Macula Densa Cells Are Systemic Interoceptors

Background: The macula densa (MD) is a specialized group of renal tubular epithelial cells traditionally recognized for their ability to sense variables in the local tissue environment (tubular fluid salt, metabolic factors) and regulate renal blood flow (RBF), glomerular filtration rate (GFR), and renin release. However, recent multiomic and intravital imaging functional studies identified their neuronal differentiation and suggested that MD cell functions are much more complex than previously thought. Their high excitability and calcium signaling activity, synaptic communication with sympathetic efferent and sensory afferent renal nerves, and the MD-specific expression of neurohormone (AVPR1A), metabolic, and incretin (GCGR, CCKBR) receptors suggest that MD cells can also sense variables in the systemic environment and regulate RBF, GFR, and tissue remodeling accordingly. The present study aimed to test if MD cells can directly sense and respond to systemic hemodynamic inputs that may be developed into mechanistic targets for glomerular diseases. Methods: Intracellular Ca2+ signaling by MD and other renal cell types was performed using intravital multiphoton microscopy (MPM) in Sox2–GCaMP5-tdTomato mice that ubiquitously express the genetically encoded calcium reporter GCaMP5 in all kidney cell types in response to agonist injection via the cannulated carotid artery and acute unilateral nephrectomy (UNX). Results: In contrast to other renal cell types,MD cells instantaneously responded to several diverse hemodynamic and metabolic stimuli with >2-fold increases in steady-state Ca2+ and/or firing frequency, including neurohormone administration (arginine-vasopressin, gastrin, b-isoproterenol), and metabolic states (hyperglycemia). Among all renal cell types, MD cells responded first and immediately to acute UNX with a significantly increased frequency of Ca2+ transients. Conclusion: This study identified the systemic interoceptor function of MD cells that may directly sense and respond to various systemic hemodynamic, metabolic, and endocrine stimuli to regulate kidney function. This new MD function may be a new mechanistic component of brain-kidney, gut-kidney, islet-kidney, and kidney-kidney axis and crosstalk to maintain body homeostasis.