in peripheral blood leukocyte and kidney DNA of the hypertensive (HT) population using he ELISA method. We found no association between HTN diagnosis and global methylation percentage in either peripheral blood leukocytes or kidney DNA. However, a negative correlation was found between global methylation and diastolic blood pressure (DBP), yet this relationship was not evident after adjustment for the effect of antihypertensive medication. Furthermore, we investigated the sensitivity of ELISA-based global methylation detection by calculating the percentage of global methylation in kidney using array based methods; the results were similar, demonstrating no association between HTN diagnosis and median kidney methylation
- Description: Doctor of Philosophy
MicroRNAs in essential hypertension and blood pressure regulation
- Marques, Francine, Charchar, Fadi
- Authors: Marques, Francine , Charchar, Fadi
- Date: 2015
- Type: Text , Book chapter
- Relation: Advances in Experimental Medicine and Biology p. 215-235
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text: false
- Reviewed:
- Description: Unravelling the complete genetic predisposition to high blood pressure (BP) has proven to be challenging. This puzzle and the fact that coding regions of the genome account for less than 2 % of the entire human DNA support the hypothesis that mechanisms besides coding genes are likely to contribute to BP regulation. Non-coding RNAs, especially microRNAs, are emerging as key players of transcription regulation in both health and disease states. They control basic functions in virtually all cell types relevant to the cardiovascular system and, thus, a direct involvement with BP regulation is highly probable. Here we review the literature about microRNAs associated with regulation of BP and hypertension, highlighting investigations, methodology and difficulties arising in the field. These molecules are being studied for exploitation in diagnostics, prognostics and therapeutics in many diseases. There have been some studies that examined biological fl uid microRNAs as biomarkers for hypertension, but most remain inconclusive due to the small sample sizes and differences in methodological standardisation. Fewer studies have analysed tissue microRNA levels in vascular smooth muscle cells and the kidney. Others focused on the interaction between single nucleotide polymorphisms and microRNA binding sites. Studies in animals have shown that angiotensin II, high- salt diet and exercise change microRNA levels in hypertension. Treatment of spontaneously hypertensive rats with a miR-22 inhibitor and treatment of hypertensive Schlager BPH/2J mice with a miR-181a mimic decreased their BP. This supports the use of microRNAs as therapeutic targets in hypertension, and future studies should test the use of other microRNAs found in human association studies. In conclusion, there is a clear need of increased pace of human, animal and functional studies to help us understand the multifaceted roles of microRNAs as critical regulators of the development and physiology of BP. © Springer International Publishing Switzerland 2015. Funding Details: APP1052659, NHMRC, National Heart Foundation of Australia Funding Details: PF12M6785, National Heart Foundation of Australia
Renal Mechanisms of Association between Fibroblast Growth Factor 1 and Blood Pressure
- Tomaszewski, Maciej, Eales, James, Denniff, Matthew, Myers, Stephen, Chew, Guatsiew, Nelson, Christopher, Christofidou, Paraskevi, Desai, Aishwarya, Büsst, Cara, Wojnar, Lukasz, Musialik, Katarzyna, Jozwiak, Jacek, Debiec, Radoslaw, Dominiczak, Anna, Navis, Gerjan, van Gilst, Wiek, van der Harst, Pim, Samani, Nilesh, Harrap, Stephen, Bogdanski, Pawel, Zukowska-Szczechowska, Ewa, Charchar, Fadi
- Authors: Tomaszewski, Maciej , Eales, James , Denniff, Matthew , Myers, Stephen , Chew, Guatsiew , Nelson, Christopher , Christofidou, Paraskevi , Desai, Aishwarya , Büsst, Cara , Wojnar, Lukasz , Musialik, Katarzyna , Jozwiak, Jacek , Debiec, Radoslaw , Dominiczak, Anna , Navis, Gerjan , van Gilst, Wiek , van der Harst, Pim , Samani, Nilesh , Harrap, Stephen , Bogdanski, Pawel , Zukowska-Szczechowska, Ewa , Charchar, Fadi
- Date: 2015
- Type: Text , Journal article
- Relation: Journal of the American Society of Nephrology Vol. 26, no. 12 (2015), p. 3151-3160
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text:
- Reviewed:
- Description: The fibroblast growth factor 1 (FGF1) gene is expressed primarily in the kidney and may contribute to hypertension. However, the biologic mechanisms underlying the association between FGF1 and BP regulation remain unknown. We report that the major allele of FGF1 single nucleotide polymorphism rs152524 was associated in a dose-dependent manner with systolic BP (P=9.65 x10(-5)) and diastolic BP (P=7.61 x10(-3)) in a meta-analysis of 14,364 individuals and with renal expression of FGF1 mRNA in 126 human kidneys (P=9.0x10(-3)). Next-generation RNA sequencing revealed that upregulated renal expression of FGF1 or of each of the three FGF1 mRNA isoforms individually was associated with higher BP. FGF1-stratified coexpression analysis in two separate collections of human kidneys identified 126 FGF1 partner mRNAs, of which 71 and 63 showed at least nominal association with systolic and diastolic BP, respectively. Of those mRNAs, seven mRNAs in five genes (MME, PTPRO, REN, SLC12A3, and WNK1) had strong prior annotation to BP or hypertension. MME, which encodes an enzyme that degrades circulating natriuretic peptides, showed the strongest differential coexpression with FGF1 between hypertensive and normotensive kidneys. Furthermore, higher level of renal FGF1 expression was associated with lower circulating levels of atrial and brain natriuretic peptides. These findings indicate that FGF1 expression in the kidney is at least under partial genetic control and that renal expression of several FGF1 partner genes involved in the natriuretic peptide catabolism pathway, reninangiotensin cascade, and sodium handling network may explain the association between FGF1 and BP.
- Authors: Tomaszewski, Maciej , Eales, James , Denniff, Matthew , Myers, Stephen , Chew, Guatsiew , Nelson, Christopher , Christofidou, Paraskevi , Desai, Aishwarya , Büsst, Cara , Wojnar, Lukasz , Musialik, Katarzyna , Jozwiak, Jacek , Debiec, Radoslaw , Dominiczak, Anna , Navis, Gerjan , van Gilst, Wiek , van der Harst, Pim , Samani, Nilesh , Harrap, Stephen , Bogdanski, Pawel , Zukowska-Szczechowska, Ewa , Charchar, Fadi
- Date: 2015
- Type: Text , Journal article
- Relation: Journal of the American Society of Nephrology Vol. 26, no. 12 (2015), p. 3151-3160
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text:
- Reviewed:
- Description: The fibroblast growth factor 1 (FGF1) gene is expressed primarily in the kidney and may contribute to hypertension. However, the biologic mechanisms underlying the association between FGF1 and BP regulation remain unknown. We report that the major allele of FGF1 single nucleotide polymorphism rs152524 was associated in a dose-dependent manner with systolic BP (P=9.65 x10(-5)) and diastolic BP (P=7.61 x10(-3)) in a meta-analysis of 14,364 individuals and with renal expression of FGF1 mRNA in 126 human kidneys (P=9.0x10(-3)). Next-generation RNA sequencing revealed that upregulated renal expression of FGF1 or of each of the three FGF1 mRNA isoforms individually was associated with higher BP. FGF1-stratified coexpression analysis in two separate collections of human kidneys identified 126 FGF1 partner mRNAs, of which 71 and 63 showed at least nominal association with systolic and diastolic BP, respectively. Of those mRNAs, seven mRNAs in five genes (MME, PTPRO, REN, SLC12A3, and WNK1) had strong prior annotation to BP or hypertension. MME, which encodes an enzyme that degrades circulating natriuretic peptides, showed the strongest differential coexpression with FGF1 between hypertensive and normotensive kidneys. Furthermore, higher level of renal FGF1 expression was associated with lower circulating levels of atrial and brain natriuretic peptides. These findings indicate that FGF1 expression in the kidney is at least under partial genetic control and that renal expression of several FGF1 partner genes involved in the natriuretic peptide catabolism pathway, reninangiotensin cascade, and sodium handling network may explain the association between FGF1 and BP.
- Jackson, Kristy, Marques, Francine, Watson, Anna, Palma-Rigo, Keisia, Nguyen-Huu, Thu-Phuc, Morris, Brian, Charchar, Fadi, Davern, Pamela, Head, Geoffrey
- Authors: Jackson, Kristy , Marques, Francine , Watson, Anna , Palma-Rigo, Keisia , Nguyen-Huu, Thu-Phuc , Morris, Brian , Charchar, Fadi , Davern, Pamela , Head, Geoffrey
- Date: 2013
- Type: Text , Journal article
- Relation: Hypertension Vol. 62 , no. 4 (2013), p. 775-781
- Full Text: false
- Reviewed:
- Description: Genetically hypertensive mice (BPH/2J) are hypertensive because of an exaggerated contribution of the sympathetic nervous system to blood pressure. We hypothesize that an additional contribution to elevated blood pressure is via sympathetically mediated activation of the intrarenal renin-angiotensin system. Our aim was to determine the contribution of the renin-angiotensin system and sympathetic nervous system to hypertension in BPH/2J mice. BPH/2J and normotensive BPN/3J mice were preimplanted with radiotelemetry devices to measure blood pressure. Depressor responses to ganglion blocker pentolinium (5 mg/kg i.p.) in mice pretreated with the angiotensin-converting enzyme inhibitor enalaprilat (1.5 mg/kg i.p.) revealed a 2-fold greater sympathetic contribution to blood pressure in BPH/2J mice during the active and inactive period. However, the depressor response to enalaprilat was 4-fold greater in BPH/2J compared with BPN/3J mice, but only during the active period (P=0.01). This was associated with 1.6-fold higher renal renin messenger RNA (mRNA; P=0.02) and 0.8-fold lower abundance of micro-RNA-181a (P=0.03), identified previously as regulating human renin mRNA. Renin mRNA levels correlated positively with depressor responses to pentolinium (r=0.99; P=0.001), and BPH/2J mice had greater renal sympathetic innervation density as identified by tyrosine hydroxylase staining of cortical tubules. Although there is a major sympathetic contribution to hypertension in BPH/2J mice, the renin-angiotensin system also contributes, doing so to a greater extent during the active period and less during the inactive period. This is the opposite of the normal renin-angiotensin system circadian pattern. We suggest that renal hyperinnervation and enhanced sympathetically induced renin synthesis mediated by lower micro-RNA-181a contributes to hypertension in BPH/2J mice.
Pathway analysis shows association between FGFBP1 and hypertension
- Tomaszewski, Maciej, Charchar, Fadi, Nelson, Christopher, Barnes, Timothy, Denniff, Matthew, Kaiser, Michael, Debiec, Radoslaw, Christofidou, Paraskevi, Rafelt, Suzanne, Van Harst, Pim Der, Wang, William, Maric, Christine, Zukowska-Szczechowska, Ewa, Samani, Nilesh
- Authors: Tomaszewski, Maciej , Charchar, Fadi , Nelson, Christopher , Barnes, Timothy , Denniff, Matthew , Kaiser, Michael , Debiec, Radoslaw , Christofidou, Paraskevi , Rafelt, Suzanne , Van Harst, Pim Der , Wang, William , Maric, Christine , Zukowska-Szczechowska, Ewa , Samani, Nilesh
- Date: 2011
- Type: Text , Journal article
- Relation: Journal of the American Society of Nephrology Vol. 22, no. 5 (2011), p. 947-955
- Full Text: false
- Reviewed:
- Description: Variants in the gene encoding fibroblast growth factor 1 (FGF1) co-segregate with familial susceptibility to hypertension, and glomerular upregulation of FGF1 associates with hypertension. To investigate whether variants in other members of the FGF signaling pathway may also associate with hypertension, we genotyped 629 subjects from 207 Polish families with hypertension for 79 single nucleotide polymorphisms in eight genes of this network. Family-based analysis showed that parents transmitted the major allele of the rs16892645 polymorphism in the gene encoding FGF binding protein 1 (FGFBP1) to hypertensive offspring more frequently than expected by chance (P = 0.005). An independent cohort of 807 unrelated Polish subjects validated this association. Furthermore, compared with normotensive subjects, hypertensive subjects had approximately 1.5- and 1.4-fold higher expression of renal FGFBP1 mRNA and protein (P = 0.04 and P = 0.001), respectively. By immunohistochemistry, hypertensionrelated upregulation of FGFBP1 was most apparent in the glomerulus and juxtaglomerular space. Taken together, these data suggest that FGFBP1 associates with hypertension and that systematic analysis of signaling pathways can identify previously undescribed genetic associations. Copyright © 2011 by the American Society of Nephrology.
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