Vasopressin Directly Regulates Cyst Growth in Polycystic Kidney Disease

Abstract

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 adolescent nephronophthisis (pcy mouse) by downregulating cAMP signaling, cell proliferation, and chloride-driven fluid secretion. [3][4][5] Clinical trials with V2 receptor antagonists have been initiated. The mechanism by which these drugs inhibit the development of polycystic kidney disease has not been fully elucidated. In addition to V2 antagonism, these drugs could exert an effect by favoring the action of AVP on V1a receptors or by an AVP unrelated mechanism. RESULTS AND DISCUSSIONTo confirm that inhibition of AVP action on the kidney accounts for the effect of V2 receptor antagonists on the development of PKD, we generated PCK AVP ϩ/ϩ , PCK AVP ϩ/Ϫ , and PCK AVP Ϫ/Ϫ rats, as well as wild-type and Brattleboro controls, by breeding F1 rats resulting from PCK (Pkhd1 Ϫ/Ϫ ) and Brattleboro (AVP Ϫ/Ϫ ) crosses. PCK rats are homozygous for a splicing mutation (IVS35-2A3 T)

Urine Volume and Change in Estimated GFR in a Community-Based Cohort Study

“…However, this association may be explained, in part, by greater diuretic use among those with higher urine volumes and the decreased ability of the kidneys to concentrate urine as function declines; and, thus, in CKD patients, high urine volume with low osmolality could be the result, not the cause, of faster decline (9,22). Evidence supporting the latter conclusion is provided by highly controlled studies in rats in which high hydration shows a persistent benefit in preserving renal function (8,(22)(23)(24)(25). Furthermore, an experimental study that randomized elderly men to increase fluid intake saw no change in eGFR over a 6-month follow-up (26), although a longer follow-up may be necessary to discern an appreciable effect on kidney function.…”

Inhibition thérapeutique de mTOR dans la polykystose rénale autosomique dominante

“…Les fortes concentrations d'AMPc intracellulaire observées dans les cellules tubulaires rénales kystiques stimuleraient la kystogenèse via une augmentation de la prolifération cellulaire et/ ou une augmentation de la sécrétion chlorée intrakystique. Deux types de traitements peuvent réduire la synthèse d'AMPc par les cellules tubulaires réna-les : les antagonistes des récepteurs V2R à la vasopressine (tolvaptan) et les analogues de la somatostatine (octréotide, lanréotide) [3,4]. L'efficacité de ces produits est actuellement testée contre placebo sur l'évolution à 3 ans du volume rénal total mesuré par IRM (imagerie par résonance magnétique).…”

“…Bien que principalement exprimé dans le SNC, le BDNF joue également un rôle dans d'autres tissus en périphérie. Par exemple, il semble impliqué dans la régulation de l'homéo-stasie glucidique, mais aussi dans les processus liés à l'angiogenèse [3]. La découverte de l'expression du système BDNF/TrkB dans le placenta [4] suggé-rait son implication dans le développe-ment placentaire et foetal, ce qui a, de fait, été démontré récemment.…”

Novel Treatments of Autosomal Dominant Polycystic Kidney Disease

“…Present understanding holds that mutations of responsible genes, either PKD1 or PKD2, occur during embryogenesis and variably combine with "second hit" mutations within renal tubular epithelial cells that alter the intracellular level of polycystins, leading to epithelial cyst formations early in life (2)(3)(4)(5)(6). Cyst pathogenesis includes disordered nephron epithelial cell proliferations resulting in regional nephron bulging, accelerated apoptosis, loss of epithelial cell polarity, epithelial cell dedifferentiation, and eventual "pinching off" of the altered nephron regions into isolated cysts (3,6).…”

“…Cyst pathogenesis includes disordered nephron epithelial cell proliferations resulting in regional nephron bulging, accelerated apoptosis, loss of epithelial cell polarity, epithelial cell dedifferentiation, and eventual "pinching off" of the altered nephron regions into isolated cysts (3,6). Vasopressinmediated fluid transport into cysts coupled with direct stimulation of cystic growths are considered central pathogenic growth variables (2)(3)(4).…”