20 results on '"Hinrichs GR"'
Search Results
2. Reverse Phenotypes of Patients with Genetically Confirmed Liddle Syndrome.
- Author
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Granhøj J, Nøhr TK, Hinrichs GR, Rasmussen M, and Svenningsen P
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- Humans, Adult, Genetic Association Studies, Female, Male, Hypertension genetics, Hypertension physiopathology, Hypertension drug therapy, Renin blood, Renin genetics, Hypokalemia genetics, Hypokalemia blood, Adolescent, Young Adult, Genetic Predisposition to Disease, Child, Mutation, Liddle Syndrome genetics, Liddle Syndrome diagnosis, Epithelial Sodium Channels genetics, Phenotype
- Abstract
Background: Liddle syndrome was initially characterized by hypertension, hypokalemia, metabolic alkalosis, and suppressed plasma renin and aldosterone, resulting from gain-of-function variants in the epithelial Na + channel (ENaC). Efficient treatment with ENaC inhibitors is available, but the phenotypic spectrum of genetically confirmed Liddle syndrome is unknown, and some patients may remain undiagnosed and at risk of inefficient treatment. In this study, we used a reverse phenotyping approach to investigate the Liddle syndrome phenotypic spectrum and genotype-phenotype correlations., Methods: Pubmed, Embase, Scopus, and the Human Gene Mutation Database were searched for articles reporting Liddle syndrome variants. The genetic variants were systematically classified to identify patients with genetically confirmed Liddle syndrome. We identified 62 articles describing 45 unique variants within 86 Liddle syndrome families, and phenotypic data were pooled for 268 patients with confirmed Liddle syndrome., Results: The Liddle syndrome variants localized to exon 13 of SCNN1B and SCNN1G , disrupting the PPPxY motif critical for downregulating ENaC activity. Hypertension sensitive to ENaC inhibition was present in 97% of adults carrying Liddle syndrome variants while hypokalemia, metabolic alkalosis, and plasma renin and aldosterone suppression showed incomplete penetrance. In addition, 95% and 55% of patients had a family history of hypertension or cerebrovascular events, respectively. The genotype had minor phenotypic effects; however, probands compared with relatives showed significant phenotypic discrepancies consistent with selection bias for initial genetic screening., Conclusions: Patients with genetically confirmed Liddle syndrome displayed a phenotypic spectrum, with ENaC-sensitive hypertension and family history of hypertension being the most common features. The phenotype seemed independent of the specific gene or variant type involved., (Copyright © 2024 by the American Society of Nephrology.)
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- 2024
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3. Amiloride Reduces Urokinase/Plasminogen-Driven Intratubular Complement Activation in Glomerular Proteinuria.
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Isaksson GL, Hinrichs GR, Andersen H, Bach ML, Weyer K, Zachar R, Henriksen JE, Madsen K, Lund IK, Mollet G, Bistrup C, Birn H, Jensen BL, and Palarasah Y
- Subjects
- Humans, Mice, Animals, Plasminogen metabolism, Amiloride pharmacology, Fibrinolysin metabolism, Inflammasomes, Mice, Inbred NOD, Proteinuria metabolism, Complement Activation, Anaphylatoxins, Fibrosis, Urokinase-Type Plasminogen Activator metabolism, Diabetic Nephropathies
- Abstract
Significance Statement: Proteinuria predicts accelerated decline in kidney function in CKD. The pathologic mechanisms are not well known, but aberrantly filtered proteins with enzymatic activity might be involved. The urokinase-type plasminogen activator (uPA)-plasminogen cascade activates complement and generates C3a and C5a in vitro / ex vivo in urine from healthy persons when exogenous, inactive, plasminogen, and complement factors are added. Amiloride inhibits uPA and attenuates complement activation in vitro and in vivo . In conditional podocin knockout (KO) mice with severe proteinuria, blocking of uPA with monoclonal antibodies significantly reduces the urine excretion of C3a and C5a and lowers tissue NLRP3-inflammasome protein without major changes in early fibrosis markers. This mechanism provides a link to proinflammatory signaling in proteinuria with possible long-term consequences for kidney function., Background: 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 sodium dodecyl sulfate-polyacrylamide gel electrophoresis, immunoblotting, and ELISA. Urine and plasma from patients with diabetic nephropathy treated with high-dose amiloride and from mice with proteinuria (podocin knockout [KO]) 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 KO in mice led to severe proteinuria and C3a and C5a urine excretion, which was attenuated reversibly by amiloride treatment for 4 days and reduced by >50% by inhibitory anti-uPA antibodies without altering proteinuria. NOD-, LRR- and pyrin domain-containing protein 3-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 BP reduction., Clinical Trial Registry Name and Registration Number: Increased Activity of a Renal Salt Transporter (ENaC) in Diabetic Kidney Disease, NCT01918488 and Increased Activity of ENaC in Proteinuric Kidney Transplant Recipients, NCT03036748 ., (Copyright © 2024 by the American Society of Nephrology.)
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- 2024
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4. The GLP-1-mediated gut-kidney cross talk in humans: mechanistic insight.
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Hinrichs GR, Hovind P, and Asmar A
- Subjects
- Animals, Humans, Hypoglycemic Agents pharmacology, Signal Transduction, Glucagon-Like Peptide-1 Receptor, Glucagon-Like Peptide 1 pharmacology, Kidney
- Abstract
Incretin-based therapy is an antidiabetic and antiobesity approach mimicking glucagon-like peptide-1 (GLP-1) with additional end-organ protection. This review solely focuses on randomized, controlled mechanistic human studies, investigating the renal effects of GLP-1. There is no consensus about the localization of GLP-1 receptors (GLP-1Rs) in human kidneys. Rodent and primate data suggest GLP-1R distribution in smooth muscle cells in the preglomerular vasculature. Native GLP-1 and GLP-1R agonists elicit renal effects. Independently of renal plasma flow and glomerular filtration rate, GLP-1 has a natriuretic effect but only during volume expansion. This is associated with high renal extraction of GLP-1, suppression of angiotensin II, and increased medullary as well as cortical perfusion. These observations may potentially indicate that impaired GLP-1 sensing could establish a connection between salt sensitivity and insulin resistance. It is concluded that a functional GLP-1 kidney axis exists in humans, which may play a role in renoprotection.
- Published
- 2024
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5. Amiloride evokes significant natriuresis and weight loss in kidney transplant recipients with and without albuminuria.
- Author
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Hinrichs GR, Nielsen JR, Birn H, Bistrup C, and Jensen BL
- Subjects
- Humans, Amiloride pharmacology, Amiloride therapeutic use, Albuminuria, Natriuresis, Renin, Aldosterone, Angiotensin II, Blood Pressure Monitoring, Ambulatory, Sodium metabolism, Weight Loss, Body Weight, Water, Epithelial Sodium Channels, Kidney Transplantation adverse effects, Hypertension, Water-Electrolyte Imbalance
- Abstract
Albuminuria in kidney transplant recipients (KTRs) is associated with hypertension and aberrant glomerular filtration of serine proteases that may proteolytically activate the epithelial Na
+ channel (ENaC). The present nonrandomized, pharmacodynamic intervention study aimed to investigate if inhibition of ENaC increases Na+ excretion and reduces extracellular volume in KTRs dependent on the presence of albuminuria. KTRs with and without albuminuria (albumin-to-creatinine ratio > 300 mg/g, n = 7, and <30 mg/g, n = 7, respectively) were included and ingested a diet with fixed Na+ content (150 mmol/day) for 5 days. On the last day, amiloride at 10 mg was administered twice. Body weight, 24-h urine electrolyte excretion, body water content, and ambulatory blood pressure as well as plasma renin, angiotensin II, and aldosterone concentrations were determined before and after amiloride. Amiloride led to a significant decrease in body weight, increase in 24-h urinary Na+ excretion, and decrease in 24-h urinary K+ excretion in both groups. Urine output increased in the nonalbuminuric group only. There was no change in plasma renin, aldosterone, and angiotensin II concentrations after amiloride, whereas a significant decrease in nocturnal systolic blood pressure and increase in 24-h urine aldosterone excretion was observed in albuminuric KTRs only. There was a significant correlation between 24-h urinary albumin excretion and amiloride-induced 24-h urinary Na+ excretion. In conclusion, ENaC activity contributes to Na+ and water retention in KTRs with and without albuminuria. ENaC is a relevant pharmacological target in KTRs; however, larger and long-term studies are needed to evaluate whether the magnitude of this effect depends on the presence of albuminuria. NEW & NOTEWORTHY Amiloride has a significant natriuretic effect in kidney transplant recipients (KTRs) that relates to urinary albumin excretion. The epithelial Na+ channel may be a relevant direct pharmacological target to counter Na+ retention and hypertension in KTRs. Epithelial Na+ channel blockers should be further investigated as a mean to mitigate Na+ and water retention and to potentially obtain optimal blood pressure control in KTRs.- Published
- 2023
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6. Water In and Water Out-Or Just the Opposite? The Need to Understand Our Patients' Illnesses in Their Own Words.
- Author
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Hinrichs GR and Mortensen LA
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- 2023
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7. A Novel AQP2 Sequence Variant Causing Aquaporin-2 Retention in the Cytoplasm and Autosomal Dominant Nephrogenic Diabetes Insipidus.
- Author
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Hinrichs GR, Baltzer S, Pallien T, Svenningsen P, Dalgaard EB, Hertz JM, Bistrup C, Jensen BL, and Klussmann E
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- 2022
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8. Proteinuria is accompanied by intratubular complement activation and apical membrane deposition of C3dg and C5b-9 in kidney transplant recipients.
- Author
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Isaksson GL, Nielsen MB, Hinrichs GR, Krogstrup NV, Zachar R, Stubmark H, Svenningsen P, Madsen K, Bistrup C, Jespersen B, Birn H, Palarasah Y, and Jensen BL
- Subjects
- Adolescent, Adult, Aged, Albuminuria blood, Albuminuria urine, Cell Membrane metabolism, Cross-Sectional Studies, Epithelial Cells metabolism, Extracellular Vesicles metabolism, Humans, Kidney Tubules, Proximal metabolism, Middle Aged, Peptide Fragments blood, Treatment Outcome, Young Adult, Albuminuria immunology, Cell Membrane immunology, Complement Activation, Complement C3b urine, Complement Membrane Attack Complex urine, Epithelial Cells immunology, Extracellular Vesicles immunology, Kidney Transplantation adverse effects, Kidney Tubules, Proximal immunology, Peptide Fragments urine
- Abstract
Proteinuria predicts accelerated decline in kidney function in kidney transplant recipients (KTRs). We hypothesized that aberrant filtration of complement factors causes intraluminal activation, apical membrane attack on tubular cells, and progressive injury. Biobanked samples from two previous studies in albuminuric KTRs were used. The complement-activation split products C3c, C3dg, and soluble C5b-9-associated C9 neoantigen were analyzed by ELISA in urine and plasma using neoepitope-specific antibodies. Urinary extracellular vesicles (uEVs) were enriched by lectin and immunoaffinity isolation and analyzed by immunoblot analysis. Urine complement excretion increased significantly in KTRs with an albumin-to-creatinine ratio of ≥300 mg/g compared with <30 mg/g. Urine C3dg and C9 neoantigen excretion correlated significantly to changes in albumin excretion from 3 to 12 mo after transplantation. Fractional excretion of C9 neoantigen was significantly higher than for albumin, indicating postfiltration generation. C9 neoantigen was detected in uEVs in six of the nine albuminuric KTRs but was absent in non-albuminuric controls ( n = 8). In C9 neoantigen-positive KTRs, lectin affinity enrichment of uEVs from the proximal tubules yielded signal for iC3b, C3dg, C9 neoantigen, and Na
+ -glucose transporter 2 but only weakly for aquaporin 2. Coisolation of podocyte markers and Tamm-Horsfall protein was minimal. Our findings show that albuminuria is associated with aberrant filtration and intratubular activation of complement with deposition of C3 activation split products and C5b-9-associated C9 neoantigen on uEVs from the proximal tubular apical membrane. Intratubular complement activation may contribute to progressive kidney injury in proteinuric kidney grafts. NEW & NOTEWORTHY The present study proposes a mechanistic coupling between proteinuria and aberrant filtration of complement precursors, intratubular complement activation, and apical membrane attack in kidney transplant recipients. C3dg and C5b-9-associated C9 neoantigen associate with proximal tubular apical membranes as demonstrated in urine extracellular vesicles. The discovery suggests intratubular complement as a mediator between proteinuria and progressive kidney damage. Inhibitors of soluble and/or luminal complement activation with access to the tubular lumen may be beneficial.- Published
- 2022
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9. A mini-review of pharmacological strategies used to ameliorate polyuria associated with X-linked nephrogenic diabetes insipidus.
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Mortensen LA, Bistrup C, Jensen BL, and Hinrichs GR
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- Animals, Arginine Vasopressin metabolism, Humans, Protein Transport physiology, Diabetes Insipidus, Nephrogenic metabolism, Diabetes Mellitus metabolism, Polyuria metabolism, Receptors, Vasopressin metabolism
- Abstract
Nephrogenic diabetes insipidus (NDI) is characterized by renal resistance to the antidiuretic hormone arginine vasopressin (AVP), which leads to polyuria, plasma hyperosmolarity, polydipsia, and impaired quality of living. Inherited forms are caused by X-linked loss-of-function mutations in the gene encoding the vasopressin 2 receptor (V2R) or autosomal recessive/dominant mutations in the gene encoding aquaporin 2 (AQP2). A common acquired form is lithium-induced NDI. AVP facilitates reabsorption of water through increased abundance and insertion of AQP2 in the apical membrane of principal cells in the collecting ducts. In X-linked NDI, V2R is dysfunctional, which leads to impaired water reabsorption. These patients have functional AQP2, and thus the challenge is to achieve AQP2 membrane insertion independently of V2R. The current treatment is symptomatic and is based on distally acting diuretics (thiazide or amiloride) and cyclooxygenase inhibitors (indomethacin). This mini-review covers published data from trials in preclinical in vivo models and a few human intervention studies to improve NDI by more causal approaches. Promising effects on NDI in preclinical studies have been demonstrated by the use of pharmacological approaches with secretin, Wnt5a, protein kinase A agonist, fluconazole, prostaglandin E
2 EP2 and EP4 agonists, statins, metformin, and soluble prorenin receptor agonists. In patients, only casuistic reports have evaluated the effect of statins, phosphodiesterase inhibitors (rolipram and sildenafil), and the guanylate cyclase stimulator riociguat without amelioration of symptoms. It is concluded that there is currently no established intervention that causally improves symptoms or quality of life in patients with NDI. There is a need to collaborate to improve study quality and conduct formal trials.- Published
- 2020
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10. Treatment of Nephrogenic Diabetes Insipidus Patients With cGMP-Stimulating Drugs Does Not Mitigate Polyuria or Increase Urinary Concentrating Ability.
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Hinrichs GR, Mortensen LA, Bistrup C, Dieperink HH, and Jensen BL
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- 2020
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11. Sodium retention by uPA-plasmin-ENaC in nephrotic syndrome-Authors reply.
- Author
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Hinrichs GR, Weyer K, Friis UG, Svenningsen P, Lund IK, Nielsen R, Mollet G, Antignac C, Bistrup C, Jensen BL, and Birn H
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- Fibrinolysin, Humans, Sodium, Urokinase-Type Plasminogen Activator, Epithelial Sodium Channels, Nephrotic Syndrome
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- 2020
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12. Mechanisms of sodium retention in nephrotic syndrome.
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Hinrichs GR, Jensen BL, and Svenningsen P
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- Animals, Epithelial Sodium Channels physiology, Humans, Hypertension etiology, Nephrotic Syndrome metabolism, Sodium metabolism
- Abstract
Purpose of Review: Proteinuria in nephrotic syndrome is associated with sodium retention and edema. Recent studies from mice, rats and humans have shown that the sodium retention depends on urinary serine proteases and that it can be mitigated by blockers (amiloride, triamterene) of the epithelial sodium channel ENaC. The present review outlines the mechanisms of protease-stimulated sodium retention during proteinuric diseases., Recent Findings: Inhibition of protease activity in nephrotic mice using aprotinin alleviates sodium retention. From both human and mice studies, an increased proteolytic cleavage of the γENaC subunit plays a role in ENaC activation. In animal models, urokinase-plasmin contributes but not as sole mediators of sodium retention. Across experimental models, human case reports and small intervention trials, amiloride alleviates nephrotic sodium retention and low-renin hypertension with high efficacy., Summary: Although the exact mechanisms for proteolytic ENaC activation are not resolved, multiple, redundant proteases are involved. Experimental and clinical evidence indicate that aberrant proteolytic ENaC activation is a primary driver of sodium retention in nephrotic syndrome and contributes to hypertension in conditions with low-grade proteinuria. Thus, we foresee increased and personalized use of amiloride treatment of nephrotic and other proteinuric disease patients with associated sodium retention and hypertension.
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- 2020
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13. Nephrotic syndrome is associated with increased plasma K + concentration, intestinal K + losses, and attenuated urinary K + excretion: a study in rats and humans.
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Ydegaard R, Svenningsen P, Bistrup C, Andersen RF, Stubbe J, Buhl KB, Marcussen N, Hinrichs GR, Iraqi H, Zamani R, Dimke H, and Jensen BL
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- Adolescent, Aldosterone metabolism, Amiloride pharmacology, Angiotensin II Type 2 Receptor Blockers pharmacology, Animals, Child, Child, Preschool, Diuretics, Down-Regulation, Epithelial Sodium Channels metabolism, Humans, Infant, Kidney drug effects, Kidney metabolism, Male, Mineralocorticoid Receptor Antagonists pharmacology, Nephrotic Syndrome blood, Nephrotic Syndrome urine, Potassium blood, Potassium urine, Potassium Channels metabolism, Puromycin Aminonucleoside, Rats, Rats, Sprague-Dawley, Sodium-Potassium-Exchanging ATPase metabolism, Nephrotic Syndrome metabolism, Potassium metabolism
- Abstract
The present study tested the hypotheses that nephrotic syndrome (NS) leads to renal K
+ loss because of augmented epithelial Na+ channel (ENaC) activity followed by downregulation of renal K+ secretory pathways by suppressed aldosterone. The hypotheses were addressed by determining K+ balance and kidney abundance of K+ and Na+ transporter proteins in puromycin aminonucleoside (PAN)-induced rat nephrosis. The effects of amiloride and angiotensin II type 1 receptor and mineralocorticoid receptor (MR) antagonists were tested. Glucocorticoid-dependent MR activation was tested by suppression of endogenous glucocorticoid with dexamethasone. Urine and plasma samples were obtained from pediatric patients with NS in acute and remission phases. PAN-induced nephrotic rats had ENaC-dependent Na+ retention and displayed lower renal K+ excretion but elevated intestinal K+ secretion that resulted in less cumulated K+ in NS. Aldosterone was suppressed at day 8 . The NS-associated changes in intestinal, but not renal, K+ handling responded to suppression of corticosterone, whereas angiotensin II type 1 receptor and MR blockers and amiloride had no effect on urine K+ excretion during NS. In PAN-induced nephrosis, kidney protein abundance of the renal outer medullary K+ channel and γ-ENaC were unchanged, whereas the Na+ -Cl- cotransporter was suppressed and Na+ -K+ -ATPase increased. Pediatric patients with acute NS displayed suppressed urine Na+ -to-K+ ratios compared with remission and elevated plasma K+ concentration, whereas fractional K+ excretion did not differ. Acute NS is associated with less cumulated K+ in a rat model, whereas patients with acute NS have elevated plasma K+ and normal renal fractional K+ excretion. In NS rats, K+ balance is not coupled to ENaC activity but results from opposite changes in renal and fecal K+ excretion with a contribution from corticosteroid MR-driven colonic secretion.- Published
- 2019
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14. Urokinase-type plasminogen activator contributes to amiloride-sensitive sodium retention in nephrotic range glomerular proteinuria in mice.
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Hinrichs GR, Weyer K, Friis UG, Svenningsen P, Lund IK, Nielsen R, Mollet G, Antignac C, Bistrup C, Jensen BL, and Birn H
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- Animals, Epithelial Sodium Channel Blockers pharmacology, Gene Expression Regulation drug effects, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins metabolism, Membrane Proteins genetics, Membrane Proteins metabolism, Mice, Mice, Knockout, Peptide Hydrolases urine, Plasminogen urine, Urokinase-Type Plasminogen Activator, Water metabolism, Weight Loss drug effects, Amiloride pharmacology, Kidney Glomerulus metabolism, Nephrotic Syndrome metabolism, Proteinuria metabolism, Sodium metabolism
- Abstract
Aim: Activation of sodium reabsorption by urinary proteases has been implicated in sodium retention associated with nephrotic syndrome. The study was designed to test the hypothesis that nephrotic proteinuria in mice after conditional deletion of podocin leads to urokinase-dependent, amiloride-sensitive plasmin-mediated sodium and water retention., Methods: Ten days after podocin knockout, urine and faeces were collected for 10 days in metabolic cages and analysed for electrolytes, plasminogen, protease activity and ability to activate γENaC by patch clamp and western blot. Mice were treated with amiloride (2.5 mg kg
-1 for 2 days and 10 mg kg-1 for 2 days) or an anti-urokinase-type plasminogen activator (uPA) targeting antibody (120 mg kg-1 /24 h) and compared to controls., Results: Twelve days after deletion, podocin-deficient mice developed significant protein and albuminuria associated with increased body wt, ascites, sodium accumulation and suppressed plasma renin. This was associated with increased urinary excretion of plasmin and plasminogen that correlated with albumin excretion, urine protease activity co-migrating with active plasmin, and the ability of urine to induce an amiloride-sensitive inward current in M1 cells in vitro. Amiloride treatment in podocin-deficient mice resulted in weight loss, increased sodium excretion, normalization of sodium balance and prevention of the activation of plasminogen to plasmin in urine in a reversible way. Administration of uPA targeting antibody abolished urine activation of plasminogen, attenuated sodium accumulation and prevented cleavage of γENaC., Conclusions: Nephrotic range glomerular proteinuria leads to urokinase-dependent intratubular plasminogen activation and γENaC cleavage which contribute to sodium accumulation., (© 2019 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)- Published
- 2019
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15. Albuminuria in kidney transplant recipients is associated with increased urinary serine proteases and activation of the epithelial sodium channel.
- Author
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Hinrichs GR, Michelsen JS, Zachar R, Friis UG, Svenningsen P, Birn H, Bistrup C, and Jensen BL
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- Albuminuria enzymology, Albuminuria etiology, Albuminuria physiopathology, Animals, Biomarkers urine, Blood Pressure, Cells, Cultured, Cross-Sectional Studies, Female, Humans, Hypertension etiology, Hypertension physiopathology, Hypertension urine, Male, Membrane Potentials, Mice, Middle Aged, Proteolysis, Risk Factors, Treatment Outcome, Water-Electrolyte Balance, Water-Electrolyte Imbalance etiology, Water-Electrolyte Imbalance physiopathology, Water-Electrolyte Imbalance urine, Albuminuria urine, Epithelial Sodium Channels urine, Exosomes enzymology, Kidney Transplantation adverse effects, Serine Proteases urine, Transplant Recipients
- Abstract
Albuminuria predicts adverse renal outcome in kidney transplant recipients. The present study addressed the hypothesis that albuminuria is associated with increased urine serine proteases with the ability to activate the epithelial sodium channel (ENaC) and with greater extracellular volume and higher blood pressure. In a cross-sectional design, kidney transplant recipients with ( n = 18) and without ( n = 19) albuminuria were included for office blood pressure measurements, estimation of volume status by bioimpedance, and collection of spot urine and plasma samples. Urine was analyzed for serine proteases and for the ability to activate ENaC current in vitro. Urine exosome protein was immunoblotted for prostasin and γ-ENaC protein. In the present study, it was found that, compared with nonalbuminuria (8.8 mg/g creatinine), albuminuric (1,722 mg/g creatinine) kidney transplant recipients had a higher systolic and diastolic blood pressure, despite receiving significantly more antihypertensives, and a greater urinary total plasminogen, active plasmin, active urokinase-type plasminogen activator, and prostasin protein abundance, which correlated significantly with u-albumin. Fluid overload correlated with systolic blood pressure, urinary albumin/creatinine, and plasminogen/creatinine. Urine from albuminuric kidney transplant recipients evoked a greater amiloride- and aprotinin-sensitive inward current in single collecting duct cells (murine cell line M1). γENaC subunits at 50 and 75 kDa showed increased abundance in urine exosomes from albuminuric kidney transplant recipients when compared with controls. These findings show that albuminuria in kidney transplant recipients is associated with hypertension, ability of urine to proteolytically activate ENaC current, and increased abundance of γENaC. ENaC activity could contribute to hypertension and adverse outcome in posttransplant proteinuria.
- Published
- 2018
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16. Amiloride resolves resistant edema and hypertension in a patient with nephrotic syndrome; a case report.
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Hinrichs GR, Mortensen LA, Jensen BL, and Bistrup C
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- Adult, Antihypertensive Agents therapeutic use, Diabetic Nephropathies drug therapy, Drug Therapy, Combination, Epithelial Sodium Channel Blockers therapeutic use, Humans, Male, Amiloride therapeutic use, Diuretics therapeutic use, Edema drug therapy, Hypertension drug therapy, Nephrotic Syndrome drug therapy
- Abstract
Sodium and fluid retention is a hallmark and a therapeutic challenge of the nephrotic syndrome (NS). Studies support the "overfill" theory of NS with pathophysiological proteolytic activation of the epithelial sodium channel (ENaC) which explains the common observation of suppressed renin -angiotensin system and poor therapeutic response to ACE inhibitors. Blockade of ENaC by the diuretic amiloride would be a rational intervention compared to the traditionally used loop diuretics. We describe a 38-year-old male patient with type1 diabetes who developed severe hypertension (200/140 mmHg), progressive edema (of at least 10 L), and overt proteinuria (18.5 g/24 h), despite combined administration of five antihypertensive drugs. Addition of amiloride (5 mg/day) to treatment resulted in resolution of edema, weight loss of 7 kg, reduction in blood pressure (150/100-125/81 mmHg), increased 24 h urinary sodium excretion (127-165 mmol/day), decreased eGFR (41-29 mL/min), and increased plasma potassium concentration (4.6-7.8 mmol/L). Blocking of ENaC mobilizes nephrotic edema and lowers blood pressure in NS. However, acute kidney injury and dangerous hyperkalemia is a potential risk if amiloride is added to multiple other antihypertensive medications as ACEi and spironolactone. The findings support that ENaC is active in NS and is a relevant target in adult NS patients., (© 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)
- Published
- 2018
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17. Physiology and pathophysiology of the plasminogen system in the kidney.
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Svenningsen P, Hinrichs GR, Zachar R, Ydegaard R, and Jensen BL
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- Animals, Fibrinolysin metabolism, Humans, Kidney metabolism, Kidney physiology, Kidney Diseases metabolism, Kidney Diseases pathology, Plasminogen metabolism
- Abstract
The plasminogen system is important for fibrinolysis in addition to tissue remodeling and inflammation with significance for kidney disease. The system consists of the circulating zymogen plasminogen (Plg) and the tissue- and urokinase-type plasminogen activators, tPA and uPA, expressed in the glomeruli, endothelium and tubular epithelium, respectively, and the inhibitors α
2 -antiplasmin and plasminogen activator inhibitor-type1, PAI-1. Plasminogen is activated by surface receptors, some with renal expression: urokinase-type plasminogen activator receptor (uPAR), plasminogen receptor KT (Plg-RKT ), and tPA, most evident in the endothelium. Plasmin may exert effects through protease-activated receptors, PARs, expressed in the kidney. Deletion of plasminogen system component genes confers no major developmental or renal phenotypes in normal mice. In glomerular injury and renal interstitial fibrosis, deletion of various components, notably Plg, uPA, PAI, and uPAR is associated with protection suggesting a disease promoting effect of plasmin, in some cases exerted through PAR1 receptor activation. Plasminogen and uPA are aberrantly filtrated across the glomerular barrier in proteinuria, and plasminogen is activated in the tubular fluid. In the tubular fluid, plasmin may activate proteolytically the epithelial sodium channel (ENaC) and inhibit the apical calcium transporter transient receptor potential cation channel subfamily V member 5 (TRPV5), which could explain impaired sodium excretion and enhanced calcium excretion in proteinuria. Amiloride, a potassium-sparing diuretic, inhibits urokinase and plasmin activation in the tubular fluid and uPAR expression in vitro, which highlights new indications for an old drug. Protease inhibitors lowered blood pressure and antagonized fibrosis in salt-sensitive Dahl rats. Current knowledge indicates that the plasminogen system aggravates renal disease by direct and indirect hypertensive effects and is a promising target to antagonize disease progression.- Published
- 2017
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18. Albuminuria is associated with an increased prostasin in urine while aldosterone has no direct effect on urine and kidney tissue abundance of prostasin.
- Author
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Oxlund C, Kurt B, Schwarzensteiner I, Hansen MR, Stæhr M, Svenningsen P, Jacobsen IA, Hansen PB, Thuesen AD, Toft A, Hinrichs GR, Bistrup C, and Jensen BL
- Subjects
- Adult, Aged, Albuminuria blood, Albuminuria etiology, Animals, Antihypertensive Agents adverse effects, Antihypertensive Agents therapeutic use, Diabetic Nephropathies complications, Female, Humans, Hypertension complications, Hypertension drug therapy, Kidney drug effects, Kidney metabolism, Male, Mice, Mice, Inbred C57BL, Middle Aged, Rats, Rats, Sprague-Dawley, Serine Endopeptidases blood, Serine Endopeptidases metabolism, Spironolactone adverse effects, Spironolactone therapeutic use, Albuminuria urine, Aldosterone blood, Antihypertensive Agents pharmacology, Serine Endopeptidases urine, Spironolactone pharmacology
- Abstract
The proteinase prostasin is a candidate mediator for aldosterone-driven proteolytic activation of the epithelial sodium channel (ENaC). It was hypothesized that the aldosterone-mineralocorticoid receptor (MR) pathway stimulates prostasin abundance in kidney and urine. Prostasin was measured in plasma and urine from type 2 diabetic patients with resistant hypertension (n = 112) randomized to spironolactone/placebo in a clinical trial. Prostasin protein level was assessed by immunoblotting in (1) human and rat urines with/without nephrotic syndrome, (2) human nephrectomy tissue, (3) urine and kidney from aldosterone synthase-deficient (AS
-/- ) mice and ANGII- and aldosterone-infused mice, and in (4) kidney from adrenalectomized rats. Serum aldosterone concentration related to prostasin concentration in urine but not in plasma. Plasma prostasin concentration increased significantly after spironolactone compared to control. Urinary prostasin and albumin related directly and were reduced by spironolactone. In patients with nephrotic syndrome, urinary prostasin protein was elevated compared to controls. In rat nephrosis, proteinuria coincided with increased urinary prostasin, unchanged kidney tissue prostasin, and decreased plasma prostasin while plasma aldosterone was suppressed. Prostasin protein abundance in human nephrectomy tissue was similar across gender and ANGII inhibition regimens. Prostasin urine abundance was not different in AS-/- and aldosterone-infused mice. Prostasin kidney level was not different from control in adrenalectomized rats and AS-/- mice. We found no evidence for a direct relationship between mineralocorticoid receptor signaling and kidney and urine prostasin abundance. The reduction of urinary prostasin in spironolactone-treated patients is most likely the result of an improved glomerular filtration barrier function and generally reduced proteinuria.- Published
- 2017
- Full Text
- View/download PDF
19. A novel mutation affecting the arginine-137 residue of AVPR2 in dizygous twins leads to nephrogenic diabetes insipidus and attenuated urine exosome aquaporin-2.
- Author
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Hinrichs GR, Hansen LH, Nielsen MR, Fagerberg C, Dieperink H, Rittig S, and Jensen BL
- Subjects
- Arginine genetics, Blotting, Western, Exosomes metabolism, Humans, Male, Pedigree, Point Mutation, Young Adult, Aquaporin 2 urine, Diabetes Insipidus, Nephrogenic genetics, Mutation, Missense genetics, Receptors, Vasopressin genetics, Twins, Dizygotic genetics
- Abstract
Mutations in the vasopressin V2 receptor gene AVPR2 may cause X-linked nephrogenic diabetes insipidus by defective apical insertion of aquaporin-2 in the renal collecting duct principal cell. Substitution mutations with exchange of arginine at codon 137 can cause nephrogenic syndrome of inappropriate antidiuresis or congenital X-linked nephrogenic diabetes insipidus. We present a novel mutation in codon 137 within AVPR2 with substitution of glycine for arginine in male dizygotic twins. Nephrogenic diabetes insipidus was demonstrated by water deprivation test and resistance to vasopressin administration. While a similar urine exosome release rate was shown between probands and controls by western blotting for the marker ALIX, there was a selective decrease in exosome aquaporin-2 versus aquaporin-1 protein in probands compared to controls., (© 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.)
- Published
- 2016
- Full Text
- View/download PDF
20. Aberrant glomerular filtration of urokinase-type plasminogen activator in nephrotic syndrome leads to amiloride-sensitive plasminogen activation in urine.
- Author
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Stæhr M, Buhl KB, Andersen RF, Svenningsen P, Nielsen F, Hinrichs GR, Bistrup C, and Jensen BL
- Subjects
- Adult, Animals, Child, Epithelial Sodium Channels metabolism, Humans, Male, Nephrotic Syndrome chemically induced, Puromycin Aminonucleoside, Rats, Rats, Sprague-Dawley, Amiloride pharmacology, Epithelial Sodium Channel Blockers pharmacology, Kidney Glomerulus metabolism, Nephrotic Syndrome metabolism, Plasminogen urine, Urokinase-Type Plasminogen Activator metabolism
- Abstract
In nephrotic syndrome, aberrant glomerular filtration of plasminogen and conversion to active plasmin in preurine are thought to activate proteolytically epithelial sodium channel (ENaC) and contribute to sodium retention and edema. The ENaC blocker amiloride is an off-target inhibitor of urokinase-type plasminogen activator (uPA) in vitro. It was hypothesized that uPA is abnormally filtered to preurine and is inhibited in urine by amiloride in nephrotic syndrome. This was tested by determination of Na(+) balance, uPA protein and activity, and amiloride concentration in urine from rats with puromycin aminonucleoside (PAN)-induced nephrotic syndrome. Urine samples from 6 adult and 18 pediatric patients with nephrotic syndrome were analyzed for uPA activity and protein. PAN treatment induced significant proteinuria in rats which coincided with increased urine uPA protein and activity, increased urine protease activity, and total plasminogen/plasmin concentration and Na(+) retention. Amiloride (2 mg·kg(-1)·24 h(-1)) concentration in urine was in the range 10-20 μmol/l and reduced significantly urine uPA activity, plasminogen activation, protease activity, and sodium retention in PAN rats, while proteinuria was not altered. In paired urine samples, uPA protein was significantly elevated in urine from children with active nephrotic syndrome compared with remission phase. In six adult nephrotic patients, urine uPA protein and activity correlated positively with 24 h urine protein excretion. In conclusion, nephrotic syndrome is associated with aberrant filtration of uPA across the injured glomerular barrier. Amiloride inhibits urine uPA activity which attenuates plasminogen activation and urine protease activity in vivo. Urine uPA is a relevant target for amiloride in vivo., (Copyright © 2015 the American Physiological Society.)
- Published
- 2015
- Full Text
- View/download PDF
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