Abstract Body: Introduction: Continuous measurements (24/7) of arterial pressure (AP) and renal blood flow (RBF), along with intermittent sampling of arterial and renal venous blood and urine in freely moving rats, have enabled the determination of sequential changes in global substrate metabolism and their association with physiological responses in the kidney. It was found that salt loading in Sprague-Dawley (SD) rats resulted in an increase in RBF and renal O₂ consumption with minimal changes in AP. At the same time, TCA cycle pathway was downregulated with reduced metabolism of free fatty acids and amino acids, while glycolysis was upregulated, in the kidney cortex (Cx). In contrast, no significant changes were observed in metabolism-related pathways in the outer medulla (OM). (PMID: 37575482). Here, we report transcriptomic responses of Dahl salt-sensitive (SS) rats to the HS diet as compared to the salt-resistant SD rats.
Method: Male SS rats were fed a 0.4% NaCl (LS) diet. At 8 weeks of age, the rats were implanted with an RBF probe together with an arterial and a renal venous catheter. RBF and AP were measured continuously, and arterial and renal venous blood and urine were sampled when rats were fed the LS and on days 7, 14, and 21 after switching to the 4.0% NaCl (HS) diet. From separate groups of rats subjected to the same protocol, Cx and OM were removed for mRNAseq analysis (Novogene, Inc).
Results: When switching to the HS diet, mean AP of SS rats rose from 122 ± 2 to 164 ± 5 mmHg by HS21. RBF (mL/min/g kidney weight) fell significantly over the 3 weeks of the HS diet averaging 7.2 ± 0.6 (LS) to 4.6 ± 0.7 (HS21). The gene set enrichment analysis (GSEA) of the mRNAseq data revealed that only a few metabolic pathways were enriched in HS7 in Cx such as glycosphingolipid biosynthesis, while metabolic pathways such as linolenic acid and arachidonic acid metabolism and glycosphingolipid biosynthesis were enriched in OM. Downregulation of the lysine degradation and glutathione metabolic pathways was observed in both Cx and OM in HS21. In general, fewer metabolic pathways responded to HS in SS rats compared to SD in Cx (22 in SD vs 7 in SS).

Conclusion: The Cx of SS rats appear less capable of adjusting to the increased metabolic needs imposed by a HS diet compared to SD rats in contrast to the OM. The functional implications of this are being examined and the metabolomic analysis of blood, tissue and urine samples is currently in progress at the JAX lab.