The Succinate Receptor as a Novel Therapeutic Target for Oxidative and Metabolic Stress-Related Conditions

Abstract

The succinate receptor (also known as GPR91) is a G protein-coupled receptor that is closely related to the family of P2Y purinoreceptors. It is expressed in a variety of tissues, including blood cells, adipose tissue, the liver, retina, and kidney. In these tissues, this receptor and its ligand succinate have recently emerged as novel mediators in local stress situations, including ischemia, hypoxia, toxicity, and hyperglycemia. Amongst others, the succinate receptor is involved in recruitment of immune cells to transplanted tissues. Moreover, it was shown to play a key role in the development of diabetic retinopathy. However, most prominently, the role of locally increased succinate levels and succinate receptor activation in the kidney, stimulating the systemic and local renin–angiotensin system, starts to unfold: the succinate receptor is a key mediator in the development of hypertension and possibly fibrosis in diabetes mellitus and metabolic syndrome. This makes the succinate receptor a promising drug target to counteract or prevent cardiovascular and fibrotic defects in these expanding disorders. Recent development of SUCNR1-specific antagonists opens novel possibilities for research in models for these disorders and may eventually provide novel opportunities for the treatment of patients.

Succinate: a metabolic signal in inflammation

“…SUCNR1 is highly expressed in mouse kidney, liver, spleen, small intestine [27], and on DCs [8]. The signaling cascade activated by SUCNR1 has only recently emerged [29] (Figure 3). Human embryonic kidney (HEK) 293 cells stably expressing SUCNR1 were stimulated with succinate, resulting in inositol trisphosphate (IP3) accumulation, calcium mobilization, and extracellular signalregulated kinase (ERK) phosphorylation [27] similar to Gi and Gq signaling cascades.…”

Hemodynamic effects of succinate-containing dialyzing solution

“…При этом сукцинат внутри клетки увеличивает про-дукцию VEGF за счет ингибиции пролилгидроксилазы -фермента, ответственного за катаболизм фактора, инду- цируемого гипоксией (HIF), активирующего экспрессию генов VEGF, в то время как стимуляция мембранных ре-цепторов GPR91 сукцината при повышении его концен-трации во внеклеточном пространстве стимулирует вы-свобождение VEGF независимо от HIF [35][36][37]. Таким образом, гипонатриемический эффект СДР может быть обусловлен высвобождением ионов натрия из депо в сое-динительной ткани в кровоток, что улучшает уравнове-шивание содержания натрия в крови и межклеточной жидкости во время ГД.…”

Insight into SUCNR1 (GPR91) structure and function

“…In the present article we will use the AA numbering according to a 330-AA protein, although the current databases sometimes report SUCNR1 as being 334-AA long. There is a high degree of homology between man and mouse (68%) with the exception of the C-terminal tail, which is 12 AA shorter in rodents (Ariza et al, 2012;Wittenberger et al, 2001). In humans, other genes have been found on the same locus and consist in a cluster of P2Y 1 ,P2Y 12 ,P2Y 13 ,H963 (GPR171) and GPR87 (Abbracchio et al, 2006).…”

“…In their seminal paper, Wittenberger et al speculated that all these receptors originated from a common ancestor, presumably a nucleotide receptor (Wittenberger et al, 2001). Several comprehensive reviews have been published on the receptor or succinate role in metabolic/oxidative stress conditions (Ariza et al, 2012;PetiPeterdi et al, 2013). The present work, in addition to discussing the most recent developments, considers extensively the mechanisms linking SUCNR1-activated signaling pathways and all (patho)physiological states where the receptor might play a role.…”