Activation of the renal GLP-1R leads to expression of Ren1 in the renal vascular tree.

The GLP-1 receptor (GLP-1R) in the kidney is expressed exclusively in vascular smooth muscle cells in arteries and arterioles. Downstream effects of the activation of the renal vascular GLP-1R are elusive but may involve regulation of the renin-angiotensin-aldosterone system (RAAS). The expression of Ren1 in the mouse renal vasculature was investigated by in situ hybridization after a single subcutaneous dose of liraglutide, semaglutide and after repeated injections of liraglutide. Single and repeated exposure to GLP-1R agonists induced expression of Ren1 in the renal vascular smooth muscle cell compartment compared with vehicle injected controls (p < .0001) for both semaglutide and liraglutide. The present data show a robust induction of Ren1 expression in the vascular smooth muscle cells of the kidney after single and repeated GLP-1R activation and this renin recruitment may be involved in the effects of GLP-1R agonist treatment on kidney disease.

Recruited renin-containing renal microvascular cells demonstrate the calcium paradox regulatory phenotype.

Renin is the critical regulatory enzyme for production of angiotensin (Ang)-II, a potent vasoconstrictor involved in regulating blood pressure and in the pathogenesis of hypertension. Chronic sodium deprivation enhances renin secretion from the kidney, due to recruitment of additional cells from the afferent renal microvasculature to become renin-producing rather than just increasing release from existing juxtaglomerular (JG) cells. JG cells secrete renin inversely proportional to extra- and intracellular calcium, a unique phenomenon characteristic of the JG regulatory phenotype known as the "calcium paradox." It is not known if renin secreted from recruited renin-containing cells is regulated similarly to native JG cells, and therefore acquires this JG cell phenotype. We hypothesized that non-JG cells in renal microvessels recruited to produce renin in response to chronic dietary sodium restriction would demonstrate the calcium paradox, characteristic of the JG cell phenotype. Histology showed recruitment of upstream arteriolar renin in response to sodium restriction compared to normal-diet rats. Renin fluorescence intensity increased 53% in cortices of sodium-restricted rats (P<0.001). We measured renin release from rat afferent microvessels, isolated using iron oxide nanopowder and incubated in either normal or low-calcium media. Basal renin release from normal sodium-diet rat microvessels in normal calcium media was 298.1±44.6 ng AngI/mL/hour/mg protein, and in low-calcium media increased 39% to 415.9±71.4 ng AngI/mL/hour/mg protein (P<0.025). Renin released from sodium-restricted rat microvessels increased 50% compared to samples from normal-diet rats (P<0.04). Renin release in normal calcium media was 447.0±54.3 ng AngI/mL/hour/mg protein, and in low-calcium media increased 36% to 607.6±96.1 ng AngI/mL/hour/mg protein (P<0.05). Thus, renin-containing cells recruited in the afferent microvasculature not only express and secrete renin but demonstrate the calcium paradox, suggesting renin secretion from recruited renin-containing cells share the JG phenotype for regulating renin secretion.