Luminal Succinate and Acidosis: Effects on Blood Pressure

Abstract

Succinate (Suc) is well known as a Krebs cycle intermediate but extracellular Suc has been associated with a variety of pathologic processes. A distinct GPCR receptor for Suc (Sucnr1) was identified in the kidney and some (but not all) studies have documented that Suc infusions increase blood pressure (BP) via paracrine signaling. Luminal Suc has been reported to activate Sucnr1, stimulate renin release and alter BP in certain circumstances.In the nephron, apical NaDC1 (Na+ dicarboxylate cotransporter) is located only in the proximal tubule, reabsorbs filtered citrate and Suc, and is upregulated in acidosis. Thus NaDC1’s regulation is important in preventing calcium stones and promoting acid‐base homeostasis via effects of citrate reabsorption but its role in BP regulation is not known. Our purpose was to explore the role of NaDC1, luminal Suc, and acidosis in BP regulation.To address these issues, we used NaDC1 KO and WT mice on normal diet or 72 hr acid diet (0.4 M HCl). In initial clearance (CL) studies, KO mice had increased urinary Suc and citrate but no statistical difference in BP even with the infusion of 1 mmol/kg Suc. Suc infused WT did not have increased BP in CL. Acid diet reduced urinary Suc in WT, but had no consistent effect on BP in either KO or WT in CL.Since recent reports suggested that Suc may affect BP exclusively during more active periods (nocturnal in mice), we additionally examined BP using telemetry (BP/T) for 24/7 monitoring. During 8 PM‐5 AM on a normal diet mean arterial pressure (MAP) was significantly higher in KO than in WT. Acidosis appeared to lessen these BP/T differences. As an example of this, Figure 1 shows MAP at selected time points in a 24 hour cycle, 8 AM, 9 PM, 5AM and 8AM.To determine whether Sucnr1 gene expression alterations could influence these results, droplet digital PCR (Bio Rad) was performed. Data are expressed as copy numbers of target gene in 1 ng PCR reaction. Thus with ddPCR we determined on normal diet, Sucnr1 expression levels in KO (1343.6 ± 51) are significantly increased from that in WT (1052.8 ± 50, p< 0.007). Furthermore, on 72 hr acid diet the expression of Sucnr1 in KO (1039.6 ± 33) fell while in WT increased to 1148 ± 50, p <0.006).In sum, on normal diet, Sucnr1 expression is significantly greater in NaDC1 KO vs WT and in chronic acidosis expression decreases in KO but increases in WT. On normal diet MAP in KO is significantly higher than in WT while acidosis diminishes these differences (by slightly lowering KO MAP but raising slightly WT MAP).These diverse findings illustrate that NaDC1 (and presumably luminal Suc) can regulate BP but that this regulation varies with time of day (or associated factors such as activity) and acidosis.Support or Funding InformationNIH, DCI PTRF, LA CaTSMAP differences in NaDC1 KO mice vs WT mice on a normal dietFigure 1