Cyclosporine metabolic side effects: association with the WNK4 system

Melnikov, Semyon; Mayan, Haim; Uchida, Shinichi; Holtzman, Eliezer J.; Farfel, Zvi

doi:10.1111/j.1365-2362.2011.02517.x

Cited by 55 publications

(49 citation statements)

References 33 publications

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“…Although cyclosporine and tacrolimus have different intracellular binding proteins, they both activate NCC, and this effect therefore appears to be a class effect [45]. Again, cyclosporine and tacrolimus do not seem to activate NCC directly, but influence the WNKs [76]. This possibility was already suggested by the side-effect profile of these drugs, which is similar to the phenotype of FHHt.…”

Section: Drugs Stimulating Nccsupporting

confidence: 49%

“…To fully grasp the potential of these insights for the treatment of human disease will likely require a more complete understanding of the molecular physiology of this fascinating cotransporter. Footnote: ¶ When high dietary K increases aldosterone, NCC may be inhibited; * Some of these effects may be mediated through aldosterone; † In a model of cyclosporine nephrotoxicity , 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 23 NCC was downregulated, but this may be attributed to kidney failure and reduced reninangiotensin activity [76]. …”

Section: Perspectivesmentioning

confidence: 99%

“…Drugs stimulating NCC activity have also been identified recently and they include the calcineurin inhibitors cyclosporine and tacrolimus (Table 1) [44,76]. Calcineurin inhibitors are potent immunosuppressive drugs that are used clinically to prevent rejection after transplantation and sometimes in autoimmune disorders.…”

Section: Drugs Stimulating Nccmentioning

confidence: 99%

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The sodium chloride cotransporter SLC12A3: new roles in sodium, potassium, and blood pressure regulation

Moes

Lubbe

Zietse

et al. 2013

Pflugers Arch - Eur J Physiol

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SLC12A3 encodes the thiazide-sensitive sodium chloride cotransporter (NCC), which is primarily expressed in the kidney, but also in intestine and bone. In the kidney, NCC is located in the apical plasma membrane of epithelial cells in the distal convoluted tubule. Although NCC reabsorbs only 5 to 10 % of filtered sodium, it is important for the fine-tuning of renal sodium excretion in response to various hormonal and non-hormonal stimuli. Several new roles for NCC in the regulation of sodium, potassium, and blood pressure have been unraveled recently. For example, the recent discoveries that NCC is activated by angiotensin II but inhibited by dietary potassium shed light on how the kidney handles sodium during hypovolemia (high angiotensin II) and hyperkalemia. The additive effect of angiotensin II and aldosterone maximizes sodium reabsorption during hypovolemia, whereas the inhibitory effect of potassium on NCC increases delivery of sodium to the potassium-secreting portion of the nephron. In addition, great steps have been made in unraveling the molecular machinery that controls NCC. This complex network consists of kinases and ubiquitinases, including WNKs, SGK1, SPAK, Nedd4-2, Cullin-3, and Kelch-like 3. The pathophysiological significance of this network is illustrated by the fact that modification of each individual protein in the network changes NCC activity and results in salt-dependent hypotension or hypertension. This review aims to summarize these new insights in an integrated manner while identifying unanswered questions.

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Section: Drugs Stimulating Nccsupporting

confidence: 49%

Section: Perspectivesmentioning

confidence: 99%

See 1 more Smart Citation

The sodium chloride cotransporter SLC12A3: new roles in sodium, potassium, and blood pressure regulation

Moes

Lubbe

Zietse

et al. 2013

Pflugers Arch - Eur J Physiol

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show abstract

“…The administration of these drugs is associated with an increased hypertension rate and two groups have observed that tacrolimus (56) and cyclosporine (78) in rodents induce phosphorylation and activation of NCC, thus increasing salt reabsorption and hypertension. Inhibition of the phosphatase calcineurin and, thus, prevention of NCC dephosphorylation is the likely mechanism because elimination of the FKBP12-binding protein along the nephron precluded the hypertensive effect of this compound; this protein is required for the tacrolimus inhibition of calcineurin (65).…”

Section: F137 Slc12 Cotransporters In the Kidneymentioning

confidence: 99%

Physiological role of SLC12 family members in the kidney

Bazúa‐Valenti

Castañeda‐Bueno

Gamba

2016

American Journal of Physiology-Renal Physiology

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The solute carrier family 12, as numbered according to Human Genome Organisation (HUGO) nomenclature, encodes the electroneutral cation-coupled chloride cotransporters that are expressed in many cells and tissues; they play key roles in important physiological events, such as cell volume regulation, modulation of the intracellular chloride concentration, and transepithelial ion transport. Most of these family members are expressed in specific regions of the nephron. The Na-K-2Cl cotransporter NKCC2, which is located in the thick ascending limb, and the Na-Cl cotransporter, which is located in the distal convoluted tubule, play important roles in salt reabsorption and serve as the receptors for loop and thiazide diuretics, respectively (Thiazide diuretics are among the most commonly prescribed drugs in the world.). The activity of these transporters correlates with blood pressure levels; thus, their regulation has been a subject of intense research for more than a decade. The K-Cl cotransporters KCC1, KCC3, and KCC4 are expressed in several nephron segments, and their role in renal physiology is less understood but nevertheless important. Evidence suggests that they are involved in modulating proximal tubule glucose reabsorption, thick ascending limb salt reabsorption and collecting duct proton secretion. In this work, we present an overview of the physiological roles of these transporters in the kidney, with particular emphasis on the knowledge gained in the past few years.

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“…Cyclosporine is also known to cause a combination of metabolic side effects including hypertension, hyperkalemia, hypercalciuria and hypomagnesemia. To overcome the drawback it has been reported to minimize the dosage or to limit the duration of therapy [39,40]. The ability of CsA to increase nerve regeneration in vivo is reported to be dose-related the rat in systemic administration [18].…”

Section: Discussionmentioning

confidence: 99%

Peripheral Nerve Regeneration using Silicone Rubber Chamber Combined by Local Administration of Cyclosporin a in Streptozotocin Induced Diabetic Rats

Mohammadi¹

2015

Int J Oral Craniofac Sci

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Introduction: The repair of peripheral nerve injuries is still one of the most challenging tasks and concerns in neurosurgery. Effect of cyclosporin (CsA) loaded silicon conduit as an in situ delivery system of CsA in bridging the defects was studied using a sciatic nerve regeneration model in diabetic rats. Methods:A 10-mm sciatic nerve defect was bridged using a silicon conduit (SIL/CsA) filled with 10 µL carrier-drug dilution (10 ng/mL CsA). In control group (SIL), the conduit was filled with the same volume of the phosphate buffered solution. The regenerated fibers were studied 4, 8, 12 and 16 weeks after surgery. Result:The functional and electrophysiological studies confirmed faster recovery of the regenerated axons in CsA treated than control group (P < 0.05). The mean ratios of gastrocnemius muscles weight were measured. There was statistically significant difference between the muscle weight ratios of SIL/CsA and SIL groups (P<0.05). Morphometric indices of regenerated fibers showed number and diameter of the myelinated fibers in SIL/CsA were significantly higher than in control group. Conclusion:Cyclosporin when loaded in a silicon conduit resulted in improvement of functional recovery and quantitative morphometric indices of sciatic nerve in diabetic rats.

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Cyclosporine metabolic side effects: association with the WNK4 system

Abstract: These observations may explain in part the mechanism of cyclosporine-induced hypertension, hyperkalemia and hypercalciuria.

Cited by 55 publications

References 33 publications

The sodium chloride cotransporter SLC12A3: new roles in sodium, potassium, and blood pressure regulation

The sodium chloride cotransporter SLC12A3: new roles in sodium, potassium, and blood pressure regulation

Physiological role of SLC12 family members in the kidney

Peripheral Nerve Regeneration using Silicone Rubber Chamber Combined by Local Administration of Cyclosporin a in Streptozotocin Induced Diabetic Rats

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