Microarray Analysis of Gene Expression in the Renal Inner Medulla of the Dahl Salt-Resistant and Salt-Sensitive Rat
The inner medulla contains several mechanisms that play a central role in fluid-volume homeostasis. We hypothesized that transcriptional regulation of the inner medulla in response to a high sodium diet differs between the Dahl salt-resistant (SR) and salt-sensitive (SS) rats. SR and SS (16 wk) were placed on either a 0.5% (low) or 4.0% (high) NaCl diet. After 5 weeks, total RNA from the renal inner medulla was isolated from two rats in each of the following groups: SR/low, SR/high, SS/low, and SS/high. Labeled cRNA was hybridized to microarrays representing 7000 genes (Affymetrix). In response to increased Na intake in the SR rat, 46 genes were up-regulated and 7 genes down-regulated (>2-fold changes). This adaptive response included the up-regulation of guanylin (3-fold;3X), cytochrome P450 (8X), cyclooxygenase-2 (3X), kidney-specific androgen-regulated protein (8X) and the down regulation of Tamm-Horsfall protein (-39X). In contrast, high salt in SS rats revealed the differential expression of only one gene, the up-regulation of guanylin (3X). To investigate the general absence of a transcriptional response in SS rats, we found that, 23 genes were expressed at higher levels and 14 at lower levels in SS/low compared to SR/low. Interestingly, 7 of 23 genes that were elevated in the SS/low, were the same genes that were up-regulated in the SR/high. Thus, components of the adaptive response to high Na in SR rats are operating in SS rats prior to a Na challenge. Ten genes were increased and four were decreased in the SS/high when compared to the SR/high. The ROMK K+ channel (3X), Na-K-2Cl cotransporter (6X), and an ATPase inhibitor (8X) were expressed at higher levels in the SS/high. A majority of the other genes not mentioned have not been studied in the context of sodium handling or hypertension. These findings reveal clear differences in the basal gene expression within the inner medulla between SR and SS rats. Furthermore, these results show that salt-sensitivity is associated with a diminished transcriptional response to a high salt diet which supports the hypothesis that this region of the kidney contributes to genetic salt-sensitive hypertension.