Addition of fructose to a high-salt diet increases the expression of aldosterone-response genes

Abstract

Proximal tubules (PT) reabsorb fructose via a Na-dependent mechanism. Knocking out the Sodium-Linked Cotransporter 5 (SGLT5, Slc5A10) increases urinary fructose. Elevated dietary fructose increases transport rates in PT, contributing to salt-sensitive hypertension. Whether dietary fructose also elevates transport in other segments of the nephron that do not express known fructose transporters, is a matter of debate. The aldosterone-sensitive distal tubule (ASDT) consists of the late distal convoluted tubule, connecting tubule and collecting duct, and it is essential for regulating fluid volume and blood pressure. We hypothesize that fructose metabolism in PT could affect aldosterone signaling in the distal tubule of rats fed a high-salt diet. We obtained kidney-cortex bulk RNAseq transcriptomes from wild-type and SGLT 5 (-/-) Sprague Dawley rats fed a solid diet containing 4% NaCl and either 20% fructose (FHS) or glucose (GHS). We used Weighted Correlation Network Analysis (WGCNA) to: 1st) create a gene coexpression network of the kidney cortex, and 2nd) identify genes whose expression changes in response to fructose in both wild-type and SGLT5 (-/-). Then, we used open source transcriptomes from mouse ASDT epithelial cells (PMID: 29521601) treated with and without aldosterone to map genes whose expression changes in response to aldosterone to the coexpression modules correlated with dietary fructose. The mouse transcriptome contained 8619 genes that mapped to the rat kidney transcriptome. Of these genes, 454 were significantly changed by aldosterone (ALDO). WGCNA yielded 35 coexpression modules. Five modules were significantly associated with dietary fructose in wild-type. These correlations were blunted in SGLT5 (-/-). Enrichment analysis indicated that 4 of the 35 modules were enriched for ALDO, 2 of which (Paleturquoise: p<5x10-6 and Orange: p<3x10-2) were also correlated with fructose in wild-type (Paleturquoise: p<3x10-2 and Orange: p<4x10-2). Paleturquoise contained 108 genes of which 74 mapped to the mouse transcriptome, and 15 to ALDO. Ontology enrichments in Paleturquoise indicate that it contains genes involved in Na, Cl and HCO3 transport. Importantly, the Amiloride-Sensitive Epithelial Sodium Channel Alpha Subunit (ENaCα; Scnn1a) and the Thiazide-Sensitive Sodium-Chloride Cotransporter (NCC; Slc12a3) belong in this module. Orange contained 148 genes, of which 34 mapped to mouse transcriptomes, and only 5 to ALDO. Orange’s ontology enrichment was largely immune processes, which explain the low number of mapping genes, as ALDO is a tubular epithelial cell signature. We conclude that even on a high-salt diet, kidneys from rats given fructose present higher transcriptional activation of aldosterone-responsive genes than those given glucose. In addition, Orange may be mediating proinflammatory actions of fructose. These effects depend on fructose reabsorption by PTs, as SGLT5 deletion blunts the effects of HSF on ALDO-enriched modules. CWRU-SOM Department of Physiology and Biophysics Pitot grant to A.G-V. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.