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Yang B, Zhou W, Cui L, Tian L, Ni Y, Yang M, Yang Y. The predictive value of free thyroxine combined with tubular atrophy/interstitial fibrosis for poor prognosis in patients with IgA nephropathy. Front Endocrinol (Lausanne) 2024; 15:1372824. [PMID: 38808109 PMCID: PMC11130362 DOI: 10.3389/fendo.2024.1372824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Accepted: 04/29/2024] [Indexed: 05/30/2024] Open
Abstract
Background IgA nephropathy (IgAN), the most common type of glomerulonephritis, has great individual differences in prognosis. Many studies showed the relationship between thyroid hormones and chronic kidney disease. However, the relationship between free thyroxine (FT4), as a thyroid hormone, and IgAN is still unclear. This study aimed to evaluate the impact of FT4 on IgAN prognosis. Methods This retrospective study involved 223 patients with biopsy-proven IgAN. The renal composite outcomes were defined as: (1) ESRD, defined as eGFR < 15 ml/(min·1.73 m2) or initiation of renal replacement therapy (hemodialysis, peritoneal dialysis, renal transplantation); (2) serum creatinine doubled from baseline; (3) eGFR decreased by more than 50% from baseline. The predictive value was determined by the area under the curve (AUC). Kaplan-Meier and Cox proportional hazards analyses assessed renal progression and prognosis. Results After 38 (26-54) months of follow-up, 23 patients (10.3%) experienced renal composite outcomes. Kaplan-Meier survival curve analysis showed that the renal survival rate of the IgAN patients with FT4<15.18pmol/L was lower than that with FT4≥15.18pmol/L (P < 0. 001). Multivariate Cox regression model analysis showed that FT4 was a protective factor for poor prognosis of IgAN patients, whether as a continuous variable or a categorical variable (HR 0.68, 95%CI 0.51-0.90, P =0.007; HR 0.04, 95%CI 0.01-0.20, P <0.001). ROC curve analysis showed that FT4 combined with t score had a high predictive value for poor prognosis of IgAN patients (AUC=0.881, P<0.001). Conclusion FT4 was a protective factor for IgAN. In addition, FT4 combined with tubular atrophy/interstitial fibrosis had a high predictive value for poor prognosis of IgAN.
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Affiliation(s)
- Bixia Yang
- Department of Nephrology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Wen Zhou
- Department of Nephrology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Liqin Cui
- Department of Nephrology, The Third Affiliated Hospital of Soochow University, Changzhou, China
- Changzhou Medical Center, Nanjing Medical University, Changzhou, China
| | - Li Tian
- Department of Nephrology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Yanhong Ni
- Department of Nephrology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Min Yang
- Department of Nephrology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Yan Yang
- Department of Nephrology, The Third Affiliated Hospital of Soochow University, Changzhou, China
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2
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Santiago-Moreno J, Pequeño B, Martinez-Madrid B, Castaño C, Bóveda P, Velázquez R, Toledano-Díaz A, Álvarez-Rodríguez M, Rodríguez-Martínez H. Expression of Aquaglyceroporins in Spermatozoa from Wild Ruminants Is Influenced by Photoperiod and Thyroxine Concentrations. Int J Mol Sci 2022; 23:ijms23062903. [PMID: 35328325 PMCID: PMC8950870 DOI: 10.3390/ijms23062903] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 03/01/2022] [Accepted: 03/04/2022] [Indexed: 12/26/2022] Open
Abstract
This work identified the presence of AQPs in frozen-thawed sperm of wild ruminants and assessed the influence of the interaction between photoperiod and thyroxine on AQP expression, and on testosterone secretion. Thyroxine and melatonin were administered to ibexes. In a second experiment, performed in mouflons, circulating thyroxine was reduced via treatment with propylthiouracil (PTU), and an artificial long day (LD) photoperiod established. In the ibexes, the melatonin treatment increased the blood plasma testosterone concentration, reduced the cryoresistance ratio (CR) for sperm viability and the presence of an intact acrosome, and increased the percentage of sperm with AQP7 in the acrosome and of AQP3 and AQP10 in the midpiece. In the mouflons, neither the PTU treatment, the LD, nor the combination of both affected the CR of any sperm variable. The percentage of sperm with AQP3 increased in the post-acrosome region but decreased in the tail in the LD+PTU group. The percentage of sperm with AQP10 in the principal piece and endpiece was lower in the PTU+LD group than in the control and LD groups. The influence of photoperiod/melatonin on AQP expression might be indirectly exerted through changes in the testosterone concentration, and thus ultimately affect sperm cryoresistance.
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Affiliation(s)
- Julián Santiago-Moreno
- Department of Animal Reproduction, Spanish National Institute for Agricultural and Food Research and Technology (INIA-CSIC), 28040 Madrid, Spain; (B.P.); (C.C.); (P.B.); (R.V.); (A.T.-D.)
- Correspondence: ; Tel.: +34-1-3474020
| | - Belén Pequeño
- Department of Animal Reproduction, Spanish National Institute for Agricultural and Food Research and Technology (INIA-CSIC), 28040 Madrid, Spain; (B.P.); (C.C.); (P.B.); (R.V.); (A.T.-D.)
| | - Belen Martinez-Madrid
- Department of Animal Medicine & Surgery, Faculty of Veterinary Medicine, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain;
| | - Cristina Castaño
- Department of Animal Reproduction, Spanish National Institute for Agricultural and Food Research and Technology (INIA-CSIC), 28040 Madrid, Spain; (B.P.); (C.C.); (P.B.); (R.V.); (A.T.-D.)
| | - Paula Bóveda
- Department of Animal Reproduction, Spanish National Institute for Agricultural and Food Research and Technology (INIA-CSIC), 28040 Madrid, Spain; (B.P.); (C.C.); (P.B.); (R.V.); (A.T.-D.)
| | - Rosario Velázquez
- Department of Animal Reproduction, Spanish National Institute for Agricultural and Food Research and Technology (INIA-CSIC), 28040 Madrid, Spain; (B.P.); (C.C.); (P.B.); (R.V.); (A.T.-D.)
| | - Adolfo Toledano-Díaz
- Department of Animal Reproduction, Spanish National Institute for Agricultural and Food Research and Technology (INIA-CSIC), 28040 Madrid, Spain; (B.P.); (C.C.); (P.B.); (R.V.); (A.T.-D.)
| | - Manuel Álvarez-Rodríguez
- Department of Biomedical & Clinical Sciences (BKV), Obstetrics & Gynecology, Linköping University, SE-58185 Linkoping, Sweden; (M.Á.-R.); (H.R.-M.)
| | - Heriberto Rodríguez-Martínez
- Department of Biomedical & Clinical Sciences (BKV), Obstetrics & Gynecology, Linköping University, SE-58185 Linkoping, Sweden; (M.Á.-R.); (H.R.-M.)
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3
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Ma C, de Baaij JHF, Millar PJ, Gault VA, de Galan BE, Bindels RJM, Hoenderop JGJ. Effect of Dapagliflozin Treatment on the Expression of Renal Sodium Transporters/Channels on High-Fat Diet Diabetic Mice. Nephron Clin Pract 2019; 142:51-60. [PMID: 30799406 DOI: 10.1159/000496617] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Accepted: 12/21/2018] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Inhibition of the Na+/glucose co-transporter 2 is a new therapeutic strategy for diabetes. It is unclear how proximal loss of Na+ (and glucose) affects the subsequent Na+ transporters in the proximal tubule (PT), thick ascending limb of loop of Henle (TAL), distal convoluted tubule (DCT) and collecting duct (CD). METHODS Mice on a high fat diet were administered 3 doses streptozotocin 6 days prior to oral dapagliflozin administration or vehicle for 18 days. A control group of lean mice were also included. Body weight and glucose were recorded at regular intervals during treatment. Renal Na+ transporters expression in nephron segments were analyzed by RT-qPCR and Western blot. RESULTS Dapagliflozin treatment resulted in a significant reduction in body weight and blood glucose compared to vehicle-treated controls. mRNA results showed that Na+-hydrogen antiporter 3 (NHE3), Na+/phosphate cotransporter (NaPi-2a) and epithelial Na+ channel expression was increased, Ncx1, ENaCβ and ENaCγ expression declined (p all < 0.05), respectively, in dapagliflozin-treated mice when compared with saline vehicle mice. Na-K-2Cl cotransporters and Na-Cl cotransporter mRNA expression was not affected by dapagliflozin treatment. Na+/K+-ATPase (Atp1b1) expression was also increased significantly by dapagliflozin treatment, but it did not affect Atp1a1 and glucose transporter 2 expression. Western blot analysis showed that NaPi-2a, NHE3 and ATP1b1 expression was upregulated in dapagliflozin-treated diabetic mice when compared with saline vehicle mice (p < 0.05). CONCLUSION Our findings suggest that dapagliflozin treatment augments compensatory changes in the renal PT in diabetic mice.
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Affiliation(s)
- Chao Ma
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Jeroen H F de Baaij
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Paul J Millar
- SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, United Kingdom
| | - Victor A Gault
- SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, United Kingdom
| | - Bastiaan E de Galan
- Internal Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - René J M Bindels
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Joost G J Hoenderop
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands,
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AQP4 and HIVAN. Exp Mol Pathol 2018; 105:71-75. [PMID: 29778884 DOI: 10.1016/j.yexmp.2018.05.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Accepted: 05/13/2018] [Indexed: 11/21/2022]
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Musso CG, Castañeda A, Giordani M, Mombelli C, Groppa S, Imperiali N, Rosa Diez G. Hyponatremia in kidney transplant patients: its pathophysiologic mechanisms. Clin Kidney J 2018; 11:581-585. [PMID: 30094023 PMCID: PMC6070118 DOI: 10.1093/ckj/sfy016] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Accepted: 01/18/2018] [Indexed: 01/12/2023] Open
Abstract
Kidney transplant patients (KTPs), and particularly those with advanced chronic kidney rejection, may be affected by opportunistic infections, metabolic alterations and vascular and oncologic diseases that promote clinical conditions that require a variety of treatments, the combinations of which may predispose them to hyponatremia. Salt and water imbalance can induce abnormalities in volemia and/or serum sodium depending on the nature of this alteration (increase or decrease), its absolute magnitude (mild or severe) and its relative magnitude (body sodium:water ratio). Hyponatremia appears when the body sodium:water ratio is reduced due to an increase in body water or a reduction in body sodium. Additionally, hyponatremia is classified as normotonic, hypertonic and hypotonic and while hypotonic hyponatremia is classified in hyponatremia with normal, high or low extracellular fluid. The main causes of hyponatremia in KTPs are hypotonic hyponatremia secondary to water and salt contraction with oral hydration (gastroenteritis, sepsis), free water retention (severe renal failure, syndrome of inappropriate antidiuretic hormone release, hypothyroidism), chronic hypokalemia (rapamycin, malnutrition), sodium loss (tubular dysfunction secondary to nephrocalcinosis, acute tubular necrosis, tubulitis/rejection, interstitial nephritis, adrenal insufficiency, aldosterone resistance, pancreatic drainage, kidney–pancreas transplant) and hyponatremia induced by medication (opioids, cyclophosphamide, psychoactive, potent diuretics and calcineurinic inhibitors). In conclusion, KTPs are predisposed to develop hyponatremia since they are exposed to immunologic, infectious, pharmacologic and oncologic disorders, the combinations of which alter their salt and water homeostatic capacity.
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Affiliation(s)
- Carlos G Musso
- Human Physiology Department, Instituto Universitario del Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.,Nephrology Division, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - Alejandrina Castañeda
- Human Physiology Department, Instituto Universitario del Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - María Giordani
- Human Physiology Department, Instituto Universitario del Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.,Nephrology Division, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - Cesar Mombelli
- Nephrology Division, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - Silvia Groppa
- Nephrology Division, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - Nora Imperiali
- Human Physiology Department, Instituto Universitario del Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.,Nephrology Division, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - Guillermo Rosa Diez
- Nephrology Division, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
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Massolt ET, Salih M, Beukhof CM, Kam BL, Burger J, Visser WE, Hoorn EJ, Peeters RP. Effects of Thyroid Hormone on Urinary Concentrating Ability. Eur Thyroid J 2017; 6:238-242. [PMID: 29071235 PMCID: PMC5649223 DOI: 10.1159/000478521] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Revised: 06/09/2017] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Hypothyroidism has been associated with impaired urinary concentrating ability. However, previous reports on thyroid hormone and urinary concentrating ability in humans only studied a limited number of patients with autoimmune thyroid disease or used healthy controls instead of paired analysis within the same patients. OBJECTIVE To study the urinary concentrating ability in athyreotic patients with differentiated thyroid cancer on and off levothyroxine treatment as they are exposed to different thyroid states as part of their treatment in the absence of an autoimmune disease. DESIGN AND METHODS We studied 9 patients (mean age of 42.7 years) during severe hypothyroid state (withdrawal of levothyroxine before radioactive iodine therapy) and TSH-suppressed state (on levothyroxine therapy). At these two points, serum and urine samples were collected after 14 h of overnight fasting without any food or drink. RESULTS Serum and urine osmolality were not significantly different between on and off levothyroxine treatment. Serum creatinine levels were significantly higher in patients off versus on levothyroxine treatment (87.0 vs. 71.0 µmol/L, respectively; p = 0.044) and, correspondingly, the estimated glomerular filtration rate was significantly lower (89.6 vs. 93.1 mL/min, respectively; p = 0.038). CONCLUSION Short-term, severe hypothyroidism has no effect on urinary concentrating ability. Our study confirms the well-known effects of thyroid hormone on serum creatinine concentrations.
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Affiliation(s)
- Elske T. Massolt
- Division of Endocrinology, Erasmus MC, Rotterdam, The Netherlands
- Rotterdam Thyroid Center, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
- *Elske T. Massolt, Rotterdam Thyroid Center, Department of Internal Medicine, Erasmus MC, Mailbox 2040, room Ee 500, NL–3000 CA Rotterdam (The Netherlands), E-Mail
| | - Mahdi Salih
- Department of Nephrology and Transplantation, Erasmus MC, Rotterdam, The Netherlands
| | - Carolien M. Beukhof
- Division of Endocrinology, Erasmus MC, Rotterdam, The Netherlands
- Rotterdam Thyroid Center, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
| | - Boen L.R. Kam
- Department of Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands
| | - J.W. Burger
- Division of Surgical Oncology, Department of Surgery, Erasmus MC, Rotterdam, The Netherlands
| | - W. Edward Visser
- Division of Endocrinology, Erasmus MC, Rotterdam, The Netherlands
- Rotterdam Thyroid Center, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
| | - Ewout J. Hoorn
- Department of Nephrology and Transplantation, Erasmus MC, Rotterdam, The Netherlands
| | - Robin P. Peeters
- Division of Endocrinology, Erasmus MC, Rotterdam, The Netherlands
- Rotterdam Thyroid Center, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
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Musso CG, Belloso WH, Glassock RJ. Water, electrolytes, and acid-base alterations in human immunodeficiency virus infected patients. World J Nephrol 2016; 5:33-42. [PMID: 26788462 PMCID: PMC4707166 DOI: 10.5527/wjn.v5.i1.33] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Revised: 09/05/2015] [Accepted: 11/17/2015] [Indexed: 02/06/2023] Open
Abstract
The clinical spectrum of human immunodeficiency virus (HIV) infection associated disease has changed significantly over the past decade, mainly due to the wide availability and improvement of combination antiretroviral therapy regiments. Serious complications associated with profound immunodeficiency are nowadays fortunately rare in patients with adequate access to care and treatment. However, HIV infected patients, and particularly those with acquired immune deficiency syndrome, are predisposed to a host of different water, electrolyte, and acid-base disorders (sometimes with opposite characteristics), since they have a modified renal physiology (reduced free water clearance, and relatively increased fractional excretion of calcium and magnesium) and they are also exposed to infectious, inflammatory, endocrinological, oncological variables which promote clinical conditions (such as fever, tachypnea, vomiting, diarrhea, polyuria, and delirium), and may require a variety of medical interventions (antiviral medication, antibiotics, antineoplastic agents), whose combination predispose them to undermine their homeostatic capability. As many of these disturbances may remain clinically silent until reaching an advanced condition, high awareness is advisable, particularly in patients with late diagnosis, concomitant inflammatory conditions and opportunistic diseases. These disorders contribute to both morbidity and mortality in HIV infected patients.
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Colombero C, Venara M, Gonzalez D, Roman RJ, Nowicki S. Cytochrome P4504A inhibitors attenuate the exaggerated natriuretic response to volume expansion in thyroidectomized rats. Physiol Rep 2014; 2:2/6/e12040. [PMID: 24920124 PMCID: PMC4208633 DOI: 10.14814/phy2.12040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Affiliation(s)
- Cecilia Colombero
- Centro de Investigaciones Endocrinológicas “Dr. César Bergadá” (CEDIE); CONICET - FEI - División de Endocrinología; Hospital de Niños Ricardo Gutiérrez; Buenos Aires Argentina
| | - Marcela Venara
- Centro de Investigaciones Endocrinológicas “Dr. César Bergadá” (CEDIE); CONICET - FEI - División de Endocrinología; Hospital de Niños Ricardo Gutiérrez; Buenos Aires Argentina
| | - Daniel Gonzalez
- Centro de Investigaciones Endocrinológicas “Dr. César Bergadá” (CEDIE); CONICET - FEI - División de Endocrinología; Hospital de Niños Ricardo Gutiérrez; Buenos Aires Argentina
| | - Richard J. Roman
- Department of Pharmacology and Toxicology; The University of Mississippi Medical Center; Jackson Mississippi
| | - Susana Nowicki
- Centro de Investigaciones Endocrinológicas “Dr. César Bergadá” (CEDIE); CONICET - FEI - División de Endocrinología; Hospital de Niños Ricardo Gutiérrez; Buenos Aires Argentina
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9
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The thyroid and the kidney: a complex interplay in health and disease. Int J Artif Organs 2014; 37:1-12. [PMID: 24634329 DOI: 10.5301/ijao.5000300] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/03/2013] [Indexed: 11/20/2022]
Abstract
Thyroid hormones may directly affect the kidney and altered kidney function may also contribute to thyroid disorders. The renal manifestations of thyroid disorders are based on hemodynamic alterations or/and to direct effects of thyroid hormones. The renin-angiotensin system plays a crucial role in the cross-talk between the thyroid and the kidney. Hypothyroidism may be accompanied by an increase of serum creatinine and reduction of glomerular filtration rate (GFR), whereas hyperthyroidism may increase GFR. Treatment of thyroid disorders may lead to normalization of GFR. Primary and subclinical hypothyroidism and low triiodothyronine (T3) syndrome are common features in patients with chronic kidney disease (CKD). In addition low levels of thyroid hormones may predict a higher risk of cardiovascular and overall mortality in patients with end-stage renal disease. The causal nature of this correlation remains uncertain. In this review, special emphasis is given to the thyroid pathophysiology, its impact on kidney function and CKD and the interpretation of laboratorial findings of thyroid dysfunction in CKD.
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Abstract
There are an abundance of studies of thyroid disease in rodents in a laboratory setting; however, research is limited in pet rodent populations. Validated reference intervals for thyroid testing are scarce, making interpretation of blood work difficult. Hyperthyroidism and hypothyroidism have been reported in multiple rodent species, with the most data available for guinea pigs. Thyroid neoplasia has been reported in the most common rodent species, although often as an incidental finding at necropsy. Further research is needed to determine frequencies of disease, methods of diagnosing, and treatment options with the best efficacy.
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Affiliation(s)
- Lindsay Thorson
- Central Animal Hospital, 317 Ardsley Road, Scarsdale, NY 10583, USA.
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Meuwese CL, Dekkers OM, Stenvinkel P, Dekker FW, Carrero JJ. Nonthyroidal illness and the cardiorenal syndrome. Nat Rev Nephrol 2013; 9:599-609. [PMID: 23999398 DOI: 10.1038/nrneph.2013.170] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The cardiorenal syndrome represents a final common pathway for renal and congestive heart failure and heralds a poor prognosis. Factors that link the failing heart and the failing kidneys--the so-called cardiorenal connectors--are, therefore, of clinical and therapeutic interest. Alterations in the levels and function of thyroid hormones that fit the spectrum of nonthyroidal illnesses could be considered to be cardiorenal connectors as both renal failure and heart failure progress with the development of nonthyroidal illness. In addition, circumstantial evidence suggests that nonthyroidal illness can induce deterioration in the function of the heart and the kidneys via multiple pathways. As a consequence, these reciprocal associations could result in a vicious cycle of deterioration that likely contributes to increased mortality. In this Review, we describe the evidence for a pathophysiological role of nonthyroidal illness in the cardiorenal syndrome. We also discuss the available data from studies that have investigated the efficacy of thyroid hormone replacement therapy in patients with renal failure and the rationale for interventional trials to examine the effects of normalization of the thyroid hormone profile in patients with renal failure and congestive heart failure.
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Affiliation(s)
- Christiaan L Meuwese
- Department of Clinical Epidemiology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, Netherlands
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Mansourian AR. A literature review on the adverse effects of hypothyroidism on kidney function. Pak J Biol Sci 2012; 15:709-719. [PMID: 24171256 DOI: 10.3923/pjbs.2012.709.719] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Abstract
Thyroid produce two important hormone of thyroxine or tetraidothyronine (T4) and triidothyronine (T3), which are involved in whole aspect of metabolism. T4 and T3 play vital role in all biochemical function, growth and development in human body. The basic metabolic pathways in kidney and every organ in human controlled by these hormones. T4 and T3 are involved in kidney function in health and diseases condition therefore the pathophysiology of kidney can be directly influenced and regulated by thyroid hormones. Kidney growth, haemodynamic, blood circulation, tubular, electrolyte balance and glomerular filtration rate (GFR) are among such crucial process. Hypothyroidism which accompanied with reduced thyroid hormone production adversely affect the renal functions, development and eventually leading to reduced weight, kidney vascular disorders, electrolyte, tubular transport imbalances, lower filtration rate and other adverse consequences of hypothyroidism. On other hand kidney diseases can also disrupt the thyroid function metabolism resulting in the subsequent hypothyroidism. It is an interesting subject in how thyroid and kidney in health and diseases closely interacted. For the ideal clinical follow up of either of thyroid and renal diseases the two organs should be simultaneously examined for a proper patient management. Close correlation of thyroid and kidney clinical teams are essential to check the cross reactions and adverse interactions which might be produced between these two vital organs to avoid misdiagnosis either of thyroid or kidney abnormalities.
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Affiliation(s)
- Azad Reza Mansourian
- Department of Biochemistry, Metabolic Disorders Research Center, Gorgan Medical School, Golestan University of Medical Sciences, Gorgan, Iran
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Schrier RW. The Science Behind Hyponatremia and Its Clinical Manifestations. Pharmacotherapy 2011; 31:9S-17S. [DOI: 10.1592/phco.31.5.9s] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Abstract
Urea transport proteins were initially proposed to exist in the kidney in the late 1980s when studies of urea permeability revealed values in excess of those predicted by simple lipid-phase diffusion and paracellular transport. Less than a decade later, the first urea transporter was cloned. Currently, the SLC14A family of urea transporters contains two major subgroups: SLC14A1, the UT-B urea transporter originally isolated from erythrocytes; and SLC14A2, the UT-A group with six distinct isoforms described to date. In the kidney, UT-A1 and UT-A3 are found in the inner medullary collecting duct; UT-A2 is located in the thin descending limb, and UT-B is located primarily in the descending vasa recta; all are glycoproteins. These transporters are crucial to the kidney's ability to concentrate urine. UT-A1 and UT-A3 are acutely regulated by vasopressin. UT-A1 has also been shown to be regulated by hypertonicity, angiotensin II, and oxytocin. Acute regulation of these transporters is through phosphorylation. Both UT-A1 and UT-A3 rapidly accumulate in the plasma membrane in response to stimulation by vasopressin or hypertonicity. Long-term regulation involves altering protein abundance in response to changes in hydration status, low protein diets, adrenal steroids, sustained diuresis, or antidiuresis. Urea transporters have been studied using animal models of disease including diabetes mellitus, lithium intoxication, hypertension, and nephrotoxic drug responses. Exciting new animal models are being developed to study these transporters and search for active urea transporters. Here we introduce urea and describe the current knowledge of the urea transporter proteins, their regulation, and their role in the kidney.
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Affiliation(s)
- Janet D Klein
- Renal Division, Department of Medicine, Emory University, Atlanta, Georgia, USA
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Aydin L, Mogulkoc R, Baltaci AK. Influences of hypertonic and hypovolemic treatments on vasopressin response in propylthiouracil (PTU) induced hypothyroid rat and effect on supplementation with L-thyroxine. ACTA BIOLOGICA HUNGARICA 2010; 61:1-9. [PMID: 20194094 DOI: 10.1556/abiol.61.2010.1.1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
This study was performed to investigate the effects of L-thyroxine treatment on plasma vasopressin (AVP) levels in rats with hypothyroidism induced by propylthiouracil (PTU). Animals were separated into three groups each having 6 rats: control, PTU, PTU+L-thyroxine groups. Then, the groups were further divided into 3 sub-groups including 6 rats (a; basal, b; hypertonic stimulated and c; hypovolemic stimulated). At the end of the experiments all rats were decapitated in order to obtain plasma samples for analysis in terms of Hct, osmolality, TT 3 , TT 4 and vasopressin. Haematocrit (Hct) levels were the highest in hypovolemic stimulated sub-group (P < 0.001). Osmolality levels were higher in hypertonic stimulated sub-groups (P < 0.001). Total T 3 and T 4 values were the lowest in the PTU group and the highest in the L-thyroxine treated group (P < 0.001). Plasma AVP levels were reduced by hypothyroidism. However, L-thyroxine treatment after the hypothyroidism prevented this reduction (P < 0.001). Vasopressin responses to basal, hypovolemic and hypertonic stimulations were the lowest in the PTU group (P < 0.001). The results of the present study show that basal and stimulated plasma vasopressin levels are reduced in PTU-induced hypothyroidism. However, L-thyroxine treatment following hypothyroidism prevents this reduction.
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Affiliation(s)
- Leyla Aydin
- Department of Physiology, Meram Medical School, Selcuk University, Konya, Turkey
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van Hoek I, Daminet S. Interactions between thyroid and kidney function in pathological conditions of these organ systems: a review. Gen Comp Endocrinol 2009; 160:205-15. [PMID: 19133263 DOI: 10.1016/j.ygcen.2008.12.008] [Citation(s) in RCA: 70] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2008] [Revised: 12/02/2008] [Accepted: 12/03/2008] [Indexed: 11/25/2022]
Abstract
Thyroidal status affects kidney function already in the embryonic stage. Thyroid hormones influence general tissue growth as well as tubular functions, electrolyte handling and neural input. Hyper- and hypo-functioning of the thyroid influences mature kidney function indirectly by affecting the cardiovascular system and the renal blood flow, and directly by affecting glomerular filtration, electrolyte pumps, the secretory and absorptive capacity of the tubuli, and the structure of the kidney. Hyperthyroidism accelerates several physiologic processes, a fact which is reflected in the decreased systemic vascular resistance, increased cardiac output (CO), increased renal blood flow (RBF), hypertrophic and hyperplastic tubuli, and increased glomerular filtration rate (GFR). Renal failure can progress due to glomerulosclerosis, proteinuria and oxidative stress. Hypothyroidism has a more negative influence on kidney function. Peripheral vascular resistance is increased with intrarenal vasoconstriction, and CO is decreased, causing decreased RBF. The influence on the different tubular functions is modest, although the transport capacity is below normal. The GFR is decreased up to 40% in hypothyroid humans. Despite the negative influences on glomerular and tubular kidney function, a hypothyroid state has been described as beneficial in kidney disease. Kidney disease is associated with decreased thyroid hormone concentrations caused by central effects and by changes in peripheral hormone metabolism and thyroid hormone binding proteins. Geriatric cats form an animal model of disease because both hyperthyroidism and chronic kidney disease (CKD) have high prevalence among them, and the link between thyroid and kidney affects the evaluation of clinical wellbeing and the possible treatment options.
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Affiliation(s)
- Ingrid van Hoek
- Department of Medicine & Clinical Biology of Small Animals, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
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Schrier RW. Molecular mechanisms of clinical concentrating and diluting disorders. PROGRESS IN BRAIN RESEARCH 2008; 170:539-50. [PMID: 18655907 PMCID: PMC4319677 DOI: 10.1016/s0079-6123(08)00441-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Impaired urinary dilution leading to water retention and hyponatremia may occur in patients with cardiac failure, cirrhosis, pregnancy, hypothyroidism, glucocorticoid and mineralocorticoid deficiency. The mechanisms for these defects predominantly involve the non-osmotic stimulation of arginine vasopressin release with upregulation of aquaporin 2 water channel expression and trafficking to the apical membrane of the principal cells of the collecting duct. These perturbations are reversed by V2 vasopressin receptor antagonists. In contrast, urinary concentration defects leading to polyuria are vasopressin-resistant. They may involve several factors, such as impaired counter-current concentration secondary to downregulation of Na-K-2Cl co-transporter. Vasopressin-resistant downregulation of aquaporin 2 expression has also been described as a factor in impaired urinary concentration.
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Mohebbi N, Kovacikova J, Nowik M, Wagner CA. Thyroid hormone deficiency alters expression of acid-base transporters in rat kidney. Am J Physiol Renal Physiol 2007; 293:F416-27. [PMID: 17409279 DOI: 10.1152/ajprenal.00391.2006] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Hypothyroidism in humans is associated with incomplete distal renal tubular acidosis, presenting as the inability to respond appropriately to an acid challenge by excreting less acid. Here, we induced hypothyroidism in rats with methimazole (HYPO) and in one group substituted with l-thyroxine (EU). After 4 wk, acid-base status was similar in both groups. However, after 24 h acid loading with NH(4)Cl HYPO rats displayed a more pronounced metabolic acidosis. The expression of the Na(+)/H(+) exchanger NHE3, the Na(+)-phosphate cotransporter NaPi-IIa, and the B2 subunit of the vacuolar H(+)-ATPase was reduced in the brush-border membrane of the proximal tubule of the HYPO group, paralleled by a lower abundance of the Na(+)/HCO(3)(-) cotransporter NBCe1 and a higher expression of the acid-secretory type A intercalated cell-specific Cl(-)/HCO(3)(-) exchanger AE1. In contrast to control conditions, the expression of NBCe1 was increased in the HYPO group during metabolic acidosis. In addition, net acid excretion was similar in both groups. The relative number of type A intercalated cells was increased in the connecting tubule and cortical collecting duct of the HYPO group during acidosis. Thus thyroid hormones modulate the renal response to an acid challenge and alter the expression of several key acid-base transporters. Mild hypothyroidism is associated only with a very mild defect in renal acid handling, which appears to be mainly located in the proximal tubule and is compensated by the distal nephron.
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Affiliation(s)
- Nilufar Mohebbi
- Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
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Schrier RW. Body water homeostasis: clinical disorders of urinary dilution and concentration. J Am Soc Nephrol 2006; 17:1820-32. [PMID: 16738014 DOI: 10.1681/asn.2006030240] [Citation(s) in RCA: 137] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Affiliation(s)
- Robert W Schrier
- Department of Medicine, University of Colorado School of Medicine, Denver, CO 80262, USA.
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Affiliation(s)
- Fred G Silva
- The United States and Canadian Academy of Pathology, Emory University and the Medical college of Georgia, Augusta, GA 30909, USA.
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Chen YC, Cadnapaphornchai MA, Yang J, Summer SN, Falk S, Li C, Wang W, Schrier RW. Nonosmotic release of vasopressin and renal aquaporins in impaired urinary dilution in hypothyroidism. Am J Physiol Renal Physiol 2005; 289:F672-8. [PMID: 15914774 DOI: 10.1152/ajprenal.00384.2004] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The purpose of this study was to examine protein expression of renal aquaporins (AQP) and ion transporters in hypothyroid (HT) rats in response to an oral water load compared with controls (CTL) and HT rats replaced with l-thyroxine (HT+T). Hypothyroidism was induced by aminotriazole administration for 10 wk. Body weight, water intake, urine output, solute and urea excretion, and serum and urine osmolality were comparable among the three groups at the conclusion of the 10-wk treatment period. One hour after oral gavage of water (50 ml/kg body wt), HT rats demonstrated significantly less water excretion, higher minimal urinary osmolality, and decreased serum osmolality compared with CTL and HT+T rats. Despite the hyposmolality, plasma vasopressin concentration was elevated in HT rats. These findings in HT rats were associated with an increase in protein abundance of renal cortex AQP1 and inner medulla AQP2. AQP3, AQP4, and the Na-K-2Cl cotransporter were also increased. Moreover, 1 h following the oral water load, HT rats demonstrated a significant increase in the membrane-to-vesicle fraction of AQP2 by Western blot analysis. The defect in urinary dilution in HT rats was reversed by the V2vasopressin antagonist OPC-31260. In conclusion, impaired urinary dilution in HT rats is primarily compatible with the nonosmotic release of vasopressin and increased protein expression of renal AQP2. The impairment of maximal solute-free water excretion in HT rats, however, appears also to involve diminished distal fluid delivery.
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Affiliation(s)
- Yung-Chang Chen
- Univ. of Colorado School of Medicine, 4200 E. Ninth Ave., Box C293, Denver, CO 80262, USA
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Abstract
Following the discovery of the aquaporin-1 water channel over a decade ago, molecular techniques have been developed to examine the role of renal aquaporin water channels under numerous physiological and pathological conditions. The present article reviews current knowledge regarding the function and dysfunction of renal aquaporins in disorders of water metabolism.
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Affiliation(s)
- Yung-Chang Chen
- Department of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262, USA
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Chen YC, Cadnapaphornchai MA, Summer SN, Falk S, Li C, Wang W, Schrier RW. Molecular Mechanisms of Impaired Urinary Concentrating Ability in Glucocorticoid-Deficient Rats. J Am Soc Nephrol 2005; 16:2864-71. [PMID: 16107579 DOI: 10.1681/asn.2004110944] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
The purpose of this study was to examine urinary concentrating ability and protein expression of renal aquaporins and ion transporters in glucocorticoid-deficient (GD) rats in response to water deprivation as compared with control rats. Rats underwent bilateral adrenalectomies, followed only by aldosterone replacement (GD) or both aldosterone and dexamethasone replacement (control). As compared with control rats, the GD rats demonstrated a decrease in cardiac output and mean arterial pressure. In response to 36-h water deprivation, GD rats demonstrated significantly greater urine flow rate and decreased urine osmolality as compared with control rats at comparable serum osmolality and plasma vasopressin concentrations. The initiator of the countercurrent concentrating mechanism, the sodium-potassium-2 chloride co-transporter, was significantly decreased, as was the medullary osmolality in the GD rats versus control rats. There was also a decrease in inner medulla aquaporin-2 (AQP2) and urea transporter A1 (UT-A1) in GD rats as compared with control rats. There was a decrease in outer medulla Gsalpha protein, an important factor in vasopressin-mediated regulation of AQP2. Immunohistochemistry studies confirmed the decreased expression of AQP2 and UT-A1 in kidneys of GD rats as compared with control. In summary, impairment in the urinary concentrating mechanism was documented in GD rats in association with impaired countercurrent multiplication, diminished osmotic equilibration via AQP2, and diminished urea equilibration via UT-A1. These events occurred primarily in the relatively oxygen-deficient medulla and may have been initiated, at least in part, by the decrease in mean arterial pressure and thus renal perfusion pressure in this area of the kidney.
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Affiliation(s)
- Yung-Chang Chen
- Division of Renal Diseases and Hypertension, University of Colorado Health Sciences Center, 4200 East 9th Avenue, Box B173, Denver, CO 80262, USA
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Schuurs TA, Gerbens F, van der Hoeven JAB, Ottens PJ, Kooi KA, Leuvenink HGD, Hofstra RMW, Ploeg RJ. Distinct transcriptional changes in donor kidneys upon brain death induction in rats: insights in the processes of brain death. Am J Transplant 2004; 4:1972-81. [PMID: 15575899 DOI: 10.1111/j.1600-6143.2004.00607.x] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Brain death affects hormone regulation, inflammatory reactivity and hemodynamic stability. In transplant models, donor organs retrieved from brain dead (BD) rats suffer from increased rates of primary non-function and lower graft survival. To unravel the mechanisms behind brain death we have performed DNA microarray studies with kidney-derived RNA from normo- and hypotensive BD rats, corresponding with optimal and marginal BD donors, respectively. In kidneys from normotensive donors 63 genes were identified as either up- (55) or down-regulated (8), while 90 genes were differentially expressed (67 up-regulated) in hypotensive BD donor kidneys. Most genes were categorized in different functional groups: metabolism/transport (including the down-regulated water channel Aqp-2), inflammation/coagulation (containing the largest number (16) of up-regulated genes including selectins, Il-6, alpha- and beta-fibrinogen), cell division/fibrosis (including KIM-1 involved in tubular regeneration) and defense/repair (with the cytoprotective genes HO-1, Hsp70, MnSOD2). Also, genes encoding transcription factors (including immediate early genes as Atf-3, Egr-1) and proteins involved in signal transduction (Pik3r1) were identified. Summarizing, the use of DNA microarrays has clarified parts of the process of brain death: Brain-death-induced effects ultimately lead, via activation of transcription factors and signal transduction cascades, to differential expression of different "effector" genes. Not only deleterious processes such as inflammation and fibrosis occur in brain dead donor kidneys but genes involved in protection and early repair processes are activated as well. These findings can be used to introduce specific cytoprotective interventions in the brain dead donor to better maintain or even increase organ viability.
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Affiliation(s)
- Theo A Schuurs
- Department of Surgery, University Hospital Groningen, Groningen, The Netherlands.
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Abstract
PURPOSE OF REVIEW Urea is transported across the kidney inner medullary collecting duct by urea-transporter proteins. Two urea-transporter genes have been cloned from humans and rodents: the UT-A (Slc14A2) gene encodes five protein and eight cDNA isoforms; the UT-B (Slc14A1) gene encodes a single isoform. In the past year, significant progress has been made in understanding the regulation of urea-transporter protein abundance in kidney, studies of genetically engineered mice that lack a urea transporter, identification of urea transporters outside of the kidney, cloning of urea transporters in nonmammalian species, and active urea transport in microorganisms. RECENT FINDINGS UT-A1 protein abundance is increased by 12 days of vasopressin, but not by 5 days. Analysis of the UT-A1 promoter suggests that vasopressin increases UT-A1 indirectly following a direct effect to increase the transcription of other genes, such as the Na(+)-K(+)-2Cl- cotransporter NKCC2/BSC1 and the aquaporin (AQP) 2 water channel, that begin to increase inner medullary osmolality. UT-A1 protein abundance is also increased by adrenalectomy, and is decreased by glucocorticoids or mineralocorticoids. However, each hormone works through its own receptor. Knockout mice that lack UT-A1 and UT-A3, or lack UT-B, have a urine-concentrating defect and a decrease in inner medullary interstitial urea content. SUMMARY Urea transporters play a critical role in the urine-concentrating mechanism. Their abundance is regulated by vasopressin, glucocorticoids, and mineralocorticoids. These regulatory mechanisms may be important in disease states such as diabetes because changes in urea-transporter abundance in diabetic rats require glucocorticoids and vasopressin.
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Affiliation(s)
- Jeff M Sands
- Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
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Jiang M, Yi X, Hsu S, Wang CY, Dong Z. Role of p53 in cisplatin-induced tubular cell apoptosis: dependence on p53 transcriptional activity. Am J Physiol Renal Physiol 2004; 287:F1140-7. [PMID: 15315938 DOI: 10.1152/ajprenal.00262.2004] [Citation(s) in RCA: 140] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Tubular damage by cisplatin leads to acute renal failure, which limits its use in cancer therapy. In tubular cells, a primary target for cisplatin is presumably the genomic DNA. However, the pathway relaying the signals of DNA damage to tubular cell death is unclear. In response to DNA damage, the tumor suppressor gene p53 is induced and is implicated in subsequent DNA repair and cell death by apoptosis. The current study was designed to examine the role of p53 in cisplatin-induced apoptosis in cultured rat kidney proximal tubular cells. Cisplatin at 20 microM induced apoptosis in approximately 70% of cells, which was partially suppressed by carbobenzoxy-Val-Ala-Asp-fluoromethyl ketone (VAD), a general caspase inhibitor. Of interest, cisplatin-induced apoptosis was also suppressed by pifithrin-alpha, a pharmacological inhibitor of p53. Cisplatin-induced caspase activation was completely inhibited by VAD, but only partially by pifithrin-alpha. Early during cisplatin treatment, p53 was phosphorylated and upregulated. The p53 activation was blocked by pifithrin-alpha, but not by VAD. Bcl-2 expression abolished cisplatin-induced apoptosis without blocking p53 phosphorylation or induction. The results suggest that p53 activation might be an early signal for apoptosis during cisplatin treatment. To further determine the role of p53, tubular cells were stably transfected with a dominant-negative mutant of p53 with diminished transcriptional activity. Expression of the mutant attenuated cisplatin-induced apoptosis and caspase activation. In conclusion, the results support an important role for p53 in cisplatin-induced apoptosis in renal tubular cells. p53 May regulate apoptosis through the transcription of apoptotic genes.
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Affiliation(s)
- Man Jiang
- Department of Cellular Biology and Anatomy, Medical College of Georgia, 1459 Laney Walker Blvd., Augusta, GA 30912, USA
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Chen YC, Ginès P, Yang J, Summer SN, Falk S, Russell NS, Schrier RW. Increased vascular heme oxygenase-1 expression contributes to arterial vasodilation in experimental cirrhosis in rats. Hepatology 2004; 39:1075-87. [PMID: 15057912 DOI: 10.1002/hep.20151] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Vascular heme oxygenase (HO) regulates vascular tone in normal conditions and in some pathologic circumstances (e.g., sepsis). However, its possible role in the pathogenesis of arterial vasodilation in cirrhosis is unknown. To address this question, the expression and activity of HO in arterial vessels was studied in rats at 1, 2, and 4 weeks after bile duct ligation (BDL) or sham operation. A progressively increased expression of HO-1 was found in aorta and mesenteric arteries of BDL rats in a close chronologic relationship with the progression from acute cholestatic liver injury (1 week) to the fully developed cirrhosis with intense systemic arterial vasodilation (4 weeks). No changes were found in the expression of the constitutive isoform HO-2. HO-1 was mainly located in vascular smooth muscle cells of the arterial wall. Aortic HO activity increased in parallel with the expression of HO-1 (up to 600% in rats with cirrhosis compared with sham rats) and correlated with hemodynamic parameters. Increased expression of HO-1 and HO activity were also found in other organs, such as liver and spleen, though to a lesser extent compared with vascular tissue. The acute administration of an inhibitor of HO to cirrhotic rats, at a dose that normalized aortic HO activity, was associated with significantly greater effects on arterial pressure, total peripheral vascular resistance, and cardiac index, compared with effects in sham rats. In conclusion, these findings are consistent with a role for HO in the pathogenesis of arterial vasodilation in cirrhosis.
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Affiliation(s)
- Yung-Chang Chen
- Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado, USA
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