Ps-bpb07-6: novel humoral and neuronal pathways for direct blood pressure control by macula densa cells

Objective: According to traditional physiological knowledge, macula densa (MD) cells of the juxtaglomerular apparatus (JGA) in the kidney maintain body fluid homeostasis and blood pressure (BP) indirectly by controlling renal and glomerular hemodynamics and renin secretion based on local sensory inputs. However, recently identified microanatomical (long, axon-like basal cell processes, secretory vesicles) and functional (high level of protein synthesis) features of MD cells suggest they perform non-traditional functions. The present study addressed the hypothesis that MD cells can directly and acutely control distant cardiovascular organ functions and blood pressure via novel secreted hormones and communications with renal nerves. Design and method: A comprehensive research approach used transgenic mouse models (MD-GFP, MD-Ai27 mice that selectively express the depolarizing channel rhodopsin ChR2 in MD cells), intravital multiphoton imaging, systemic BP monitoring via the cannulated carotid artery, whole mount kidney imaging and 3D analysis, and single-cell transcriptomic analysis. Results: Bulk and single cell MD transcriptome analysis identified the high expression of secreted angiogenic and vasoactive factors (Pappa2, Vash2, Cyr61, Aard, Pamr1) and synaptic proteins (Unc5d, Tenm2, Hpcal4, Nsg2, Syp, Syt5, Grin2c, Gabrr2, Begain) with their altered kidney and plasma levels in disease and MD gain and loss-of-function conditions. Immunohistochemistry and 3D tissue volume rendering of optically cleared whole-mount MD-GFP kidneys identified the high MD expression of synaptophysin and the close anatomical association between MD cell basal processes and tyrosin-hydroxylase (TH)+ or calcitonin gene-related peptide (CGRP)+ sympathetic and sensory nerve endings. Optogenetic MD stimulation was induced by blue light (470 nm) exposure of the whole left kidney of MD-Ai27 mice, which maneuver acutely and reversibly increased systemic BP by 22 ± 5mmHg (P < 0.05, n = 5). Conclusions: MD cells secrete hormones that target the vasculature and form synapses with sympathetic and sensory renal nerves. These novel MD and JGA pathways may be involved in direct BP control and represent exciting future therapeutic opportunities for renal and cardiovascular disease and hypertension.