pituitrin and Polycystic-Kidney-Diseases

Chronic kidney disease (CKD) imposes a significant global health burden. In the United States, one in three adults are at risk for CKD currently affecting over 28 million Americans. While several studies have demonstrated the benefit of treating traditional risk factors in CKD, including hypertension with pharmacologic agents such as blockade of the renin-angiotensin system (RAAS), there is scarce data on the advantages of sodium and fluid management in this population. Both experimental and observational studies have shown improvement in hypertension and cardiovascular outcomes with sodium restriction to ≤2.3 grams per day, however, to date there are very few randomized controlled trials demonstrating a benefit in sodium reduction for the prevention or progression of CKD. Similarly, studies on increasing fluid consumption have shown to be advantageous in polycystic kidney disease as well as chronic nephrolithiasis, yet no randomized controlled trials exist on the fluid management in patients with kidney disease. This review aims to explore the evidence of sodium restriction and fluid management in the CKD population as well as underlying mechanisms and clinical barriers of sodium and water management as conservative therapy.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Conservative Treatment; Disease Progression; Fluid Therapy; Humans; Hypertension; Hypertrophy, Left Ventricular; Hyponatremia; Polycystic Kidney Diseases; Renal Insufficiency, Chronic; Renin-Angiotensin System; Risk Factors; Sodium Chloride; United States; Vasopressins

Increased cell proliferation and fluid secretion, probably driven by alterations in intracellular calcium homeostasis and cyclic adenosine 3,5-phosphate, play an important role in the development and progression of polycystic kidney disease. Hormone receptors that affect cyclic adenosine monophosphate and are preferentially expressed in affected tissues are logical treatment targets. There is a sound rationale for considering the arginine vasopressin V2 receptor as a target. The arginine vasopressin V2 receptor antagonists OPC-31260 and tolvaptan inhibit the development of polycystic kidney disease in cpk mice and in three animal orthologs to human autosomal recessive polycystic kidney disease (PCK rat), autosomal dominant polycystic kidney disease (Pkd2/WS25 mice), and nephronophthisis (pcy mouse). PCK rats that are homozygous for an arginine vasopressin mutation and lack circulating vasopressin are markedly protected. Administration of V2 receptor agonist 1-deamino-8-D-arginine vasopressin to these animals completely recovers the cystic phenotype. Administration of 1-deamino-8-D-arginine vasopressin to PCK rats with normal arginine vasopressin aggravates the disease. Suppression of arginine vasopressin release by high water intake is protective. V2 receptor antagonists may have additional beneficial effects on hypertension and chronic kidney disease progression. A number of clinical studies in polycystic kidney disease have been performed or are currently active. The results of phase 2 and phase 2-3 clinical trials suggest that tolvaptan is safe and well tolerated in autosomal dominant polycystic kidney disease. A phase 3, placebo-controlled, double-blind study in 18- to 50-yr-old patients with autosomal dominant polycystic kidney disease and preserved renal function but relatively rapid progression, as indicated by a total kidney volume >750 ml, has been initiated and will determine whether tolvaptan is effective in slowing down the progression of this disease.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Clinical Trials as Topic; Drug Evaluation, Preclinical; Humans; Polycystic Kidney Diseases; Vasopressins

Polycystic kidney disease is an inherited multisystem disorder. It causes progressive loss of kidney function, flank pain, urinary tract infection, arterial hypertension and vascular abnormalities. Until the present time the treatment of polycystic kidney disease has been symptomatic. New approaches based on cell culture of cyst wall epithelia and on the discovery of polycystins 1 and 2 have lead to novel treatment protocols to attack the origin of the disease. These protocols involve vasopressin antagonists, rapamycin and somatostatin at the present time.

Topics: Animals; Humans; Polycystic Kidney Diseases; Sirolimus; Somatostatin; Vasopressins

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Calcium; Calcium Channel Blockers; Embolization, Therapeutic; Humans; Membrane Proteins; Mutation; Octreotide; Polycystic Kidney Diseases; Proteins; Renal Artery; TRPP Cation Channels; Vasopressins

The first non-peptide vasopressin receptor antagonist (VRA) was recently approved by the United States Food and Drug Administration, and several others are now in late stages of clinical development. Phase 3 trials indicate that these agents predictably reduce urine osmolality, increase electrolyte-free water excretion, and raise serum sodium concentration. They are likely to become a mainstay of treatment of euvolemic and hypervolemic hyponatremia. Although tachyphylaxis to the hydro-osmotic effect of these agents does not appear to occur, their use is accompanied by an increase in thirst, and they do not always eliminate altogether the need for water restriction during treatment of hyponatremia. Experience with use of these agents for treatment of acute, severe, life-threatening hyponatremia as well as chronic hyponatremia is limited. Further studies are needed to determine how they are best used in these situations, but the risk of overly rapid correction of hyponatremia seems low. Results of long-term trials to determine the ability of VRAs to reduce morbidity or mortality in congestive heart failure or to slow the progression of polycystic kidney disease are awaited with great interest.

Topics: Antidiuretic Hormone Receptor Antagonists; Azepines; Benzamides; Benzazepines; Clinical Trials as Topic; Diabetes Insipidus, Nephrogenic; Fibrosis; Heart Failure; Humans; Hyponatremia; Osmolar Concentration; Polycystic Kidney Diseases; Pyrroles; Receptors, Vasopressin; Sodium; Tolvaptan; United States; United States Food and Drug Administration; Vasopressins

Angiotensin (Ang) II signalling in the hypothalamic paraventricular nucleus (PVN) via Ang type-1a receptors (AT1R) regulates vasopressin release and sympathetic nerve activity - two effectors of blood pressure regulation. We determined the cellular expression and function of AT1R in the PVN of a rodent model of polycystic kidney disease (PKD), the Lewis polycystic kidney (LPK) rat, to evaluate its contribution to blood pressure regulation and augmented vasopressin release in PKD.. PVN AT1R gene expression was quantified with fluorescent in situ hybridization in LPK and control rats. PVN AT1R function was assessed with pharmacology under urethane anaesthesia in LPK and control rats instrumented to record arterial pressure and sympathetic nerve activity.. AT1R gene expression was upregulated in the PVN, particularly in corticotrophin-releasing hormone neurons, of LPK versus control rats. PVN microinjection of Ang II produced larger increases in systolic blood pressure in LPK versus control rats (36 ± 5 vs. 17 ± 2 mm Hg; p < 0.01). Unexpectedly, Ang II produced regionally heterogeneous sympathoinhibition (renal: -33%; splanchnic: -12%; lumbar: no change) in LPK and no change in controls. PVN pre-treatment with losartan, a competitive AT1R antagonist, blocked the Ang II-mediated renal sympathoinhibition and attenuated the pressor response observed in LPK rats. The Ang II pressor effect was also blocked by systemic OPC-21268, a competitive V1A receptor antagonist, but unaffected by hexamethonium, a sympathetic ganglionic blocker.. Collectively, our data suggest that upregulated AT1R expression in PVN sensitizes neuroendocrine release of vasopressin in the LPK, identifying a central mechanism for the elevated vasopressin levels present in PKD.

Topics: Angiotensin II; Animals; Blood Pressure; In Situ Hybridization, Fluorescence; Kidney; Paraventricular Hypothalamic Nucleus; Polycystic Kidney Diseases; Rats; Rats, Inbred Lew; Receptor, Angiotensin, Type 1; Rodentia; Sympathetic Nervous System; Vasopressins

Hypertension and baroreflex dysfunction confer poorer outcomes in patients with polycystic kidney disease (PKD).. We examined whether hypothalamic paraventricular nucleus (PVN) activation or circulating vasopressin contribute to hypertension and baroreflex dysfunction in the Lewis polycystic kidney (LPK) rat.. Bilateral PVN inhibition with muscimol reduced SBP further in urethane-anaesthetized adult LPK rats than in control Lewis rats (-43 ± 4 vs. -18 ± 3 mmHg; P < 0.0001, n = 14), but was not associated with a greater reduction in sympathetic nerve activity (SNA) or improvement in HR or SNA baroreflex function. Blockade of ionotropic glutamatergic input to the PVN with kynurenic acid also reduced SBP (P < 0.001), but not SNA, further in both adult and juvenile LPK rats. No differences in AMPA or NMDA receptor mRNA expression were noted. Systemic V1A receptor antagonism using OPC-21268 reduced SBP in adult LPK rats only (P < 0.001) and had no effect on the depressor response to PVN inhibition (P = 0.39). Combined peripheral V1A receptor antagonism and PVN inhibition, however, normalized SBP in adult LPK rats (122 ± 11 vs. 115 ± 6 mmHg; LPK vs. Lewis, P > 0.05, n = 10).. Our data show that in the LPK rat model of PKD, hypertension is contributed to by increased PVN neuronal activity and, through an independent mechanism, systemic V1A receptor activation. Treatments that reduce PVN neuronal activity and/or inhibit peripheral V1A receptors may provide novel treatment strategies to ameliorate hypertension in individuals with PKD and limit overall disease progression.

Topics: Animals; Disease Models, Animal; Hypertension; Paraventricular Hypothalamic Nucleus; Polycystic Kidney Diseases; Rats; Vasopressins

Polycystic kidney disease (PKD) is a group of monogenetic conditions characterised by the progressive accumulation of multiple renal cysts and hypertension. One of the earliest features of PKD is a reduction in urinary concentrating capacity that impairs extracellular fluid conservation. Urinary concentrating impairment predisposes PKD patients to periods of hypohydration when fluid loss is not adequately compensated by fluid intake. The hypohydrated state provides a blood hyperosmotic stimulus for vasopressin release to minimise further water loss. However, over-activation of renal V2 receptors contributes to cyst expansion. Although suppressing vasopressin release with high water intake has been shown to impair disease progression in rodent models, whether this approach is efficacious in patients remains uncertain. The neural osmoregulatory pathway that controls vasopressin secretion also exerts a stimulatory action on vasomotor sympathetic activity and blood pressure during dehydration. Recurrent dehydration leads to a worsening of hypertension in rodents and cross-sectional data suggests that reduced urinary concentrating ability may contribute to hypertension development in the clinical PKD population. Experimental studies are required to evaluate this hypothesis and to determine the underlying mechanism.

Topics: Animals; Disease Progression; Drinking; Humans; Hypertension; Osmoregulation; Polycystic Kidney Diseases; Receptors, Vasopressin; Urine; Vasopressins

Glycogen synthase kinase 3β (GSK3β), a serine/threonine protein kinase, is commonly known to be regulated at the level of its activity. However, in some diseases including polycystic kidney disease (PKD), GSK3β expression is increased and plays a pathophysiological role. The current studies aimed to determine the mechanism for the increased GSK3β expression in PKD and its significance to disease progression. In mouse models of PKD, increases in renal GSK3β corresponded with increases in renal cAMP levels and disease progression. In vivo and in vitro studies revealed that GSK3β is a cAMP-responsive gene, and elevated cAMP levels, as seen in PKD, can increase GSK3β expression. In normal mice, vasopressin signaling induced by water deprivation increased GSK3β expression, which decreased following rehydration. Examination of the GSK3β promoter revealed five potential binding sites for the transcription factor, cAMP response element binding protein (CREB). CREB was found to bind to GSK3β promoter and essential for cAMP-mediated regulation of GSK3β. Importantly, this regulation was demonstrated to be part of a feed-forward loop in which cAMP through CREB regulates GSK3β expression, and GSK3β in turn positively regulates cAMP generation. GSK3β or CREB inhibition reduced transepithelial fluid secretion and cyst expansion in vitro Thus, disruption at any point of this destructive cycle may be therapeutically useful to reduce cyst expansion and preserve renal function in PKD.

Topics: Animals; Body Fluids; Cyclic AMP; Cyclic AMP Response Element-Binding Protein; Dogs; Gene Knockout Techniques; Glycogen Synthase Kinase 3 beta; Humans; Kidney; Madin Darby Canine Kidney Cells; Mice, Inbred C57BL; Polycystic Kidney Diseases; RNA, Messenger; Signal Transduction; TRPP Cation Channels; Vasopressins

Mutations in Ankyrin repeat and sterile alpha motif domain containing 6 (ANKS6) play a causative role in renal cyst formation in the PKD/Mhm(cy/+) rat model of polycystic kidney disease and in nephronophthisis in humans. A network of protein partners of ANKS6 is emerging and their functional characterization provides important clues to understand the role of ANKS6 in renal biology and in mechanisms involved in the formation of renal cysts. Following experimental confirmation of interaction between ANKS6and ANKS3 using a Yeast two hybrid system, we demonstrated that binding between the two proteins occurs through their sterile alpha motif (SAM) and that the amino acid 823 in rat ANSK6 is key for this interaction. We further showed their interaction by co-immunoprecipitation and showed in vivo in mice that ANKS3 is present in renal cilia. Downregulated expression of Anks3 in vivo in mice by Locked Nucleic Acid (LNA) modified antisense oligonucleotides was associated with increased transcription of vasopressin-induced genes, suggesting changes in renal water permeability, and altered transcription of genes encoding proteins involved in cilium structure, apoptosis and cell proliferation. These data provide experimental evidence of ANKS3-ANKS6 direct interaction through their SAM domain and co-localisation in mouse renal cilia, and shed light on molecular mechanisms indirectly mediated by ANKS6 in the mouse kidney, that may be affected by altered ANKS3-ANKS6 interaction. Our results contribute to improved knowledge of the structure and function of the network of proteins interacting with ANKS6, which may represent therapeutic targets in cystic diseases.

Topics: Amino Acid Motifs; Animals; Ankyrin Repeat; Apoptosis; Carrier Proteins; Cell Proliferation; Cilia; Down-Regulation; Kidney; Mice; Mice, Inbred C57BL; Mutation; Polycystic Kidney Diseases; Protein Binding; Signal Transduction; Vasopressins

Renal water reabsorption is controlled by arginine vasopressin (AVP), which binds to V2 receptors, resulting in protein kinase A (PKA) activation, phosphorylation of aquaporin 2 (AQP2) at serine 256, and translocation of AQP2 to the plasma membrane. However, AVP also causes dephosphorylation of AQP2 at S261. Recent studies showed that cyclin-dependent kinases (cdks) can phosphorylate AQP2 peptides at S261 in vitro. We investigated the possible role of cdks in the phosphorylation of AQP2 and identified a new PKA-independent pathway regulating AQP2 trafficking. In ex vivo kidney slices and MDCK-AQP2 cells, R-roscovitine, a specific inhibitor of cdks, increased pS256 levels and decreased pS261 levels. The changes in AQP2 phosphorylation status were paralleled by increases in cell surface expression of AQP2 and osmotic water permeability in the absence of forskolin stimulation. R-Roscovitine did not alter cAMP-dependent PKA activity but specifically reduced protein phosphatase 2A (PP2A) expression and activity in MDCK cells. Notably, we found reduced PP2A expression and activity and reduced pS261 levels in Pkd1(+/-) mice displaying a syndrome of inappropriate antidiuresis with high levels of pS256, despite unchanged AVP and cAMP. Similar to previous findings in Pkd1(+/-) mice, R-roscovitine treatment caused a significant decrease in intracellular calcium in MDCK cells. Our data indicate that reduced activity of PP2A, secondary to reduced intracellular Ca(2+) levels, promotes AQP2 trafficking independent of the AVP-PKA axis. This pathway may be relevant for explaining pathologic states characterized by inappropriate AVP secretion and positive water balance.

Topics: Animals; Aquaporin 2; Calcium Signaling; Cyclic AMP-Dependent Protein Kinases; Cyclin-Dependent Kinases; Haploinsufficiency; In Vitro Techniques; Male; Mice; Polycystic Kidney Diseases; Protein Phosphatase 2; Purines; Rats, Sprague-Dawley; Roscovitine; Vasopressins

Polycystic kidney disease (PKD) is a ciliopathy characterized by renal cysts and hypertension. These changes are presumably due to altered fluid and electrolyte transport in the collecting duct (CD). This is the site where vasopressin (AVP) stimulates vasopressin-2 receptor (V2R)-mediated aquaporin-2 (AQP2) insertion into the apical membrane. Since cysts frequently occur in the CD, we studied V2R and AQP2 trafficking and function in CD cell lines with stunted and normal cilia [cilia (-), cilia (+)] derived from the orpk mouse (hypomorph of the Tg737/Ift88 gene). Interestingly, only cilia (-) cells grown on culture dishes formed domes after apical AVP treatment. This observation led to our hypothesis that V2R mislocalizes to the apical membrane in the absence of a full-length cilium. Immunofluorescence indicated that AQP2 localizes to cilia and in a subapical compartment in cilia (+) cells, but AQP2 levels were elevated in both apical and basolateral membranes in cilia (-) cells after apical AVP treatment. Western blot analysis revealed V2R and glycosylated AQP2 in biotinylated apical membranes of cilia (-) but not in cilia (+) cells. In addition, apical V2R was functional upon apical desmopressin (DDAVP) treatment by demonstrating increased cAMP, water transport, and benzamil-sensitive equivalent short-circuit current (I(sc)) in cilia (-) cells but not in cilia (+) cells. Moreover, pretreatment with a PKA inhibitor abolished DDAVP stimulation of I(sc) in cilia (-) cells. Thus we propose that structural or functional loss of cilia leads to abnormal trafficking of AQP2/V2R leading to enhanced salt and water absorption. Whether such apical localization contributes to enhanced fluid retention and hypertension in PKD remains to be determined.

Topics: Animals; Aquaporin 2; Cell Line; Cilia; Cyclic AMP-Dependent Protein Kinases; Isoquinolines; Kidney Tubules, Collecting; Mice; Polycystic Kidney Diseases; Receptors, Vasopressin; Sulfonamides; Vasopressins

Topics: Arginine Vasopressin; Humans; Polycystic Kidney Diseases; Polycystic Kidney, Autosomal Dominant; Polycystic Kidney, Autosomal Recessive; Vasopressins

The polycystic kidney diseases (PKD) are a group of genetic disorders causing renal failure and death from infancy to adulthood. Arginine vasopressin (AVP) V2 receptor antagonists inhibit cystogenesis in animal models of cystic kidney diseases, presumably by downregulating cAMP signaling, cell proliferation, and chloride-driven fluid secretion. For confirmation that the protective effect of these drugs is due to antagonism of AVP, PCK (Pkhd1(-/-)) and Brattleboro (AVP(-/-)) rats were crossed to generate rats with PKD and varying amounts of AVP. At 10 and 20 weeks of age, PCK AVP(-/-) rats had lower renal cAMP and almost complete inhibition of cystogenesis compared with PCK AVP(+/+) and PCK AVP(+/-) rats. The V2 receptor agonist 1-deamino-8-d-arginine vasopressin increased renal cAMP and recovered the full cystic phenotype of PCK AVP(-/-) rats and aggravated the cystic disease of PCK AVP(+/+) rats but did not induce cystic changes in wild-type rats. These observations indicate that AVP is a powerful modulator of cystogenesis and provide further support for clinical trials of V2 receptor antagonists in PKD.

Topics: Animals; Arginine Vasopressin; Body Weight; Cell Division; Crosses, Genetic; Cyclic AMP; Cysts; Female; Kidney; Male; Organ Size; Polycystic Kidney Diseases; Rats; Rats, Brattleboro; Vasopressins

Hypotension is frequently encountered during hemodialysis (HD). One of the main factors of the HD-induced hypotension is acute reduction of circulating plasma volume by water removal, which is induced by the poor plasma refilling from the extravascular space into vessels. The determinants of plasma refilling, however, have not been clearly identified. Recently, we devised a mathematical model of water transport in HD patients, which can estimate the plasma-refilling coefficient (Kr) during HD. In the present study, we evaluated the factors determining plasma refilling by using this model. In 13 patients undergoing regular HD, the changes of Kr during HD were calculated from the model. Levels of ANP, cGMP, cAMP, endothelin, angiotensin II and vasopressin were measured before and after HD. Kr fell from 750.4 +/- 558.0 to 112.8 +/- 81.9 ml/mm Hg/h during HD. The rate of water removal during HD showed no significant correlation with the changes of Kr. Among the hormones and nucleotides measured here, plasma ANP level and cGMP were significantly correlated with Kr (r = 0.78, p < 001 and r = 0.62, p < 0.01, respectively). Our findings suggest that severe reduction in the level of serum ANP during HD, which is induced by water removal, plays some role in HD-induced hypotension through the attenuation of plasma refilling in HD patients.

Topics: Adult; Aged; Angiotensin II; Atrial Natriuretic Factor; Blood Pressure; Blood Vessels; Cyclic AMP; Cyclic GMP; Endothelins; Female; Fluid Shifts; Glomerulonephritis; Hematocrit; Hemodynamics; Humans; Male; Middle Aged; Nephrosclerosis; Plasma; Polycystic Kidney Diseases; Renal Dialysis; Vasopressins; Water

Topics: Adolescent; Adult; Aged; Blood; Child; Dehydration; Female; Glomerular Filtration Rate; Humans; Iodine Radioisotopes; Iothalamic Acid; Kidney Concentrating Ability; Kidney Failure, Chronic; Kidney Medulla; Loop of Henle; Male; Middle Aged; Osmolar Concentration; Polycystic Kidney Diseases; Sodium; Sodium Chloride; Urine; Vasopressins; Water