Search

Contains fulltext : 177624.pdf (Publisher’s version ) (Closed access) Lithium is the mainstay treatment for patients with bipolar disorder, but it generally causes nephrogenic diabetes insipidus (NDI), a disorder in which the renal urine concentrating ability has become vasopressin insensitive. Li-NDI is caused by lithium uptake by collecting duct principal cells and downregulation of aquaporin-2 (AQP2) water channels, which are essential for water uptake from tubular urine. Recently, we found that the prophylactic administration of acetazolamide to mice effectively attenuated Li-NDI. To evaluate whether acetazolamide might benefit lithium-treated patients, we administered acetazolamide to mice with established Li-NDI and six patients with a lithium-induced urinary concentrating defect. In mice, acetazolamide partially reversed lithium-induced polyuria and increased urine osmolality, which, however, did not coincide with increased AQP2 abundances. In patients, acetazolamide led to the withdrawal of two patients from the study due to side effects. In the four remaining patients acetazolamide did not lead to clinically relevant changes in maximal urine osmolality. Urine output was also not affected, although none of these patients demonstrated overt lithium-induced polyuria. In three out of four patients, acetazolamide treatment increased serum creatinine levels, indicating a decreased glomerular filtration rate (GFR). Strikingly, these three patients also showed a decrease in systemic blood pressure. All together, our data reveal that acetazolamide does not improve the urinary concentrating defect caused by lithium, but it lowers the GFR, likely explaining the reduced urine output in our mice and in a recently reported patient with lithium-induced polyuria. The reduced GFR in patients prone to chronic kidney disease development, however, warrants against application of acetazolamide in Li-NDI patients without long-term (pre)clinical studies.

Contains fulltext : 138192.pdf (Publisher’s version ) (Closed access) Lithium is the most common cause of nephrogenic diabetes insipidus (Li-NDI). Hydrochlorothiazide (HCTZ) combined with amiloride is the mainstay treatment in Li-NDI. The paradoxical antidiuretic action of HCTZ in Li-NDI is generally attributed to increased sodium and water uptake in proximal tubules as a compensation for increased volume loss due to HCTZ inhibition of the Na-Cl cotransporter (NCC), but alternative actions for HCTZ have been suggested. Here, we investigated whether HCTZ exerted an NCC-independent effect in Li-NDI. In polarized mouse cortical collecting duct (mpkCCD) cells, HCTZ treatment attenuated the Li-induced downregulation of aquaporin-2 (AQP2) water channel abundance. In these cells, amiloride reduces cellular Li influx through the epithelial sodium channel (ENaC). HCTZ also reduced Li influx, but to a lower extent. HCTZ increased AQP2 abundance on top of that of amiloride and did not affect the ENaC-mediated transcellular voltage. MpkCCD cells did not express NCC mRNA or protein. These data indicated that in mpkCCD cells, HCTZ attenuated lithium-induced downregulation of AQP2 independently of NCC and ENaC. Treatment of Li-NDI NCC knockout mice with HCTZ revealed a significantly reduced urine volume, unchanged urine osmolality, and increased cortical AQP2 abundance compared with Li-treated NCC knockout mice. HCTZ treatment further resulted in reduced blood Li levels, creatinine clearance, and alkalinized urinary pH. Our in vitro and in vivo data indicate that part of the antidiuretic effect of HCTZ in Li-NDI is NCC independent and may involve a tubuloglomerular feedback response-mediated reduction in glomerular filtration rate due to proximal tubular carbonic anhydrase inhibition.

Contains fulltext : 125312.pdf (Publisher’s version ) (Closed access) Binding of vasopressin to its type 2 receptor in renal collecting ducts induces cAMP signaling, transcription and translocation of aquaporin (AQP)2 water channels to the plasma membrane, and water reabsorption from the prourine. Demeclocycline is currently used to treat hyponatremia in patients with the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Demeclocycline's mechanism of action, which is poorly understood, is studied here. In mouse cortical collecting duct (mpkCCD) cells, which exhibit deamino-8-d-arginine vasopressin (dDAVP)-dependent expression of endogenous AQP2, demeclocycline decreased AQP2 abundance and gene transcription but not its protein stability. Demeclocycline did not affect vasopressin type 2 receptor localization but decreased dDAVP-induced cAMP generation and the abundance of adenylate cyclase 3 and 5/6. The addition of exogenous cAMP partially corrected the demeclocycline effect. As in patients, demeclocycline increased urine volume, decreased urine osmolality, and reverted hyponatremia in an SIADH rat model. AQP2 and adenylate cyclase 5/6 abundances were reduced in the inner medulla but increased in the cortex and outer medulla, in the absence of any sign of toxicity. In conclusion, our in vitro and in vivo data indicate that demeclocycline mainly attenuates hyponatremia in SIADH by reducing adenylate cyclase 5/6 expression and, consequently, cAMP generation, AQP2 gene transcription, and AQP2 abundance in the renal inner medulla, coinciding with a reduced vasopressin escape response in other collecting duct segments.

Contains fulltext : 172732.pdf (Publisher’s version ) (Closed access) To reduce lithium-induced nephrogenic diabetes insipidus (lithium-NDI), patients with bipolar disorder are treated with thiazide and amiloride, which are thought to induce antidiuresis by a compensatory increase in prourine uptake in proximal tubules. However, thiazides induced antidiuresis and alkalinized the urine in lithium-NDI mice lacking the sodium-chloride cotransporter, suggesting that inhibition of carbonic anhydrases (CAs) confers the beneficial thiazide effect. Therefore, we tested the effect of the CA-specific blocker acetazolamide in lithium-NDI. In collecting duct (mpkCCD) cells, acetazolamide reduced the cellular lithium content and attenuated lithium-induced downregulation of aquaporin-2 through a mechanism different from that of amiloride. Treatment of lithium-NDI mice with acetazolamide or thiazide/amiloride induced similar antidiuresis and increased urine osmolality and aquaporin-2 abundance. Thiazide/amiloride-treated mice showed hyponatremia, hyperkalemia, hypercalcemia, metabolic acidosis, and increased serum lithium concentrations, adverse effects previously observed in patients but not in acetazolamide-treated mice in this study. Furthermore, acetazolamide treatment reduced inulin clearance and cortical expression of sodium/hydrogen exchanger 3 and attenuated the increased expression of urinary PGE2 observed in lithium-NDI mice. These results show that the antidiuresis with acetazolamide was partially caused by a tubular-glomerular feedback response and reduced GFR. The tubular-glomerular feedback response and/or direct effect on collecting duct principal or intercalated cells may underlie the reduced urinary PGE2 levels with acetazolamide, thereby contributing to the attenuation of lithium-NDI. In conclusion, CA activity contributes to lithium-NDI development, and acetazolamide attenuates lithium-NDI development in mice similar to thiazide/amiloride but with fewer adverse effects. 01 juli 2016

Lithium causes nephrogenic diabetes insipidus (Li-NDI) and hydrochlorothiazide (HCTZ) forms, together with amiloride, the mainstay treatment for Li-NDI patients. Earlier, we found that HCTZ, primar...

Contains fulltext : 96456.pdf (Publisher’s version ) (Closed access) Maintenance of the osmobalance is important for life. In this process, in which brain and kidney act in concert, mammals have to cope with significant deviations as drinking water reduces plasma osmolality, whereas salty food increases it. To restore homeostasis, specialized nuclei within the hypothalamus play a pivotal role in detecting changes in plasma osmolality and initiating appropriate responses. These responses are accomplished by either changing the intake of water or the excretion of water by the kidney. In the past decade, several novel findings have made significant contributions to our insights in the process of systemic osmoregulation. Novel proteins have been identified in the brain as well as in the kidney that are fulfilling important roles in the process of systemic osmoregulation. In this review, recent evidence of the involvement of TRPV channels (TRPV1, TRPV2, and TRPV4) and proteins, such as sodium channels NALCN and Na(x), in neuronal osmoregulation, as well as; e.g., the purinergic P2Y2 receptor in renal osmoregulation, are discussed, and integrated with existing knowledge of systemic osmoregulation.

Item does not contain fulltext Astrocyte swelling and brain edema are major neuropathological findings in the acute form of hepatic encephalopathy (fulminant hepatic failure), and substantial evidence supports the view that elevated brain ammonia level is an important etiological factor in this condition. Although the mechanism by which ammonia brings about astrocyte swelling remains to be determined, oxidative/nitrosative stress and mitogen-activated protein kinases (MAPKs) have been considered as important elements in this process. One factor known to be activated by both oxidative stress and MAPKs is nuclear factor kappaB (NFkappaB), a transcription factor that activates many genes, including inducible nitric oxide synthase (iNOS). As the product of iNOS, nitric oxide (NO), is known to cause astrocyte swelling, we examined the potential involvement of NFkappaB in ammonia-induced astrocyte swelling. Western blot analysis of cultured astrocytes showed a significant increase in NFkappaB nuclear translocation (a measure of NFkappaB activation) from 12 h to 2 days after treatment with NH(4)Cl (5 mM). Cultures treated with anti-oxidants, including superoxide dismutase, catalase, and vitamin E as well as the MAPKs inhibitors, SB239063 (an inhibitor of p38-MAPK) and SP600125 (an inhibitor of c-Jun N-terminal kinase), significantly diminished NFkappaB activation by ammonia, supporting a role of oxidative stress and MAPKs in NFkappaB activation. The activation of NFkappaB was associated with increased iNOS protein expression and NO generation, and these changes were blocked by BAY 11-7082, an inhibitor of NFkappaB. Additionally, ammonia-induced astrocyte swelling was inhibited by the NFkappaB inhibitors, BAY 11-7082 and SN-50, thereby implicating NFkappaB in the mechanism of astrocyte swelling. Our studies indicate that cultured astrocytes exposed to ammonia display NFkappaB activation, which is likely to be a consequence of oxidative stress and activation of MAPKs. NFkappaB activation appears to contribute to the mechanism of ammonia-induced astrocyte swelling, apparently through its up-regulation of iNOS protein expression and the subsequent generation of NO.