Functional expression of the amylin receptor Amy3 in the macula densa

Organ crosstalk, including the gut-kidney axis, plays important roles in the physiological control and maintenance of whole-body energy metabolism and homeostasis. Food intake is known to increases renal blood flow (RBF) and glomerular filtration rate (GFR) to facilitate urinary excretion of metabolic waste postprandially. Gut hormones (incretins) produced in the gastrointestinal tract and pancreas and secreted into the blood act on many organs to aid digestion and whole-body metabolism. While incretins are known to directly regulate the function of many different renal cell types, the key cell and molecular mechanisms of the gut-kidney axis are not fully understood. Macula densa (MD) cells play central roles in controlling renal hemodynamics, renin secretion, and tissue remodeling. We recently reported the high MD-specific expression of gastrin (Cckbr) and glucagon (Gcgr) receptors, suggesting that MD cells may play much more complex sensory and regulatory roles in the kidney and the body than previously thought, including their potential role as a new key element in the gut-kidney axis. Another incretin, amylin is secreted by pancreatic b-cells, controls postprandial glycemia and satiety, and is an exciting new target in anti-obesity drug development. However, the renal effects of amylin and the intrarenal expression of amylin receptors (Amyr) are not fully understood. Amyrs are heterodimers consisting of the calcitonin receptor (Calcr), and one of three receptor activity-modifying proteins (Ramps). This study tested the hypothesis that amylin has direct actions on MD cells as a new mechanism of gut-kidney crosstalk in the control of body metabolism. High-resolution MD bulk and single-cell transcriptome analysis detected Calcr expression and a 6-fold enrichment of Ramp3 in MD vs control cells. Immunofluorescence on human kidney tissue sections translated and validated the MD-specific expression of Ramp3. Single cell MD Ca 2+ signaling was analyzed in vivo using intravital multiphoton microscopy (MPM) of Sox2-GCaMP6/tdTomato mice that express the ratiometric Ca 2+ reporter GCaMP6f/tdTomato in all renal cells. The injection of recombinant amylin (0.25 ug/animal in PBS bolus) into the cannulated carotid artery caused immediate and significant elevations in cell calcium (approximately 3-fold elevations in baseline) in MD cells, but not in other renal cell types. This study uncovered new regulatory mechanisms of systemic metabolism via islet-kidney crosstalk that involves the role of pancreas-derived amylin acting specifically and directly on MD cells in the kidney. MD sensing and responding to amylin may be involved in postprandial adjustments of renal hemodynamics, renin, and renal excretion. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.