Purinergic signaling is enhanced in the absence of UT‐A1 and UT‐A3

• Published in: Physiological reports 2021-01, Vol.9 (1), p.e14636-n/a
• Main Authors: Himmel, Nathaniel J., Rogers, Richard T., Redd, Sara K., Wang, Yirong, Blount, Mitsi A.
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; ATP; Collecting duct; Cyclic AMP; Disease Models, Animal; Kidney Medulla - metabolism; Kidney Tubules, Collecting - metabolism; Male; Membrane Transport Proteins - deficiency; Membrane Transport Proteins - genetics; Membrane Transport Proteins - metabolism; Membranes; Mice; Mice, Inbred C57BL; Mice, Knockout; Original Research; Osmolar Concentration; P2Y receptors; Paracrine signalling; Physiology; Polyuria; Prostaglandin E2; Proteins; Purine P2Y receptors; Receptors, Purinergic P2Y2 - metabolism; Signal Transduction; Sodium; Urea; Urea - metabolism; Urea Transporters; Urine; urine concentration; Vasopressin
• ISSN: 2051-817X
• DOI: 10.14814/phy2.14636

ATP is an important paracrine regulator of renal tubular water and urea transport. The activity of P2Y2, the predominant P2Y receptor of the medullary collecting duct, is mediated by ATP, and modulates urinary concentration. To investigate the role of purinergic signaling in the absence of urea transport in the collecting duct, we studied wild‐type (WT) and UT‐A1/A3 null (UT‐A1/A3 KO) mice in metabolic cages to monitor urine output, and collected tissue samples for analysis. We confirmed that UT‐A1/A3 KO mice are polyuric, and concurrently observed lower levels of urinary cAMP as compared to WT, despite elevated serum vasopressin (AVP) levels. Because P2Y2 inhibits AVP‐stimulated transport by dampening cAMP synthesis, we suspected that, similar to other models of AVP‐resistant polyuria, purinergic signaling is increased in UT‐A1/A3 KO mice. In fact, we observed that both urinary ATP and purinergic‐mediated prostanoid (PGE2) levels were elevated. Collectively, our data suggest that the reduction of medullary osmolality due to the lack of UT‐A1 and UT‐A3 induces an AVP‐resistant polyuria that is possibly exacerbated by, or at least correlated with, enhanced purinergic signaling. ATP, an important paracrine regulator of renal tubular water and urea transport, activates P2Y2 – the predominant P2Y receptor of the medullary collecting duct involved in urinary concentration. Our studies demonstrated that mice lacking inner medullary urea transport (UT‐A1/A3 KO mice) were polyuric and had lower levels of urinary cAMP as compared to WT mice despite also having elevated serum vasopressin (AVP) levels. Both urinary ATP and purinergic‐mediated prostanoid (PGE2) levels were elevated in UT‐A1/A3 KO mice suggesting that, like some other known models of AVP‐resistant polyuria, purinergic signaling is increased in UT‐A1/A3 KO mice.