Circulating succinate is elevated in rodent models of hypertension and metabolic disease.
BACKGROUND
Recent evidence suggests that succinate, long known as an intermediate in the citric acid cycle, may also have a role as a signaling molecule through GPR91 and that activation of this receptor results in blood pressure (BP) elevation via the renin-angiotensin system. We sought to test the hypothesis that GPR91 contributes to BP elevation in hypertension. In addition we investigated whether elevated succinate in diabetes could contribute to the increased rate of gluconeogenesis in that condition.


METHODS
Circulating succinate concentration was measured using liquid chromatography tandem mass spectrometry in rodent models of hypertension and metabolic disease as well as in human hypertensives and type 2 diabetics in comparison to control subjects.


RESULTS
Elevated succinate was detected in spontaneously hypertensive rats (SHR), ob/ob mice, db/db mice, and fa/fa rats in comparison to their non-diseased controls. The changes in concentration are consistent with activation of GPR91. In contrast, neither human hypertensives nor diabetic patients had elevated succinate in comparison to controls.


CONCLUSIONS
These findings are consistent with a role of GPR91 signaling in rodent hypertension and diabetes models but not in the analogous human diseases.
Sadagopan
Nalini
N
Pfizer Global Research & Development, Ann Arbor, Michigan, USA.
Li
Wenlin
W
Roberds
Steven L
SL
Major
Terry
T
Preston
Gregory M
GM
Yu
Ying
Y
Tones
Michael A
MA
D000328:Adult; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D015992:Body Mass Index; D002851:Chromatography, High Pressure Liquid; D003920:Diabetes Mellitus / Q000097:blood; D005260:Female; D006801:Humans; D006973:Hypertension / Q000097:blood*; D008297:Male; D008659:Metabolic Diseases / Q000097:blood*; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009752:Nutritional Status; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D013386:Succinates / Q000097:blood*; D053719:Tandem Mass Spectrometry
D043562:Receptors, G-Protein-Coupled; D013386:Succinates; C523503:Sucnr1 protein, rat