PMID- 26175142 OWN - NLM STAT- MEDLINE DCOM- 20160414 LR - 20220331 IS - 1460-2385 (Electronic) IS - 0931-0509 (Linking) VI - 30 IP - 10 DP - 2015 Oct TI - Role of the endogenous nitric oxide inhibitor asymmetric dimethylarginine (ADMA) and brain-derived neurotrophic factor (BDNF) in depression and behavioural changes: clinical and preclinical data in chronic kidney disease. PG - 1699-705 LID - 10.1093/ndt/gfv253 [doi] AB - BACKGROUND: Patients with chronic kidney disease (CKD) exhibit a high prevalence of neuropsychiatric alterations, including depression and behavioural changes. CKD is also associated with decreased physical activity not fully explained by co-morbidities. In patients without CKD, the brain-derived neurotropic factor (BDNF) as well as the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA) had been suspected to be involved in major depression. The aim of our study was to examine the role of ADMA and BDNF in the behaviour of haemodialysis patients (CKD5D) as well as in a rat model of 5/6 nephrectomy and chronic ADMA infusion alone. METHODS: Eleven (5F/6M) CKD5D patients underwent Beck Depression Inventory (BDI) testing along with analysis of ADMA and BDNF. Male Sprague-Dawley rats were randomly assigned to four groups: (i) saline infusion; (ii) ADMA (250 microg/kg/day) infusion via osmotic mini pumps; (iii) 5/6 nephrectomy; (iv) untreated controls. After 28 days, the animals underwent behavioural tests measuring anxiety, locomotion and investigative behaviour. Animals were sacrificed, blood samples were drawn and analysed and hippocampal immunohistology for BDNF was performed. RESULTS: In CKD5D patients, decreased BDNF levels correlated with higher scores of depression (Pearson r = -0.8156, P = 0.002). ADMA infusion led to a significant decrease of BDNF while the decrease of BDNF in 5/6 nephrectomy was not significant. However, an attenuated hippocampal BDNF expression could be detected in 5/6 nephrecomized animals. Decreased spontaneous locomotor activity was shown in ADMA-infused rats [15.9 (13.5-26.1) lines crossed/min] and 5/6 nephrectomy [14.6 (6.1-20.2) lines crossed/min] when compared with controls [32.5 (15.3-42.4) lines crossed/min]. Anxiety-like behaviour tested by hole investigation time was significantly more pronounced in 5/6 nephrectomy [24 (6-44) s] when compared with ADMA infusion [64 (28-93) s] and controls [33 (26-65) s]. CONCLUSIONS: Progressive renal failure in rats is accompanied by a marked increase of ADMA and a decrease in BDNF. 5/6 nephrectomy leads to significantly decreased exploratory behaviour and locomotion. Both behaviours could be reproduced by ADMA infusion alone. Indicators of anxiety were more pronounced in ADMA-infused animals when compared with 5/6 nephrectomized rats. Furthermore, an inverse relationship of BDNF and BDI in 11 CKD5D patients was shown. CI - (c) The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. FAU - Kielstein, Heike AU - Kielstein H AD - Department of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany. FAU - Suntharalingam, Mayuren AU - Suntharalingam M AD - Department of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany. FAU - Perthel, Ronny AU - Perthel R AD - Department of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany. FAU - Song, Rong AU - Song R AD - Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany. FAU - Schneider, Sabrina M AU - Schneider SM AD - Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany Department of Neurology, Philipps-University Marburg, Marburg, Germany. FAU - Martens-Lobenhoffer, Jens AU - Martens-Lobenhoffer J AD - Institute for Clinical Pharmacology, Otto-von-Guericke University, Magdeburg, Germany. FAU - Jager, Kristin AU - Jager K AD - Department of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany. FAU - Bode-Boger, Stefanie M AU - Bode-Boger SM AD - Institute for Clinical Pharmacology, Otto-von-Guericke University, Magdeburg, Germany. FAU - Kielstein, Jan T AU - Kielstein JT AD - Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150713 PL - England TA - Nephrol Dial Transplant JT - Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association JID - 8706402 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Enzyme Inhibitors) RN - 31C4KY9ESH (Nitric Oxide) RN - 63CV1GEK3Y (N,N-dimethylarginine) RN - 94ZLA3W45F (Arginine) RN - EC 1.14.13.39 (Nitric Oxide Synthase) SB - IM CIN - Nephrol Dial Transplant. 2015 Oct;30(10):1599-601. PMID: 26188339 MH - Animals MH - Arginine/*analogs & derivatives/physiology MH - Brain-Derived Neurotrophic Factor/*physiology MH - Cohort Studies MH - Cross-Sectional Studies MH - Depression/*blood/etiology/psychology MH - Depressive Disorder, Major/*blood/etiology/psychology MH - Enzyme Inhibitors/pharmacology MH - Enzyme-Linked Immunosorbent Assay MH - Female MH - Humans MH - Immunoenzyme Techniques MH - Male MH - Middle Aged MH - Nephrectomy MH - Nitric Oxide/*metabolism MH - Nitric Oxide Synthase/*antagonists & inhibitors MH - Problem Behavior MH - Rats MH - Rats, Sprague-Dawley MH - Renal Insufficiency, Chronic/*complications/psychology OTO - NOTNLM OT - ADMA OT - BDNF OT - behaviour OT - chronic kidney disease OT - depression EDAT- 2015/07/16 06:00 MHDA- 2016/04/15 06:00 CRDT- 2015/07/16 06:00 PHST- 2015/01/14 00:00 [received] PHST- 2015/05/21 00:00 [accepted] PHST- 2015/07/16 06:00 [entrez] PHST- 2015/07/16 06:00 [pubmed] PHST- 2016/04/15 06:00 [medline] AID - gfv253 [pii] AID - 10.1093/ndt/gfv253 [doi] PST - ppublish SO - Nephrol Dial Transplant. 2015 Oct;30(10):1699-705. doi: 10.1093/ndt/gfv253. Epub 2015 Jul 13.