The process of kidney regeneration recapitulates many aspect of development; it involves cell migration, proliferation and differentiation. Our previous studies point to the involvement of HCaRG “Hypertension-related calcium-regulated gene” in two major processes contributing to kidney repair, i.e. control of cell proliferation and differentiation. We extended our studies on the cellular function of HCaRG by comparing cell migration of two kidney cell lines. HCaRG expressing HEK293 cells, which undergo lower proliferation, migrated faster than control cells and presented greater adhesiveness to the extracellular matrix. Faster migration was also observed for the MDKC-C7 cells, after stably transfecting them with HCaRG cDNA. Screening of a human kidney cDNA library with HCaRG as bait revealed its interaction with several ionic transporters, among them Na+,K +,2Cl− cotransporter (NKCC) and Na,K-ATPase (NK pump). HCaRG overexpression induced major morphological changes of HEK293 cells including the formation of lamellipodia. An interaction and a co-localization were further found between HCaRG and actin at the leading edge of migrating cells. Increased activities of the NK pump and NKCC were observed in MDCK-C7 cells expressing HCaRG. These cells displayed higher content of intracellular Na+, water, and total proteins. Ouabain and bumetanide dose-dependently suppressed cells migration with keeping a higher migratory potential for the HCaRG-expressing HEK293 cells. Expression microarrays of HCaRG clones cells resulted in a profile of differential regulation of molecules involved in cell proliferation, differentiation and migration as well as molecules involved in morphogenesis and cytoskeleton organization. Among the quantitatively most up-regulated genes was the transforming growth factor-alpha (TGF-α) which has been associated with normal renal development and recovery. HCaRG-expressing cells exhibited augmented synthesis and release of activated TGF-α, and conditioned medium from these cells stimulated the migration and induced significant morphological changes of control cells in part through activation of the TFGα/EGF receptor. Taken together, these results reveal that HCaRG plays an important role in renal cell migration by induction of TGF-α secretion, its interaction with actin and its modulation of the intracellular ionic milieu required for optimal operation of the cellular migration machinery. It further provides a molecular basis for our previous and current findings that HCaRG-dependent intrarenal mechanisms enable tubule cell repair and regeneration. Keywords: Kidney, HCaRG, actin, ionic transporters, TGF alpha.