Downregulation of aquaporin-2 and -3 in aging kidney is independent of V₂vasopressin receptor

Abstract

The mechanisms underlying age-related polyuria were investigated in 10- and 30-mo-old female WAG/Rij rats. Urinary volume and osmolality were 3.9 +/- 0.3 ml/24 h and 2,511 +/- 54 mosmol/kgH(2)O in adult rats and 12.8 +/- 0.8 ml/24 h and 1,042 +/- 44 mosmol/kgH(2)O in senescent animals. Vasopressin V(2) receptor mRNA did not significantly differ between 10 and 30 mo, and [(3)H]vasopressin binding sites in membrane papilla were reduced by 30%. The cAMP content of the papilla was unchanged with age, whereas papillary osmolality was significantly lowered in senescent animals. The expression of aquaporin-1 (AQP1) and -4 was mostly unaltered from 10 to 30 mo. In contrast, aquaporin-2 (AQP2) and -3 (AQP3) expression was downregulated by 80 and 50%, respectively, and AQP2 was markedly redistributed into the intracellular compartment, in inner medulla of senescent animals, but not in renal cortex. These results indicate that age-related polyuria is associated with a downregulation of AQP2 and AQP3 expression in the medullary collecting duct, which is independent of vasopressin-mediated cAMP accumulation.

Tonicity-Responsive Enhancer Binding Protein Is an Essential Regulator of Aquaporin-2 Expression in Renal Collecting Duct Principal Cells

“…Several studies performed on animals (11)(12)(13)(14)(15) and cell lines (16,17,29) have documented increased AQP2 abundance in response to extracellular hypertonicity. Using cultured mpkCCD cl4 cells, we showed previously that hyperosmolarity induces large, time-dependent variation of AQP2 mRNA and protein and that these changes are not due to changes in AQP2 protein turnover or mRNA stability but rather to altered AQP2 gene transcription (17).…”

“…This has been illustrated by in vivo experiments in water-restricted animals treated with V 2 -receptor antagonists that display increased AQP2 content (11,12) and in water-loaded animals that display decreased AQP2 content despite ongoing V 2 receptor stimulation (11,13). In addition, cAMP-independent decreased AQP2 expression that occurs in parallel with low levels of medullary osmolarity in senescent rats was reverted by raising medullary osmolarity (14,15). In vitro experiments using primary cultured inner medullary CD cells have shown further that extracellular hypertonicity stimulates AQP2 expression independent of PKA activity (16,17).…”

Osmolality and solute composition are strong regulators of AQP2 expression in renal principal cells

“…In rats the downregulation of AQP2 expression by V 2 R antagonist treatment was reversed by subjecting the animals to thirst (24). In addition, senescent (30-moold) rats exhibited a significantly decreased AQP2 expression and papillary osmolality compared with younger (10-mo-old) animals, while papillary cAMP remained unaffected (32).…”

Food restriction prevents age-related polyuria by vasopressin-dependent recruitment of aquaporin-2

“…However, it is still observed in senescent female WAG/Rij rats that remain free of glomerulosclerosis and have a normal number of nephrons, renal blood flow, and single renal filtration rates (10)(11)(12). Plasma AVP concentration, V 2 -receptor expression, and intracellular cAMP content in the papilla are also maintained in these old rats (15,30). By contrast, senescent female WAG/Rij rats exhibited a low papillary osmolality and a weak expression of AQP2 and AQP3, whereas expression of AQP1 and AQP4 was unaltered (30).…”