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Wong M.G.,University of Sydney | Perkovic V.,University of Sydney | Woodward M.,University of Sydney | Chalmers J.,University of Sydney | And 11 more authors.
Kidney International | Year: 2013

Albuminuria and a reduced glomerular filtration rate are conventional predictors of a future decline in kidney function in patients with type 2 diabetes mellitus. Using a nested case-control study we assessed whether circulating transforming growth factor-β1 (TGF-β1) and bone morphogenetic protein-7 (BMP-7) levels more accurately predict renal end points than the conventional markers. Cases were defined as those who developed a renal end point (doubling of serum creatinine to at least 200 μmol/l, the need for renal replacement therapy, or death due to renal disease) during the study. Using propensity scoring, two controls were selected for each of 281 cases. Participants who developed renal end points had significantly higher total TGF-β1, lower BMP-7 levels, and a higher total TGF-β1 to BMP-7 ratio at baseline. A graded increase in risk was found in individuals with lower BMP-7 levels (odds ratio 24.07, for the lowest to the highest tertile), or significantly higher TGF-β1 levels (odds ratio for the highest to the lowest tertile, 8.43). The area under the receiver operating characteristic curve (c-statistic) for the conventional predictors was 0.73. Using BMP-7 and total and active TGF-β1, the c-statistic was 0.94 (significantly higher to conventional predictors). Thus, our results suggest these novel kidney markers are better predictors of renal progression than the conventional predictors in patients with type 2 diabetes mellitus. © 2012 International Society of Nephrology. Source


Malekin S.I.,RAS Institute of Organic Chemistry | Kotelevtsev S.V.,Moscow State University | Gavrilova S.A.,Moscow State University | Fadyukova O.E.,Moscow State University | And 7 more authors.
Pathophysiology | Year: 2011

This study characterized the actions of the newly synthesized PAF precursor 1-hexadecyl-2-alkylcarbamoyl-glycerol (HAG) on blood pressure (BP) in male spontaneously hypertensive rats (SHR), SHR-stroke prone (SHRSP) and Wistar rats with 1-kidney 1-clip (1K1C) renovascular hypertension used as experimental models of human primary and secondary hypertension. Systolic blood pressure (SBP) in the tail artery and mean arterial pressure (MAP) in the abdominal aorta were measured by tail plethysmography and invasive pressure transducer, respectively. Intravenous treatment with 1. mg/kg HAG in SHR resulted in a rapid decline of MAP from 151. ± 4 to 127. ± 4. mm. Hg in 50. min (p< 0.001) that was maintained for 24. h after injection (128. ± 5. mm. Hg, p< 0.01). We also observed a profound hypotensive effect of HAG in SHRSP but not in normotensive Wistar rats. In 1K1C rats, the magnitude of the BP decline evoked by HAG was correlated with MAP measured before drug administration (R= 0.74, p< 0.005). In 1K1C rats with SBP. > 140. mm. Hg, 5. mg/kg/48. h HAG, given orally for 14 days, decreased SBP by 20-30. mm. Hg without an increase in the death rate and other adverse effects. Thus, our results show that intravenous and oral administration of HAG led to a long-lasting reduction of BP in experimental models of primary and secondary hypertension. In contrast to PAF and its derivatives, the hypotensive action of HAG was preserved for 24. h after a single administration, was absent in normotensive animals, and was not accompanied by visible side-effects, at least during 2 weeks of treatment. © 2010 Elsevier Ireland Ltd. Source


Koltsova S.V.,Center Hospitalier Of Luniversite Of Montreal Crchum Technopole Angus | Koltsova S.V.,Russian Academy of Medical Sciences | Trushina Y.,Moscow State University | Haloui M.,Center Hospitalier Of Luniversite Of Montreal Crchum Technopole Angus | And 7 more authors.
PLoS ONE | Year: 2012

Stimulus-dependent elevation of intracellular Ca2+ ([Ca2+]i) affects the expression of numerous genes - a phenomenon known as excitation-transcription coupling. Recently, we found that increases in [Na+]i trigger c-Fos expression via a novel Ca2+ i-independent pathway. In the present study, we identified ubiquitous and tissue-specific [Na+]i/[K+]i-sensitive transcriptomes by comparative analysis of differentially expressed genes in vascular smooth muscle cells from rat aorta (RVSMC), the human adenocarcinoma cell line HeLa, and human umbilical vein endothelial cells (HUVEC). To augment [Na+]i and reduce [K+]i, cells were treated for 3 hrs with the Na+,K+-ATPase inhibitor ouabain or placed for the same time in the K+-free medium. Employing Affymetrix-based technology, we detected changes in expression levels of 684, 737 and 1839 transcripts in HeLa, HUVEC and RVSMC, respectively, that were highly correlated between two treatments (p<0.0001; R2>0.62). Among these Na+ i/K+ i-sensitive genes, 80 transcripts were common for all three types of cells. To establish if changes in gene expression are dependent on increases in [Ca2+]i, we performed identical experiments in Ca2+-free media supplemented with extracellular and intracellular Ca2+ chelators. Surprisingly, this procedure elevated rather than decreased the number of ubiquitous and cell-type specific Na+ i/K+ i-sensitive genes. Among the ubiquitous Na+ i/K+ i-sensitive genes whose expression was regulated independently of the presence of Ca2+ chelators by more than 3-fold, we discovered several transcription factors (Fos, Jun, Hes1, Nfkbia), interleukin-6, protein phosphatase 1 regulatory subunit, dual specificity phosphatase (Dusp8), prostaglandin-endoperoxide synthase 2, cyclin L1, whereas expression of metallopeptidase Adamts1, adrenomedulin, Dups1, Dusp10 and Dusp16 was detected exclusively in Ca2+-depleted cells. Overall, our findings indicate that Ca2+ i-independent mechanisms of excitation-transcription coupling are involved in transcriptomic alterations triggered by elevation of the [Na+]i/[K+]i ratio. There results likely have profound implications for normal and pathological regulation of mammalian cells, including sustained excitation of neuronal cells, intensive exercise and ischemia-triggered disorders. © 2012 Koltsova et al. Source


Koltsova S.V.,Moscow State University | Tremblay J.,Center Hospitalier Of Luniversite Of Montreal Crchum Technopole Angus | Hamet P.,Center Hospitalier Of Luniversite Of Montreal Crchum Technopole Angus | Orlov S.N.,Moscow State University | Orlov S.N.,Tomsk National Research University
Cell Calcium | Year: 2015

Previously, we reported that Ca2+ depletion increased permeability of the plasma membrane for Na+. This study examined the relative impact of [Na+]i/[K+]i-mediated signaling on transcriptomic changes in cultured vascular smooth muscle cells from rat aorta (VSMC) subjected to Ca2+-depletion by extra-(EGTA) and intracellular (BAPTA-AM) Ca2+ chelators. Na+,K+-ATPase inhibition in K+-free medium during 3h led to elevation of [Na+]i and attenuation of [K+]i by ~7- and 10-fold, whereas Ca2+-depletion resulted in alteration of these parameters by ~3- and 2-fold, respectively. Augmented VSMC permeability for Na+ and elevation of the [Na+]i/[K+]i ratio was triggered by addition to Ca2+-free medium 50μM EGTA and was not affected by 10μM BAPTA-AM. Na+,K+-ATPase inhibition and Ca2+-depletion changed expression of 3677 and 4610 mRNA transcripts, respectively. We found highly significant (p<10-12) positive (R2>0.51) correlation between levels of expression of 2071 transcripts whose expression was affected by both stimuli. Among genes whose expression in Ca2+-depleted cells was augmented by more than 7-fold we noted cyclic AMP-dependent transcription factor Atf3, early growth response protein Egr1 and nuclear receptor subfamily 4, group A member Nr4a1. Dissipation of transmembrane gradients of monovalent cations in high-K+, low-Na+-medium abolished the increments of the [Na+]i/[K+]i ratio as well as the augmented expression of these genes triggered by incubation of VSMC in EGTA containing medium. Thus, our results demonstrate, for the first time, that robust transcriptomic changes triggered by Ca2+-depletion in the presence of extracellular Ca2+-chelators are at least partially mediated by elevation of the [Na+]i/[K+]i ratio and activation of Ca2+i-independent, [Na+]i/[K+]i-mediated mechanism of excitation-transcription coupling. These results shad a new light on analysis of data obtained in cells subjected to long-term exposure to Ca2+ chelators. © 2015 Elsevier Ltd. Source


Koltsova S.V.,Center Hospitalier Of Luniversite Of Montreal Crchum Technopole Angus
PloS one | Year: 2012

Stimulus-dependent elevation of intracellular Ca(2+) ([Ca(2+)](i)) affects the expression of numerous genes--a phenomenon known as excitation-transcription coupling. Recently, we found that increases in [Na(+)](i) trigger c-Fos expression via a novel Ca(2+) (i)-independent pathway. In the present study, we identified ubiquitous and tissue-specific [Na(+)](i)/[K(+)](i)-sensitive transcriptomes by comparative analysis of differentially expressed genes in vascular smooth muscle cells from rat aorta (RVSMC), the human adenocarcinoma cell line HeLa, and human umbilical vein endothelial cells (HUVEC). To augment [Na(+)](i) and reduce [K(+)](i), cells were treated for 3 hrs with the Na(+),K(+)-ATPase inhibitor ouabain or placed for the same time in the K(+)-free medium. Employing Affymetrix-based technology, we detected changes in expression levels of 684, 737 and 1839 transcripts in HeLa, HUVEC and RVSMC, respectively, that were highly correlated between two treatments (p<0.0001; R(2)>0.62). Among these Na(+) (i)/K(+) (i)-sensitive genes, 80 transcripts were common for all three types of cells. To establish if changes in gene expression are dependent on increases in [Ca(2+)](i), we performed identical experiments in Ca(2+)-free media supplemented with extracellular and intracellular Ca(2+) chelators. Surprisingly, this procedure elevated rather than decreased the number of ubiquitous and cell-type specific Na(+) (i)/K(+) (i)-sensitive genes. Among the ubiquitous Na(+) (i)/K(+) (i)-sensitive genes whose expression was regulated independently of the presence of Ca(2+) chelators by more than 3-fold, we discovered several transcription factors (Fos, Jun, Hes1, Nfkbia), interleukin-6, protein phosphatase 1 regulatory subunit, dual specificity phosphatase (Dusp8), prostaglandin-endoperoxide synthase 2, cyclin L1, whereas expression of metallopeptidase Adamts1, adrenomedulin, Dups1, Dusp10 and Dusp16 was detected exclusively in Ca(2+)-depleted cells. Overall, our findings indicate that Ca(2+) (i)-independent mechanisms of excitation-transcription coupling are involved in transcriptomic alterations triggered by elevation of the [Na(+)](i)/[K(+)](i) ratio. There results likely have profound implications for normal and pathological regulation of mammalian cells, including sustained excitation of neuronal cells, intensive exercise and ischemia-triggered disorders. Source

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