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.
Regulated cell death (RCD) is characterized by distinct molecular execution mechanisms, but its initiation, progression, and biological consequences are increasingly recognized as being shaped by cellular metabolism. Bioenergetic state, redox homeostasis, nutrient availability, metal ion metabolism, inflammatory metabolism, and organelle function collectively determine cellular susceptibility to death and influence the activation and execution of diverse RCD programs. In this review, we synthesize the metabolic hallmarks of established, independently validated, and recently proposed forms of RCD, highlighting both their mechanistic diversity and their extensive metabolic convergence. We then examine the endogenous mechanisms that maintain metabolic homeostasis and discuss how their disruption reshapes cell death responses in human disease and therapeutic contexts. Together, these insights provide a guide to the metabolic landscape of RCD and reveal metabolism not only as a modifier of cell death, but as a fundamental determinant of when, how, and with what consequences cells die. We conclude by discussing key conceptual and mechanistic challenges and emerging opportunities for therapeutically exploiting the metabolic control of RCD.
