Characterization of Rat NDRG2 (N-Myc Downstream Regulated Gene 2), a Novel Early Mineralocorticoid-specific Induced Gene

Abstract

The early phase of the stimulatory action of aldosterone on sodium reabsorption in tight epithelia involves hormone-regulated genes that remain to be identified. Using a subtractive hybridization technique on isolated renal cortical collecting ducts from rats injected with a physiological dose of aldosterone, we have identified an early response cDNA highly homologous to human and murine NDRG2 (N-Myc downstream regulated gene 2), which consists of four isoforms and belongs to a new family of differentiation-related genes. NDRG2 mRNA was expressed in classical aldosterone target epithelia, and in the kidney, it was specifically located in the collecting duct, the site of aldosterone-regulated sodium absorption. NDRG2 mRNA was increased within 45 min by aldosterone in the kidney and distal colon, whereas it was unaffected in the heart. In the RCCD2 collecting duct cell line, NDRG2 mRNA was enhanced as early as 15 min after aldosterone addition by transcription-dependent effects. NDRG2 was induced by aldosterone concentrations as low as 10 ؊9 M, and a maximal effect was observed at 10 ؊8 M. In contrast, the glucocorticoid dexamethasone was ineffective in NDRG2 expression, whereas the glucocorticoid-regulated gene sgk was induced. Taken together, these results indicate that NDRG2 regulation by aldosterone is an early mineralocorticoid-specific effect. Interestingly, NDRG2 is homologous to Drosophila MESK2, a component of the Ras pathway, suggesting that activation of the Ras cascade may play a significant role in mineralocorticoid signaling.

Expression of NDRG2 is related to tumor progression and survival of gastric cancer patients through Fas-mediated cell death

“…N-myc downstream regulated gene 2 (NDRG2), a member of a new family of differentiation-related genes, is highly expressed in adult brain, salivary gland, and skeletal muscle (Boulkroun et al, 2002;Qu et al, 2002). This family is comprised of four members, NDRG1-4, and the expression pattern of these genes is differs during development (Qu et al, 2002).…”

Regulation of N-Myc downstream regulated gene 2 by bile acids

“…Given the roles of NDRG2 in renal function [4,5] and since both FXR and NDRG2 are enriched in kidney, we investigated whether Ndrg2 expression was regulated by FXR activation in this organ. The i.p.…”

“…Notably, in addition to tumor suppression, NDRG2 has also been related to the regulation of sodium gradient in several reports. First, NDRG2 was identified as a mineralocorticoid-induced gene in renal cortical collecting duct, the site of aldosterone-regulated sodium absorption [4]. Later, studies in heterologous expression systems showed that co-expression of NDRG2 and ENaC resulted in a stimulation of ENaC-mediated Na + currents [5].…”

“…Interestingly, Ndrg2 was initially characterized as an early aldosterone-induced gene in rat kidneys [4]. Thereafter, it was proposed that NDRG2 may affect the function of the epithelial sodium channel (ENaC) [5], which is localized in the apical membranes of sodium absorbing epithelia like the distal nephron and hence plays a key role in the maintenance of blood pressure.…”

“…Similarly, the four-copy mutant IR1 construct p(mutNDRG2IR1) 4 -TK was generated by annealing 5'-GATCCTTAGAAAGAATTAGTGATTCTGGAA-3' and 5'-GATCTTCCAGAATCACTAATTCTTTCTAAG-3'. Plasmids expressing human retinoid X receptor  (RXR, NR2B1) and FXR into pSG5 have been previously described [10].…”