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Low-salt diet and cyclosporine nephrotoxicity: changes in kidney cell metabolism.

ABSTRACT: Cyclosporine (CsA) is a highly effective immunosuppressant used in patients after transplantation; however, its use is limited by nephrotoxicity. Salt depletion is known to enhance CsA-induced nephrotoxicity in the rat, but the underlying molecular mechanisms are not completely understood. The goal of our study was to identify the molecular effects of salt depletion alone and in combination with CsA on the kidney using a proteo-metabolomic strategy. Rats (n = 6) were assigned to four study groups: (1) normal controls, (2) low-salt fed controls, (3) 10 mg/kg/d CsA for 28 days on a normal diet, (4) 10 mg/kg/d CsA for 28 days on low-salt diet. Low-salt diet redirected kidney energy metabolism toward mitochondria as indicated by a higher energy charge than in normal-fed controls. Low-salt diet alone reduced phospho-AKT and phospho-STAT3 levels and changed the expression of ion transporters PDZK1 and CLIC1. CsA induced macro- and microvesicular tubular epithelial vacuolization and reduced energy charge, changes that were more significant in low-salt fed animals, probably because of their more pronounced dependence on mitochondria. Here, CsA increased phospho-JAK2 and phospho-STAT3 levels and reduced the phospho-IKK? and p65 proteins, thus activating NF-?B signaling. Decreased expression of lactate transport regulator CD147 and phospho-AKT was also observed after CsA exposure in low-salt rats, indicating a decrease in glycolysis. In summary, our study suggests a key role for PDZK1, CD147, JAK/STAT, and AKT signaling in CsA-induced nephrotoxicity and proposes mechanistic explanations on why rats fed a low-salt diet have higher sensitivity to CsA.

SUBMITTER: Klawitter J

PROVIDER: S-EPMC3831655 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Low-salt diet and cyclosporine nephrotoxicity: changes in kidney cell metabolism.

Klawitter Jelena J Klawitter Jost J Schmitz Volker V Brunner Nina N Crunk Amanda A Corby Kyler K Bendrick-Peart Jamie J Leibfritz Dieter D Edelstein Charles L CL Thurman Joshua M JM Christians Uwe U

Journal of proteome research 20121011 11

Cyclosporine (CsA) is a highly effective immunosuppressant used in patients after transplantation; however, its use is limited by nephrotoxicity. Salt depletion is known to enhance CsA-induced nephrotoxicity in the rat, but the underlying molecular mechanisms are not completely understood. The goal of our study was to identify the molecular effects of salt depletion alone and in combination with CsA on the kidney using a proteo-metabolomic strategy. Rats (n = 6) were assigned to four study group ...[more]

PMID: 23057591

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Project description:ObjectiveThe benefits of a low-salt diet for patients with chronic kidney disease (CKD) are controversial. We conducted a systematic review and meta-analysis of the effect of a low-salt diet on major clinical outcomes.DesignSystematic review and meta-analysis.Data sourcesMEDLINE by Ovid, EMBASE and the Cochrane Library databases.Eligibility criteria for selecting studiesWe included randomised controlled trials (RCTs) and cohort studies that assessed the effect of a low-salt diet on the renal composite outcomes (more than 50% decline in estimated glomerular filtration rate (eGFR) during follow-up, doubling of serum creatinine or end-stage renal disease), rate of eGFR decline, change in proteinuria, all-cause mortality events, cardiovascular (CV) events, and changes in systolic blood pressure and diastolic blood pressure.Data extraction and synthesisTwo independent researchers extracted data and evaluated their quality. Relative risks (RRs) with 95% CIs were used for dichotomous data. Differences in means (MDs) or standardised mean differences (SMDs) with 95% CIs were used to pool continuous data. We used the Cochrane Collaboration risk-of-bias tool to evaluate the quality of RCTs, and Newcastle-Ottawa Scale to evaluate the quality of cohort studies.ResultsWe found 9948 potential research records. After removing duplicates, we reviewed the titles and abstracts, and screened the full text of 230 publications. Thirty-three studies with 101 077 participants were included. A low-salt diet produced a 28% reduction in renal composite outcome events (RR: 0.72; 95% CI: 0.58 to 0.89). No significant effects were found in terms of changes in proteinuria (SMD: -0.71; 95% CI: -1.66 to 0.24), rate of eGFR (decline MD: 1.16; 95% CI: -2.02 to 4.33), risk of all-cause mortality (RR: 0.92; 95% CI: 0.58 to 1.46) and CV events (RR: 1.01; 95% CI: 0.46 to 2.22).ConclusionA low-salt diet seems to reduce the risk for renal composite outcome events in patients with CKD. However, no compelling evidence indicated that such a diet would reduce the eGFR decline rate, proteinuria, incidence of all-cause mortality and CV events. Further, more definitive studies are needed.Prospero registration numberCRD42017072395.

Project description:Calcineurin inhibitors are powerful immunosuppressants that revolutionized organ transplantation. However, non-immune effects of the calcineurin inhibitor, such as cyclosporine A (CsA), have significantly hindered their use. Specifically, nephrotoxicity, which is associated with tubulointerstitial fibrosis, inflammation, and podocyte damage, affects up to half of all transplant patients. Calcineurin is involved in many aspects of kidney development and function; therefore, mechanisms of CsA-induced nephrotoxicity are complex and not yet fully understood. MicroRNAs are short non-coding RNAs that regulate protein-coding RNA expression through post-translational repression of target messenger RNAs. MicroRNA dysregulation is known to be involved in kidney diseases including fibrosis. In this study, we compared the renal microRNA expression profiles between mice that received CsA (20 mg/kg) or vehicle daily for six weeks. The results demonstrate that CsA induces significant changes in renal microRNA expression profile. We used combined criteria of False Discovery Rate (≤0.1), fold change (≥2) and median signal strength (≥50) and identified 76 differencially expressed microRNAs. This approach identified microRNAs previously linked to renal fibrosis that includes let-7d, miR-21, miR-29, miR-30, miR-130, miR-192, and miR-200 as well as microRNAs that have not been reported to be related to nephrotoxicity or immunosuppression. Pathway analysis of microRNA/mRNA changes highlights the Wnt, TGF-β, mTOR, and VEGF pathways. The mRNA expression profiles were compared in the same samples. The change of mRNA and microRNA profiles showed close correlations. To validate that the observed microRNA and mRNA expression level changes in mice kidney tissue were directly related to CsA treatment, the expression change induced by CsA treatment of three microRNAs (miR-21, miR-186, and miR-709) and three mRNAs (BMPR1a, SMURF1 and SMAD7) were compared in HEK293 cell line. A similar trend of expression level change was induced by CsA treatment in all selected microRNAs and mRNAs in the in vitro cell model. These data provide a roadmap for future work to study the role of the known and novel candidate microRNAs in the mechanism of nephrotoxicity and their further therapeutic potential.

Project description:BACKGROUND:Kidney stone disease is common in industrialized countries. Recently, it has attracted growing attention, because of its significant association with adverse renal outcomes, including end stage renal disease. Calcium-containing kidney stones are frequent with high recurrence rates. While hypercalciuria is a well-known risk factor, restricted intake of animal protein and sodium, combined with normal dietary calcium, has been shown to be more effective in stone prevention compared with a low-calcium diet. Notably, the average sodium intake in Switzerland is twice as high as the WHO recommendation, while the intake of milk and dairy products is low. METHODS:We retrospectively analyzed Swiss recurrent kidney stone formers (rKSF) to test the impact of a low-sodium in combination with a low-calcium diet on the urinary risk profile. In patients with recurrent calcium oxalate containing stones, we investigated both, the consequence of a low-sodium diet on urinary volume and calcium excretion, and the influence of a low-sodium low-calcium diet on urinary oxalate excretion. RESULTS:Of the 169 patients with CaOx stones, 49 presented with hypercalciuria at baseline. The diet resulted in a highly significant reduction in 24-h urinary sodium and calcium excretion: from 201?±?89 at baseline to 128?±?88 mmol/d for sodium (p?<?0.0001), and from 5.67?±?3.01 to 4.06?±?2.46 mmol/d (p?<?0.0001) for calcium, respectively. Urine volume remained unchanged. Notably, no increase in oxalate excretion occurred on the restricted diet (0.39?±?0.26 vs 0.39?±?0.19 mmol/d, p?=?0.277). Calculated Psf (probability of stone formation) values were only predictive for the risk of calcium phosphate stones. CONCLUSION:A diet low in sodium and calcium in recurrent calcium oxalate stone formers resulted in a significant reduction of urinary calcium excretion, but no change in urine volume. In this population with apparently low intake of dairy products, calcium restriction does not necessarily result in increased urinary oxalate excretion. However, based on previous studies, we recommend a normal dietary calcium intake to avoid a potential increase in urinary oxalate excretion and unfavorable effects on bone metabolism in hypercalciuric KSFs.

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Low-salt diet and cyclosporine nephrotoxicity: changes in kidney cell metabolism.

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Low-salt diet and cyclosporine nephrotoxicity: changes in kidney cell metabolism.

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