Vasopressin resistance in chronic renal failure. Evidence for the role of decreased V2 receptor mRNA.

Abstract

Studies were performed to determine the mechanism underlying deficient arginine vasopressin (AVP) -stimulated adenylyl cyclase activity in chronic renal failure (CRF). As compared to control, principal cells cultured from the inner medullary collecting tubule of rats previously made uremic by 5/6 nephrectomy fail to accumulate cAMP when stimulated with AVP. CRF cells do respond normally to forskolin or cholera toxin and the defect in AVP responsiveness is not prevented by treatment with pertussis toxin, by cyclooxygenase inhibition, or by inhibition or down-regulation of protein kinase C. In contrast to their lack of responsiveness to AVP, CRF cells respond normally to other agonists of adenylyl cyclase such as isoproterenol or prostaglandin E2. Plasma membranes prepared from the inner medullae of CRF rats exhibit a marked decrease in apparent AVP receptor number but no change in the apparent number of beta adrenergic receptors. Reverse transcriptase PCR of total RNA from the inner medullae of CRF animals reveals virtual absence of V 2 receptor mRNA; mRNA for a, is present in normal abundance. These studies indicate that AVP resistance in CRF is due, at least in part, to selective downregulation of the V 2 receptor as a consequence of decreased V 2 receptor mRNA. (J. Clin. Invest. 1995.96:378-385.)

Effect of Tolvaptan in Patients With Chronic Kidney Disease Due to Diabetic Nephropathy With Heart Failure

“…Another factor may be AVP resistance of selective down-regulation of the V2 receptor. 21) It has been reported that the expression of aquaporin-2 is decreased in the collecting ducts of mice lacking the vasopressin V1a receptor. V1a receptor signaling may be fundamentally important for the expression of aquaporin-2 in the collecting ducts during control conditions and dehydration.…”

Copeptin Levels Associate with Cardiovascular Events in Patients with ESRD and Type 2 Diabetes Mellitus

“…Furthermore, resistance of V2 receptors is present already at earlier stages of chronic kidney disease, [5][6][7] probably involving activation of feedback mechanisms with a regulatory increase of plasma AVP levels. In addition, left ventricular dysfunction, 10 endothelial stress, and T2DM might also be contributive factors.…”

“…Evidence suggests that downregulation of V2 receptor mRNA and a deficient AVP-stimulated adenyl cyclase result in resistance of V2 receptors in earlier stages of chronic kidney disease. [5][6][7] These findings suggest that, in ESRD, AVP might primarily act via the V1a and V1b receptors. Thus, an increase in cardiovascular risk and all-cause mortality in ESRD patients might be partly linked to the predominant activation of V1a and V1b receptor function.…”

Urine-concentrating defects exacerbate with age in male offspring with a low-nephron endowment

“…Rats with chronic renal failure induced by a surgical reduction in renal mass have decreased urinary concentrating ability that is associated with a downregulation of AQP-2 as well (17). Furthermore, reduction in AQP-2 expression has been associated with severe urinary concentrating defects in patients with chronic renal failure irrespective of plasma AVP levels (39).…”