Aurora Kinase A Is Involved in Controlling the Localization of Aquaporin-2 in Renal Principal Cells

Abstract

The cAMP-dependent aquaporin-2 (AQP2) redistribution from intracellular vesicles into the plasma membrane of renal collecting duct principal cells induces water reabsorption and fine-tunes body water homeostasis. However, the mechanisms controlling the localization of AQP2 are not understood in detail. Using immortalized mouse medullary collecting duct (MCD4) and primary rat inner medullary collecting duct (IMCD) cells as model systems, we here discovered a key regulatory role of Aurora kinase A (AURKA) in the control of AQP2. The AURKA-selective inhibitor Aurora-A inhibitor I and novel derivatives as well as a structurally different inhibitor, Alisertib, prevented the cAMP-induced redistribution of AQP2. Aurora-A inhibitor I led to a depolymerization of actin stress fibers, which serve as tracks for the translocation of AQP2-bearing vesicles to the plasma membrane. The phosphorylation of cofilin-1 (CFL1) inactivates the actin-depolymerizing function of CFL1. Aurora-A inhibitor I decreased the CFL1 phosphorylation, accounting for the removal of the actin stress fibers and the inhibition of the redistribution of AQP2. Surprisingly, Alisertib caused an increase in actin stress fibers and did not affect CFL1 phosphorylation, indicating that AURKA exerts its control over AQP2 through different mechanisms. An involvement of AURKA and CFL1 in the control of the localization of AQP2 was hitherto unknown.

Genomic Fabrics of the Excretory System’s Functional Pathways Remodeled in Clear Cell Renal Cell Carcinoma

“…Figure 7 shows distinct statistically significant coordination partners of AVP, the neuropeptide hormone arginine vasopressin, which is a very important regulator of kidney salt and water homeostasis [84]. Our analysis detailed also how AVP-dependent water reabsorption regulates the cAMP signaling pathway [85,86] through expression correlation with genes shared by the cAMP signaling pathway with the excretory pathways. Thus, in NOR, AVP is synergistically expressed with ATP1B2, CREB3L1, CREB3L4, and FXYD2, has no antagonistic partners, and is independently expressed with PIK3CB.…”

A Novel AQP2 Sequence Variant Causing Aquaporin-2 Retention in the Cytoplasm and Autosomal Dominant Nephrogenic Diabetes Insipidus

“…The stimulation of cAMP synthesis with the activator of adenylyl cyclases, forskolin, induced a redistribution of wild-type AQP2 from intracellular domains to the plasma membrane. 8 , 9 A fraction of the mutant AQP2, as the wild-type, was found at the plasma membrane in untreated cells. Forskolin did not affect the localization of the mutant AQP2.…”

Many kinases for controlling the water channel aquaporin‐2

“…A recent example of a kinase that controls AQP2 without directly phosphorylating it is Aurora kinase A (AURKA) (Baltzer et al., 2022). The knockdown of AURKA in a siRNA screen prevented the cAMP‐induced AQP2 plasma membrane localisation in mouse collecting duct (MCD) 4 cells (Dema et al., 2020).…”