Abstract 081: Ghrelin is Produced by the Kidney and Mediates Distal Tubular Sodium Reabsorption in Rats

Ghrelin is a 28-amino acid peptide hormone that exerts powerful appetite-stimulating effects. Ghrelin receptor expression has been reported in the collecting duct, but the role of ghrelin in the kidney is unknown. The present studies confirmed ghrelin mRNA expression in inner medullary collecting duct cells (N=6) using RT PCR and sequencing of the 320-bp PCR product. Ghrelin peptide expression was also confirmed in these cells using immunohistochemistry and flow cytometry. To test intrarenal ghrelin action, 12-week-old uninephrectomized female Sprague-Dawley rats (N=26) received 3 bolus injections of ghrelin siRNA (N=7) or scrambled siRNA (N=7) into the renal interstitial (RI) space of the remaining kidney, each injection 48h apart. Following the last injection, rats received three, 1h RI infusions of 5% dextrose in water. Mean arterial pressure (MAP), urine sodium (Na + ) excretion (U Na V), glomerular filtration rate (GFR), fractional excretion of Na + (FE Na ), and fractional excretion of lithium (FE Li ) were calculated. In a separate set of rats, renal blood flow (RBF) was measured for 1h (N=6 for both ghrelin siRNA and scrambled siRNA). RI ghrelin siRNA-infused rats demonstrated significantly higher U Na V compared to scrambled siRNA-infused rats for all 3 periods (0.29±0.06 vs. 0.09±0.01, 0.35±0.09 vs. 0.11±0.03, and 0.27±0.07 vs. 0.09±0.02 μmol/min; P<0.01, P<0.05, and P<0.05 respectively) and significantly increased FE Na compared to scrambled siRNA infused rats (0.26±0.05 vs. 0.11±0.02, 0.35±0.06 vs. 0.11±0.03, and 0.24±0.04 vs. 0.10±0.03%; P<0.05, P<0.01, and P<0.05 respectively). There were no differences in in GFR, FE Li , MAP, or RBF. Since the increase in U Na V was not accompanied by similar increases in GFR, the effect of renal ghrelin inhibition suggested a tubular rather than hemodynamic, mechanism of action. To localize the specific tubular site, events distal to the renal proximal tubule were identified by changes in FE Na that occurred independently of changes in FE Li . RI ghrelin siRNA significantly increased FE Na without altering FE Li , suggesting distal nephron-dependent Na + reabsorption. Together, these data introduce ghrelin as a novel intrarenal peptide responsible for tonic Na + reabsorption at the level of the distal nephron.