Sodium depletion increases sympathetic neurite outgrowth and expression of a novel TMEM35 gene-derived protein (TUF1) in the rat adrenal zona glomerulosa

The adrenal zona glomerulosa (ZG) secretes aldosterone to regulate sodium balance. Chronic sodium restriction increases aldosterone accompanied by ZG expansion. The ZG is innervated by sympathetic, vasoactive intestinal polypeptide (VIP) and neuropeptide tyrosine (NPY), and sensory, calcitonin gene-related peptide, nerves. It is unclear whether innervation is affected by ZG growth. Therefore, we measured neurite outgrowth in the ZG of adult male rats after dietary sodium manipulation. In response to 1 wk sodium restriction, VIP and NPY fibers elongated in parallel with expansion of the ZG, shown by aldosterone synthase (AS) expression, but calcitonin gene-related peptide fibers were not affected. Sodium repletion resulted in parallel regression in VIP and NPY fiber length and AS expression. These results show that sympathetic, but not sensory, innervation is coordinated with ZG growth. Mediators underlying changes in innervation are unknown; therefore, we characterized a novel gene TMEM35 [termed the unknown factor-1 (TUF1) due to its unknown function] that shows extensive overlap with AS in ZG. After sodium restriction, TUF1 expanded in parallel with the ZG. TUF1 bound the low-affinity neurotrophin receptor, p75NTR, which was expressed in NPY fibers and showed a response similar to TUF1 after sodium manipulation. TUF1- p75NTR binding was competitively displaced by nerve growth factor but not by TUF1 lacking the p75NTR binding motif. Moreover, TUF1mRNAin rat ZG cells increased after angiotensin II exposure in vitro. Collectively, these findings suggest that TMEM35/TUF1 is a candidate for modulating neurite outgrowth in the ZG after sodium depletion.