Sensory neuron-derived CGRP ameliorates kidney injury and fibrosis via monocytes and macrophages.

Acute kidney injury (AKI) and its progression to chronic kidney disease (CKD) remain major unmet clinical challenges for which effective therapies are lacking. Although sensory neurons are recognized as key regulators of tissue injury and repair via neuroimmune crosstalk, their organization and function within the kidney are poorly understood. Here, we delineate a renal neuroimmune axis in which nociceptive neurons protect against ischemia-reperfusion (I/R)-induced kidney injury. Using whole-organ tissue clearing and three-dimensional imaging, we mapped an extensive network of nociceptive sensory fibers throughout the renal parenchyma. Ablation of TRPV1+ nociceptors aggravated renal dysfunction, tubular necrosis, and fibrosis after I/R, whereas chemogenetic activation conferred protection. Mechanistically, the sensory neuropeptide calcitonin gene-related peptide (CGRP), which is upregulated after injury, acts via the CALCRL-RAMP1 receptor complex on monocytes/macrophages, engaging the cAMP-PKA pathway to suppress pro-inflammatory cytokine and chemokine expression, thereby limiting myeloid infiltration and tubular injury. Importantly, we also found reduced renal CGRP abundance in kidneys from individuals with diabetes and older adults, who are at high risk for AKI and CKD, as well as in corresponding mouse models. In these vulnerable settings, exogenous CGRP more effectively reduced I/R-induced kidney injury. Our findings establish a dorsal root ganglia-kidney neuroimmune circuit that restrains I/R-induced renal inflammation and identify CGRP signaling as a potential therapeutic target to mitigate AKI and its progression to CKD, particularly in high-risk diabetic and elderly populations.