Glomerular expression of the ATP-sensitive P2X7 receptor in diabetic and hypertensive rat models

Vonend, Oliver; Turner, Clare M.; Chan, Choong M.; Loesch, Andrew; Dell'Anna, G. Carmen; Srai, Kaila S.; Burnstock, Geoffrey; Unwin, Robert J.
July 2004
Kidney International;Jul2004, Vol. 66 Issue 1, p157
Academic Journal
Glomerular expression of the ATP-sensitive P2X7 receptor in diabetic and hypertensive rat models. Background. The molecular identification and characterization of the adenosine triphosphate (ATP)-sensitive family of P2 receptors is comparatively new. There are two main subgroups, each with several subtypes and widespread tissue distribution, including the kidney. A unique member of the P2X subgroup of P2 receptors is the ATP-gated ion channel P2X7, which on activation can cause cell blebbing, cytokine release, and cell death by necrosis or apoptosis. We report expression of this receptor in normal rat kidney and in two chronic models of glomerular injury: streptozotocin-induced (STZ) diabetes and ren-2 transgenic (TGR) hypertension. Methods. At different time points in these models, we used a polyclonal antibody to the P2X7 receptor and immunohistochemistry to determine its expression and distribution. We also used Western blotting and real-time polymerase chain reaction (PCR) to detect changes in P2X7 receptor protein and mRNA expression, respectively. Results. We found only low-level glomerular immuno-staining for the P2X7 receptor in normal rat kidney, but intense P2X7 receptor immunostaining of glomeruli in kidneys from diabetic animals at 6 and 9 weeks, and in hypertensive animals at 12 weeks. In diabetic animals, real-time PCR demonstrated a ∼tenfold increase in glomerular P2X7 receptor mRNA relative to control, and Western blotting confirmed an increase in protein. Immunohistochemistry and immunoelectron microscopy showed staining of glomerular podocytes, which was both intracellular and at the plasma membrane. Conclusion. We conclude that the P2X7 receptor is not expressed appreciably under normal conditions, but that following glomerular injury it is significantly up-regulated, mainly in podocytes, though also in endothelial and mesangial cells, of animals with STZ-induced diabetes mellitus or TGR hypertension. Although the exact function and regulation of this receptor remain unclear, its association with inflammatory cytokine release and cell death suggests that increased expression might be involved in the pathogenesis of glomerular cell injury or repair.


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