Succinate Recapitulates a Diabetes-Like Phenotype of Renal Dysfunction and Injury in the Absence of Hyperglycemia

Background: Succinate is a well-known intermediate in the tricarboxylic acid (Krebs) cycle, where it is converted to form fumarate by succinate dehydrogenase from succinyl-CoA. Surprisingly, besides as a general metabolic intermediate, succinate can selectively activate orphan G receptor GPR91, which is highly expressed in the kidney, including glomerular vasculature, the macula densa (MD), proximal tubules, distal tubules, the cortical thick ascending limb of (cTAL) Henle’s loop, and the cortical as well as medullary collecting duct (CD). The level of succinate in patients with type 2 diabetes and obesity was much higher than healthy controls. However, the causative role of succinate in renal function is still unknown. Considering the excess succinate concentration, abundant expression of GPR91, and the importance of the kidney, we speculated that succinate could affect renal function. Methods: Male C57 BL/6 mice provided sterile drinking water containing 4% succinate ad libitum for 8 weeks and 12 weeks were used to investigate the effect of succinate on important renal functions. Results: Succinate administration markedly promoted water reabsorption via upregulating AQP2 protein and gene expression. Furthermore, Na + retention was significantly enhanced by succinate via increasing ENaC protein and gene expression. Moreover, succinate caused severe damage to the kidney, including glomerulus and proximal tubule, and tubulointerstitial fibrosis. These pathological changes were consistent with characteristics reported in diabetic kidney disease both in clinical patients and animal models. Conclusions: Other than a common metabolic intermediate in the Krebs cycle, elevated succinate in the circulation causes renal dysfunction and damage and recapitulates a diabetes-like phenotype of kidney disease, indicating that eliminating succinate from blood may improve clinic intervention in diabetic kidney disease. Funding Information: This study was supported by the National Natural Science Foundation of China (Grants 82070888, 82070882, 81770808, 81872165, 81701414, 81871211, and 81702879); National Key RD Guangdong Provincial Key RD Key Project of Nature Science Foundation of Guangdong Province, China (Grant 2019B1515120077); Guangdong Natural Science Fund (Grant 2019A1515011810, 2021A1515010434); Guangdong Science Technology Project (Grant 2017A020215075); Key Sci-Tech Research Project of Guangzhou Municipality, China (Grants 201803010017, 201807010069, and 202002020022); 2017 and 2019 Milstein Medical Asian American Partnership Foundation Research Project Award in Translational Medicine. Declaration of Interests: None. Ethics Approval Statement: All animal procedures were approved by the Animal Care and Use Committee of Sun Yat-Sen University (Ethics Committee of ZSSOM on Laboratory Animal Care No. 2020001017; Guangzhou, China).