Novel role of HIF‐1alpha in tubular Na transport in the remnant kidney (860.7)

Abstract

Remnant nephrons after subtotal nephrectomy (STN) show significant hyperfiltration. We have also shown increased oxygen consumption for tubular Na reabsorption in STN leading to hypoxia. We hypothesized that this increase may be due to a relative shift in Na transport to nephron segments distal to the proximal tubule, where oxygen costs for Na transport are higher. In STN kidney, activation of HIF‐1α, master regulator of cell response to hypoxia, lowers the elevated oxygen consumption. Hence, we also examined the effect of HIF‐1α on Na transport in different nephron segments.In the STN kidney, when adjusted for SNGFR, proximal reabsorption was lower in STN (p=0.01), and the early distal flow rate was nearly double that in shams. This was accompanied by a reduced expression of Na/H exchanger (NHE3) in the proximal tubule (p<0.05), while the expression of Na‐Cl cotransporter (NCC) in the distal tubule was increased (p<0.05). In micropuncture experiments, SNGFRs were found to be higher in STN treated with DMOG, a pharmacological HIF‐1α activator, compared to untreated STN (67±4 vs. 50±4 nl/min, p=0.01), as were the APRs (25±2 vs. 20±2 nl/min, p=0.09), but the fractional reabsorption was modestly lower (0.37 vs. 0.4). This suggests a mild effect of HIF‐1α induction on proximal reabsorption. Moreover, DMOG lowered the NHE3 expression in controls but did not have a significant effect in the STN, but significantly lowered the NCC expression in both controls and STN kidney (p<0.05). Alteration in Na transport in the thick limbs and distal tubules along with expression of NKCC2 and ENaC are currently being performed.These data suggest that there is relative shift in Na transport to the distal segments of the nephron in early STN, which increases renal oxygen consumption required for Na transport. HIF‐1α activation improves kidney oxygen consumption by lowering Na transport in these segments, thus demonstrating a novel role of HIF‐1α in regulation of the coupling between tubular transport and metabolism.Grant Funding Source: NIH