G protein‑coupled receptor kinase 4 governs early kidney development via STAT3 and Nhe3a.

G protein‑coupled receptor kinase 4 (GRK4) is a member of the receptor phosphorylating GRK family with a well characterized function in renal sodium reabsorption through the modulation of dopaminergic receptors in adults. During embryonic development, GRK4 controls renal cilium development and thus, kidney function. The loss of GRK4 in zebrafish embryos results in pronephric dilatation, massive cilium elongation, glomerular cyst formation and, as a consequence of renal dysfunction, brain edema such as hydrocephalus. Notably, these embryonic functions of GRK4 appear to be independent of G protein‑coupled receptor modulation, although the full extent of the abilities of GRK4 to modulate cellular signaling has remained unclear. The present study aimed to provide further insight on this aspect of the functions of GRK4. Using zebrafish embryos, the present study demonstrates that GRK4 is required for normal pronephros patterning. The loss of Grk4 resulted in the upregulation of the sodium‑hydrogen exchanger 3a (Nhe3a), the zebrafish homologue of human NHE3. The administration of the NHE3 inhibitor, tenapanor, restored normal kidney development and function. Of note, during embryogenesis, this modulation of Nhe3a is not connected to dopaminergic receptor signaling or to a possible nuclear function of GRK4. Instead, the present study identified elevated Stat3 activity as the underlying cause leading to increased Nhe3a transcription and subsequently, to defects in kidney development.