Rapgef3, also known as the gene encoding exchange protein directly activated by cAMP isoform 1 (EPAC1), is a guanine nucleotide exchange factor for GTPases Rap1 and Rap2 [2,3]. EPAC1-mediated cAMP signaling is spatiotemporally coordinated through interactions with various cellular partners, functioning as an important stress response switch and being involved in pathophysiological conditions of multiple diseases [3].

In vivo, selective pharmacological activation of EPAC1 increases brown adipose tissue (BAT) mass and white fat browning, enhancing energy expenditure and reducing diet-induced obesity [1]. EPAC1 specifically coordinates a network of regulators for proliferation in thermogenic adipocytes but not white adipocytes, and its loss in PDGFRα-positive preadipocytes impedes BAT growth and worsens diet-induced obesity [1]. In glomerulonephritis, total or podocyte-specific conditional deletion of Epac1 (encoded by Rapgef3) in mice accelerates the progression of the disease, with gene expression analysis showing major alterations in mitochondrial and metabolic processes in podocytes [4]. Mice lacking Epac1 (Rapgef3) also have increased microvascular permeability, indicating Epac1-dependent restriction of baseline permeability [5].

In conclusion, Rapgef3-encoded EPAC1 plays crucial roles in energy metabolism, such as in BAT growth and white fat browning, and in maintaining physiological functions in the kidney and microvasculature. The study of Rapgef3 knockout or conditional knockout mouse models has provided valuable insights into its functions in these specific biological processes and disease conditions, highlighting its potential as a therapeutic target for metabolic and kidney-related diseases.