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  • 1
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    Urine excretion of C3dg and sC5b-9 coincide with proteinuria and development of preeclampsia in pregnant women with type-1 diabetes
    Ovid Technologies (Wolters Kluwer Health) ; 2023
    In:  Journal of Hypertension Vol. 41, No. 2 ( 2023-02), p. 223-232
    Details
    In: Journal of Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 41, No. 2 ( 2023-02), p. 223-232
    Abstract: Pregnant women with type-1 diabetes have an increased risk of preeclampsia with kidney injury and cardiovascular complications. Urine excretion of plasmin and soluble membrane attack complex (sC5b-9) is elevated in severe preeclampsia. We hypothesized a coupling between these events and that active plasmin promotes intratubular complement activation and membrane deposition. Methods: Stored urine and plasma samples from pregnant women with type-1 diabetes ( n  = 88) collected at gestational weeks 12, 20, 28, 32, 36 and 38 were used. In the cohort, 14 women developed preeclampsia and were compared with 16 nonpreeclampsia controls. Results: Urine C3dg and sC5b-9-associated C9 neoantigen/creatinine ratios increased and were significantly higher in women who developed preeclampsia. Plasma concentrations did not change with gestation. Urine plasmin(ogen) correlated to urine C3dg ( r  = 0.51, P   〈  0.001) and C9 neoantigen ( r  = 0.68, P   〈  0.001); urine albumin correlated to C3dg ( r  = 0.44, P   〈  0.001) and C9 ( r  = 0.59, P   〈  0.001). Membrane-associated C3dg and C9 neoantigen was detected in urinary extracellular vesicles from patients but not controls at 36 weeks. Receiver operating characteristic curves showed that C3dg and C9 neoantigen were inferior to albumin as predictive biomarkers for preeclampsia. Conclusion: In preeclampsia, urinary excretion of activated complement relates significantly to albuminuria and to plasmin(ogen) but not to activation in plasma. Intratubular complement activation in preeclampsia is a postfiltration event tightly related to proteinuria/plasminogenuria and a possible mechanistic link to cellular damage and kidney injury.
    Type of Medium: Online Resource
    ISSN: 0263-6352 , 1473-5598
    URL: Article
    DOI: 10.1097/HJH.0000000000003288
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
    detail.hit.zdb_id: 2017684-3
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  • 2
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    Higher Maternal Cortisol Associated With Lower Blood Pressure in Offspring From 3 Months to 5 Years of Age in the Odense Child Cohort
    Ovid Technologies (Wolters Kluwer Health) ; 2023
    In:  Hypertension Vol. 80, No. 4 ( 2023-04), p. 828-836
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 80, No. 4 ( 2023-04), p. 828-836
    Abstract: Synthetic glucocorticoid exposure in late pregnancy may be associated with higher blood pressure in offspring. We hypothesized that endogenous cortisol in pregnancy relates to offspring blood pressure (OBP). Objective: To investigate associations between maternal cortisol status in third trimester pregnancy and OBP. Methods: We included 1317 mother-child pairs from Odense Child Cohort, an observational prospective cohort. Serum (s-) cortisol and 24-hour urine (u-) cortisol and cortisone were assessed in gestational week 28. Offspring systolic blood pressure and diastolic blood pressure were measured at age 3, 18 months, and 3 and 5 years. Associations between maternal cortisol and OBP were examined by mixed effects linear models. Results: All significant associations between maternal cortisol and OBP were negative. In boys in pooled analyses, 1 nmol/L increase in maternal s-cortisol was associated with average decrease in systolic blood pressure (β=−0.003 mmHg [95% CI, −0.005 to −0.0003]) and diastolic blood pressure (β=−0.002 mmHg [95% CI, −0.004 to −0.0004] ) after adjusting for confounders. At 3 months of age, higher maternal s-cortisol was significantly associated with lower systolic blood pressure (β=−0.01 mmHg [95% CI, −0.01 to −0.004]) and diastolic blood pressure (β=−0.010 mmHg [95% CI, −0.012 to −0.011] ) in boys after adjusting for confounders, which remained significant after adjusting for potential intermediate factors. Conclusions: We found temporal sex dimorphic negative associations between maternal s-cortisol levels and OBP, with significant findings in boys. We conclude that physiological maternal cortisol is not a risk factor for higher blood pressure in offspring up to 5 years of age.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/HYPERTENSIONAHA.122.20265
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
    detail.hit.zdb_id: 2094210-2
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  • 3
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    Blood Pressure and Angiogenic Markers in Pregnancy : Contributors to Pregnancy-Induced Hypertension and Offspring Cardiovascular Risk
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  Hypertension Vol. 76, No. 3 ( 2020-09), p. 901-909
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 76, No. 3 ( 2020-09), p. 901-909
    Abstract: Pregnancy-induced hypertension is a severe pregnancy complication, increasing risk of long-term cardiovascular disease in mothers and offspring. We hypothesized that maternal blood pressure in pregnancy associated with offspring blood pressure; that the associations were sex-specific; and that maternal circulating placental angiogenic markers (PlGF [placental growth factor] and sFlt-1 [soluble fms-like tyrosine kinase-1] ) mediated this relationship. We analyzed data from 2434 women and 2217 children from the Odense Child Cohort, a prospective Danish cohort study. Offspring blood pressure trajectory from 4 months to 5 years was highly associated to maternal first, second, and third trimester blood pressure, and mean blood pressure in pregnancy, independent of maternal and offspring covariates. There were offspring sex-specific associations: Girls from mothers in the highest quartile of first and third trimester blood pressure had significantly higher systolic blood pressure at 5 years than the rest of the cohort (mean difference±SEM: 1.81±0.59 and 2.11±0.59 mm Hg, respectively, all P 〈 0.01); whereas boys had significantly higher diastolic blood pressure at 5 years (mean difference±SEM: 1.11±0.45 and 1.03±0.45, respectively, all P 〈 0.05). Concentrations of PlGF at gestational week 28 correlated inversely to maternal gestational blood pressure trajectory, independent of the diagnosis of pregnancy-induced hypertension, adjusted β coefficients (95% CI) for predicting systolic blood pressure (SBP): −3.18 (−4.66 to −1.70) mm Hg, for predicting diastolic blood pressure (DBP): −2.48 (−3.57 to −1.40) mm Hg. In conclusion, maternal gestational blood pressure predicted offspring blood pressure trajectory until 5 years in a sex-differential manner. Furthermore, subtle alterations in blood pressure in early pregnancy preceded hypertension or preeclampsia, and PlGF was a mediator of cardiovascular health in pregnancy.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/HYPERTENSIONAHA.119.13966
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
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  • 4
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    Natriuretic peptides relax human intrarenal arteries through natriuretic peptide receptor type‐A recapitulated by soluble guanylyl cyclase agonists
    Wiley ; 2021
    In:  Acta Physiologica Vol. 231, No. 3 ( 2021-03)
    Details
    In: Acta Physiologica, Wiley, Vol. 231, No. 3 ( 2021-03)
    Abstract: Natriuretic peptides, BNP and ANP increase renal blood flow in experimental animals. The signalling pathway in human kidney vasculature is unknown. It was hypothesized that BNP and ANP cause endothelium‐independent relaxation of human intrarenal arteries by vascular natriuretic peptide receptor‐A, but not ‐B and ‐C, which is mimicked by agonists of soluble guanylyl cyclase sGC. Methods Human (n = 54, diameter: 665 ± 29 µm 95% CI) and control murine intrarenal arteries (n = 83, diameter 300 ± 6 µm 95% CI) were dissected and used for force recording by four‐channel wire myography. Arterial segments were pre‐contracted, then subjected to increasing concentrations of BNP, ANP, phosphodiesterase 5‐inhibitor sildenafil, sGC‐activator BAY 60‐2770 and ‐stimulator BAY 41‐2272. Endothelial nitric oxide synthase (eNOS) dependence was examined by use of L‐NAME and eNOS knockout respectively. Molecular targets (NPR A‐C, sGC, phosphodiesterase‐5 and neprilysin) were mapped by PCR, immunohistochemistry and RNAscope. Results BNP, ANP, sildenafil, sGC‐activation and ‐stimulation caused concentration‐dependent relaxation of human and murine intrarenal arteries. BNP responses were independent of eNOS and were not potentiated by low concentration of phosphodiesterase‐5‐inhibitor, sGC‐stimulator or NPR‐C blocker. PCR showed NPR‐A and C, phosphodiesterase‐5, neprilysin and sGC mRNA in renal arteries. NPR‐A mRNA and protein was observed in vascular smooth muscle and endothelial cells in arteries, podocytes, Bowmans capsule and vasa recta. NPR‐C was observed in tubules, glomeruli and vasculature. Conclusion Activation of transmembrane NPR‐A and soluble guanylyl cyclase relax human preglomerular arteries similarly to phosphodiestase‐5 inhibition. The human renal arterial bed relaxes in response to cGMP pathway.
    Type of Medium: Online Resource
    ISSN: 1748-1708 , 1748-1716
    URL: Issue
    URL: Article
    DOI: 10.1111/apha.2021.231.issue-3
    DOI: 10.1111/apha.13565
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2617148-X
    detail.hit.zdb_id: 2219379-0
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  • 5
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    Protective effect of sacubitril/valsartan (Entresto) on kidney function and filtration barrier injury in a porcine model of partial nephrectomy
    Oxford University Press (OUP) ; 2023
    In:  Nephrology Dialysis Transplantation Vol. 38, No. 1 ( 2023-01-23), p. 80-92
    Details
    In: Nephrology Dialysis Transplantation, Oxford University Press (OUP), Vol. 38, No. 1 ( 2023-01-23), p. 80-92
    Abstract: Kidney surgery often includes organ ischaemia with a risk of acute kidney injury. The present study tested if treatment with the combined angiotensin II–angiotensin II receptor type 1 and neprilysin blocker Entresto (LCZ696, sacubitril/valsartan) protects filtration barrier and kidney function after ischaemia and partial nephrectomy (PN) in pigs. Single kidney glomerular filtration rate (GFR) by technetium-99m diethylene-triamine-pentaacetate clearance was validated (n = 6). Next, four groups of pigs were followed for 15 days (n = 24) after PN (one-third right kidney, 60 min ischaemia) + Entresto (49/51 mg/day; n = 8), PN + vehicle (n = 8), sham + Entresto (49/51 mg/day; n = 4) and sham + vehicle (n = 4). GFR, diuresis and urinary albumin were measured at baseline and from each kidney after 15 days. The sum of single-kidney GFR (right 25 ± 6 mL/min, left 31 ± 7 mL/min) accounted for the total GFR (56 ± 14 mL/min). Entresto had no effect on baseline blood pressure, p-creatinine, mid-regional pro-atrial natriuretic peptide (MR-proANP), heart rate and diuresis. After 15 days, Entresto increased GFR in the uninjured kidney (+23 ± 6 mL/min, P  & lt; .05) and reduced albuminuria from both kidneys. In the sham group, plasma MR-proANP was not altered by Entresto; it increased to similar levels 2 h after surgery with and without Entresto. Fractional sodium excretion increased with Entresto. Kidney histology and kidney injury molecule-1 in cortex tissue were not different. In conclusion, Entresto protects the filtration barrier and increases the functional adaptive response of the uninjured kidney.
    Type of Medium: Online Resource
    ISSN: 0931-0509 , 1460-2385
    URL: Article
    DOI: 10.1093/ndt/gfac200
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 1465709-0
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  • 6
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    Functional adaptation after kidney tissue removal in patients is associated with increased plasma atrial natriuretic peptide concentration
    Oxford University Press (OUP) ; 2022
    In:  Nephrology Dialysis Transplantation Vol. 37, No. 11 ( 2022-10-19), p. 2138-2149
    Details
    In: Nephrology Dialysis Transplantation, Oxford University Press (OUP), Vol. 37, No. 11 ( 2022-10-19), p. 2138-2149
    Abstract: Following nephrectomy, the remaining kidney tissue adapts by an increase in glomerular filtration rate (GFR). In rats, hyperfiltration can be transferred by plasma. We examined whether natriuretic peptides, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) increase in plasma proportionally with kidney mass reduction and, if so, whether the increase relates to an increase in GFR. Methods Patients (n = 54) undergoing partial or total unilateral nephrectomy at two Danish centres were followed for 1 year in an observational study. Glomerular filtration rate was measured before, and 3 and 12 months after surgery. Natriuretic propeptides (proANP and proBNP) and aldosterone were measured in plasma before and at 24 h, 5 days, 21 days, 3 months and 12 months. Cyclic guanosine monophosphate (cGMP) was determined in urine. Results There was no baseline difference in GFR between total and partial nephrectomy (90.1 mL/min/1.73 m2 ± 14.6 versus 82.9 ± 18; P = 0.16). Single-kidney GFR increased after 3 and 12 months (12.0 and 11.9 mL/min/1.73 m2, +23.3%). There was no change in measured GFR 3 and 12 months after partial nephrectomy. ProANP and proBNP increased 3-fold 24 h after surgery and returned to baseline after 5 days. The magnitude of acute proANP and proBNP increases did not relate to kidney mass removed. ProANP, not proBNP, increased 12 months after nephrectomy. Plasma aldosterone and urine cGMP did not change. Urine albumin/creatinine ratio increased transiently after partial nephrectomy. Blood pressure was similar between the groups. Conclusion ANP and BNP increase acutely in plasma with no relation to degree of kidney tissue ablation. After 1 year, only unilateral nephrectomy patients displayed increased plasma ANP, which could support adaptation.
    Type of Medium: Online Resource
    ISSN: 0931-0509 , 1460-2385
    URL: Article
    DOI: 10.1093/ndt/gfab327
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 7
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    Protection of kidney function and tissue integrity by pharmacologic use of natriuretic peptides and neprilysin inhibitors
    Springer Science and Business Media LLC ; 2021
    In:  Pflügers Archiv - European Journal of Physiology Vol. 473, No. 4 ( 2021-04), p. 595-610
    Details
    In: Pflügers Archiv - European Journal of Physiology, Springer Science and Business Media LLC, Vol. 473, No. 4 ( 2021-04), p. 595-610
    Type of Medium: Online Resource
    ISSN: 0031-6768 , 1432-2013
    URL: Article
    DOI: 10.1007/s00424-021-02555-w
    RVK:
    WA 15000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 1463014-X
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  • 8
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    Elevated blood pressure in pregnant women with gestational diabetes according to the WHO criteria: importance of overweight
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Journal of Hypertension Vol. 40, No. 8 ( 2022-08), p. 1614-1623
    Details
    In: Journal of Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 40, No. 8 ( 2022-08), p. 1614-1623
    Abstract: Hypertension before and during early pregnancy has been associated with an increased risk of gestational diabetes mellitus (GDM) in retrospective analyses. We aimed to investigate the prospective blood pressure trackings in a population-based cohort of pregnant women, who were stratified according to their metabolic status in early third trimester. Methods: We recorded blood pressure longitudinally during pregnancy in 1230 women from the Odense Child Cohort, Denmark. Fasting glucose and insulin were measured at gestational weeks 28–30. Metabolic status was evaluated according to the WHO 2013 threshold for GDM (GDM-WHO: fasting plasma glucose ≥5.1 mmol/l), insulin and homeostatic model assessment of insulin resistance (HOMA-IR). Relationships between metabolic status in third trimester and blood pressure trajectories were evaluated with adjusted linear mixed models. Trajectory was defined as blood pressure records in pregnancy per 4 weeks interval. Results: Prevalence of GDM-WHO was 40% (498/1230). GDM-WHO was associated with 1.46 (0.22–2.70) mmHg higher SBP and 1.04 (0.07–2.01) mmHg higher DBP trajectories in the overall cohort. The associations were driven by differences in the overweight group, with 3.14 (1.05–5.25) mmHg higher SBP and 1.94 (0.42–3.47) mmHg higher DBP per 4 weeks in women with GDM-WHO compared with women without GDM-WHO. GDM-WHO was not associated with blood pressure in women with normal weight. Blood pressure trajectories were elevated across quartiles of insulin resistance. Conclusion: GDM-WHO is associated with higher blood pressure in pregnancy, and there appears to be a stronger effect in overweight women.
    Type of Medium: Online Resource
    ISSN: 0263-6352 , 1473-5598
    URL: Article
    DOI: 10.1097/HJH.0000000000003196
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 2017684-3
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  • 9
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    945-P: Elevated Blood Pressure in Pregnant Women with Gestational Diabetes According to the WHO Criteria: Importance of Obesity
    American Diabetes Association ; 2021
    In:  Diabetes Vol. 70, No. Supplement_1 ( 2021-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 70, No. Supplement_1 ( 2021-06-01)
    Abstract: Objective: Hypertension before and during early pregnancy has been associated with an increased risk of gestational diabetes mellitus (GDM) in retrospective analyses. We investigated the prospective blood pressure patterns in a population-based cohort of pregnant women, who were stratified according to their metabolic status in early 3rd trimester. Research Design and Methods: We recorded blood pressure longitudinally during pregnancy in 1,230 women from the Odense Child Cohort, Denmark. Fasting glucose and insulin were measured at gestational weeks 28-30. Metabolic status was evaluated according to the World Health Organization (WHO) 2013 threshold for GDM (GDM-WHO: fasting plasma glucose ≥5.1 mmol/l), insulin and homeostatic model assessment of insulin resistance (HOMA-IR). Relationships between metabolic status in 3rd trimester and blood pressure trajectories throughout pregnancy were evaluated with adjusted linear mixed models. Results: GDM-WHO prevalence was high, 40% (498/1,230). Significant associations between GDM-WHO and blood pressure were seen only in overweight women, with 2.48 (1.08; 3.88) mmHg higher systolic and 1.58 (0.57; 2.58) mmHg higher diastolic trajectories in women with GDM-WHO compared with differences of -0.38 (-1.51; 0.75) and 0.03 (-0.83; 0.89) mmHg in lean women with GDM-WHO. The associations were independent of progression to gestational hypertension. Blood pressure trajectories in pregnancy were elevated across insulin and HOMA-IR quartiles. Conclusions: GDM-WHO was associated with moderate elevations of blood pressure troughout pregnancy. The relationships were independent of progression to overt gestational hypertension, but largely modified by overweight status. Disclosure A. Birukov: None. R. Dechend: None. M. S. Andersen: None. D. Glintborg: None. M. B. Schulze: None. T. K. Jensen: None. L. B. Andersen: None. K. Kräker: None. E. Polemiti: None. B. L. Jensen: None. J. S. Joergensen: None. Funding German Ministry of Education and Research; State of Brandenburg (82DZD00302)
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db21-945-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2021
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  • 10
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    Amiloride Reduces Urokinase/Plasminogen-Driven Intratubular Complement Activation in Glomerular Proteinuria
    Ovid Technologies (Wolters Kluwer Health) ; 2024
    In:  Journal of the American Society of Nephrology ( 2024-01-23)
    Details
    In: Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), ( 2024-01-23)
    Abstract: Persistent proteinuria is associated with tubular interstitial inflammation and predicts progressive kidney injury. In proteinuria, plasminogen is aberrantly filtered and activated by urokinase-type plasminogen activator (uPA) which promotes kidney fibrosis. We hypothesized that plasmin activates filtered complement factors C3 and C5 directly in tubular fluid, generating anaphylatoxins and that this is attenuated by amiloride, an off-target uPA inhibitor. Methods: Purified C3, C5, plasminogen, urokinase and urine from healthy humans were used for in vitro / ex vivo studies. Complement activation was assessed by SDS-PAGE, immunoblotting and ELISA. Urine and plasma from patients with diabetic nephropathy treated with high-dose amiloride and from mice with proteinuria (podocin knockout) treated with amiloride or inhibitory anti-uPA antibodies were analyzed. Results: The combination of uPA and plasminogen generated anaphylatoxins C3a and C5a from intact C3 and C5 and was inhibited by amiloride. Addition of exogenous plasminogen was sufficient for urine from healthy humans to activate complement. Conditional podocin knockout in mice led to severe proteinuria and C3a and C5a urine excretion which was attenuated reversibly by amiloride treatment for 4 days and reduced 〉 50% by inhibitory anti-uPA antibodies without altering proteinuria. NPLR3-inflammasome protein was reduced with no concomitant effect on fibrosis. In patients with diabetic nephropathy, amiloride reduced urinary excretion of C3dg and sC5b-9 significantly. Conclusions: In conditions with proteinuria, uPA-plasmin generates anaphylatoxins in tubular fluid and promotes downstream complement activation sensitive to amiloride. This mechanism links proteinuria to intratubular proinflammatory signaling. In perspective, amiloride could exert reno-protective effects beyond natriuresis and blood pressure reduction.
    Type of Medium: Online Resource
    ISSN: 1046-6673 , 1533-3450
    URL: Article
    DOI: 10.1681/ASN.0000000000000312
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2024
    detail.hit.zdb_id: 2029124-3
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