Histopathological Study of Kidney Abnormalities in an Experimental SIADH Rat Model and Its Application to the Evaluation of the Pharmacologic Profile of VP-343, a Selective Vasopressin V2 Receptor Antagonist.

Naito, Akira; Higuchi, Hisashi; Kurasawa, Takashi; Ohtake, Yasuhiro; Matsukawa, Hiroaki; Ezure, Yohji; Koike, Kenichi; Shigenobu, Koki

doi:10.1248/bpb.24.897

Cited by 13 publications

(11 citation statements)

References 13 publications

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“…In agreement with results of others (30,44,45,60,73), our liquid diet/ dDAVP-treated control rats developed all the characteristics of SIADH. Due to increased AVP-mediated renal water uptake, they were hyponatremic (99 Ϯ 1 mM) and hypoosmotic (236 Ϯ 10 mosM), as untreated control rats held under similar conditions displayed plasma Na ϩ concentrations and osmolalities of 141 mmol/l and 283 mosM, respectively (32).…”

Section: Discussionsupporting

confidence: 93%

“…As anticipated based on previous studies (30,44,45,60,73), our control rats were hyponatremic and hypoosmotic [normal values: 141 Ϯ 1 and 283 Ϯ 5, respectively (32); Table 1]. Treatment with demeclocycline resulted in a significant reduction of hyponatremia and a nearly significant correction of the hypoosmolality (P ϭ 0.08).…”

Section: Effect Of Tetracycline Antibiotics On Aqp2 Abundance In Vitrosupporting

confidence: 78%

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Demeclocycline attenuates hyponatremia by reducing aquaporin-2 expression in the renal inner medulla

Kortenoeven

Sinke

Hadrup

et al. 2013

American Journal of Physiology-Renal Physiology

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Kortenoeven ML, Sinke AP, Hadrup N, Trimpert C, Wetzels JF, Fenton RA, Deen PM. Demeclocycline attenuates hyponatremia by reducing aquaporin-2 expression in the renal inner medulla. Am J Physiol Renal Physiol 305: F1705-F1718, 2013. First published October 23, 2013 doi:10.1152/ajprenal.00723.2012.-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. aquaporin 2; collecting duct; demeclocycline; syndrome of inappropriate antidiuretic hormone secretion; vasopressin THE KIDNEY is the main organ for the regulation of water homeostasis. In states of hypernatremia or hypovolemia, the hormone arginine vasopressin (AVP) is released from the pituitary and binds to the vasopressin type 2 receptor (V2R), which is expressed in the basolateral membrane of renal collecting duct principal cells (48). Activated V2R increases intracellular cAMP levels via G s protein and adenylate cyclase (AC), which eventually leads to the activation of PKA and subsequent phosphorylation of aquaporin (AQP)2 water channels (19,29). This results in the redistribution of AQP2 from intracellular vesicles to the apical membrane (19,29,46,72). Driven by the transcellular osmotic gradient, water enters principal cells through AQP2 and exits cells through AQP3 or AQP4, which are located in the basolateral membrane, resulting in concentrated urine. In addition, AVP also increases the expression of AQP2 via the phosphorylation of cAMP-responsive element-binding protein, which binds and activates transcription via a cAMP-responsive element in the A...

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Section: Discussionsupporting

confidence: 93%

Section: Effect Of Tetracycline Antibiotics On Aqp2 Abundance In Vitrosupporting

confidence: 78%

Demeclocycline attenuates hyponatremia by reducing aquaporin-2 expression in the renal inner medulla

Kortenoeven

Sinke

Hadrup

et al. 2013

American Journal of Physiology-Renal Physiology

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“…Vasopressin has been shown to increase intraglomerular capillary pressure and mesangial cell proliferation [22,23]. Administration of dDAVP (1-desamino-8-D arginine), a vasopressin V2 receptor agonist, caused deterioration of kidney function in vasopressin-deficient Brattleboro rats after 5/6 nephrectomy [24] and induced renal histopathological abnormalities in an experimental SIADH model [25]. Inhibition of AVP activity by increasing fluid intake improved renal function in CKD animal models [26,27].…”

Section: Discussionmentioning

confidence: 99%

Serum Sodium Levels and Patient Outcomes in an Ambulatory Clinic-Based Chronic Kidney Disease Cohort

et al. 2015

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Background: Chronic kidney disease (CKD) patients are prone to both hypo- and hypernatremia. Little has been published on the epidemiology of hypo- and hypernatremia in ambulatory patients with non-dialysis CKD. Methods: Data collected in two contemporaneous CKD cohort studies, the Renal Research Institute (RRI)-CKD study (n = 834) and the Study of Treatment of Renal Insufficiency: Data and Evaluation (STRIDE) (n = 1,348) were combined and analyzed to study the association between serum sodium (Na⁺) and clinical outcomes. Results: Baseline estimated glomerular filtration rate (eGFR) and Na⁺ were 26 ± 11 ml/min/1.73 m² and 140.2 ± 3.4 mEq/l, respectively. The prevalence of Na⁺ ≤135 mEq/l and ≥144 mEq/l was 6 and 16%, respectively. Higher baseline Na⁺ was significantly associated with male sex, older age, systolic blood pressure, BMI, serum albumin, presence of heart failure, and lower eGFR. The risk of end-stage renal disease (ESRD) was marginally significantly higher among patients with Na⁺ ≤135 mEq/l, compared with 140< Na⁺ <144 mEq/l (referent), in time-dependent models (adjusted hazard ratio, HR = 1.52, p = 0.06). Mortality risk was significantly greater at 135< Na⁺ ≤140 mEq/l (adjusted HR = 1.68, p = 0.02) and Na⁺ ≥144 mEq/l (adjusted HR = 2.01, p = 0.01). Conclusion: CKD patients with Na⁺ ≤135 mEq/l were at a higher risk for progression to ESRD, whereas both lower and higher Na⁺ levels were associated with a higher risk of mortality. While caring for CKD patients, greater attention to serum sodium levels by clinicians is warranted and could potentially help improve patient outcomes.

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“…Deleterious effects were also observed in other models. Continuous administration of desmopressin to rats, resulting in an experimental SIADH (syndrome of inappropriate antidiuretic hormone secretion) model, induced renal histopathologic abnormalities, such as dilatation of tubules, and inflammatory cell infiltration, accompanied by significant increases in the relative weight of the kidney [19] . Desmopressin administration in uninephrectomized DOCA-salt hypertensive rats (a model for salt-dependent nonmalignant hypertension) led to worsening of hypertension and renal histology and an increase in albuminuria [20] .…”

Section: Experimental Evidencementioning

confidence: 99%

Potential Deleterious Effects of Vasopressin in Chronic Kidney Disease and Particularly Autosomal Dominant Polycystic Kidney Disease

Meijer

Boertien

Zietse

et al. 2011

Kidney Blood Press Res

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The antidiuretic hormone vasopressin is crucial for regulating free water clearance in normal physiology. However, it has also been hypothesized that vasopressin has deleterious effects on the kidney. Vasopressin is elevated in animals and patients with chronic kidney disease. Suppression of vasopressin activity reduces proteinuria, renal hypertrophy, glomerulosclerosis and tubulointerstitial fibrosis in animal models. The potential detrimental influence of vasopressin is probably mediated by its effects on mesangial cell proliferation, renin secretion, renal hemodynamics, and blood pressure. In this review, we discuss the increasing body of evidence pointing towards the contribution of vasopressin to chronic kidney disease progression in general and to autosomal dominant polycystic kidney disease in particular. These data allude to the possibility that interventions directed at lowering vasopressin activity, for example by the administration of vasopressin receptor antagonists or by drinking more water, may be beneficial in chronic kidney disease.

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Histopathological Study of Kidney Abnormalities in an Experimental SIADH Rat Model and Its Application to the Evaluation of the Pharmacologic Profile of VP-343, a Selective Vasopressin V2 Receptor Antagonist.

Cited by 13 publications

References 13 publications

Demeclocycline attenuates hyponatremia by reducing aquaporin-2 expression in the renal inner medulla

Demeclocycline attenuates hyponatremia by reducing aquaporin-2 expression in the renal inner medulla

Serum Sodium Levels and Patient Outcomes in an Ambulatory Clinic-Based Chronic Kidney Disease Cohort

Potential Deleterious Effects of Vasopressin in Chronic Kidney Disease and Particularly Autosomal Dominant Polycystic Kidney Disease

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