Fig. 1.

Schematic illustration of the altered mitochondrial metabolism in diabetes and the elements of paracrine succinate/GPR91 signaling that resulted in renin release. The accelerated glucose uptake, glycolysis, and TCA cycle leads to high metabolic rate and significant succinate accumulation in the mitochondria, cytosol, and interstitium. GPR91 signaling may be involved in the cell stress response to hypoxia and hyperglycemia, leading to the overactivation of normally protective signaling pathways but also results in the activation of the renin–angiotensin system (RAS) and related pathology. Some of the depicted elements of the hypoxia response (EPO erythropoietin, GLUT1 glucose transporter-1, HIF hypoxia-inducible factor, VEGF vascular endothelial growth factor) are known to be succinate- and/or GPR91-dependent in other cell types [24] but have not been characterized in MD cells (therefore, illustrated with a question mark). GPR91 uses the classic paracrine signaling cascade between the macula densa and renin-producing JG cells that involves the activation of ERK1/2, p38, COX-2, and the generation and release of PGE₂ from the macula densa. PGE₂ then acts on adjacent JG cells via the EP2/4 receptor and cAMP to trigger renin release. Modified from reference [24]