Glycogen synthase kinase-3 regulation of urinary concentrating ability

Abstract

Purpose of review: Glycogen synthase kinase-3 (GSK3) is an enzyme that is gaining prominence as a critical signaling molecule in the epithelial cells of renal tubules. This review will focus on recent findings exploring the role of GSK3 in renal collecting ducts, especially its role in urine concentration involving vasopressin signaling.

Recent findings: Recent studies using inhibition or tissue-specific gene deletion of GSK3 revealed the mechanism by which GSK3 regulates aquaporin 2 water channels via adenylate cyclase or the prostaglandin-E2 pathway. In other studies, postnatal treatment with lithium, an inhibitor of GSK3, increased cell proliferation and led to microcyst formation in rat kidneys. These studies suggest that loss of GSK3 activity could interfere with renal water transport at two levels. In the short term, it could disrupt vasopressin signaling in collecting duct cells and in the long term it could alter the structure of the collecting ducts, making them less responsive to the hydro-osmotic effects of vasopressin.

Summary: Ongoing studies reveal the crucial role played by GSK3 in the regulation of vasopressin action in the renal collecting ducts and suggest a possible use of GSK3 inhibitors in disease conditions associated with disrupted vasopressin signaling.

Figure 1

GSK3-mediated regulation of vasopressin signaling in the collecting duct: inhibition of GSK3 by Li⁺ increases COX2 expression and PGE₂ production in the renal medullary interstitial cells. PGE₂ binds to EP1/EP3 receptors, antagonizing the AVP (vasopressin)-mediated cAMP generation. GSK3 also positively regulates adenylate cyclase activity, cAMP generation and AQP2 expression and trafficking in response to AVP. COX, cyclooxygenase; GSK3, glycogen synthase kinase-3; PGE, prostaglandin.