Renal denervation prevents long-term sequelae of ischemic renal injury

Abstract

Signals that drive interstitial fibrogenesis after renal ischemia reperfusion injury remain undefined. Sympathetic activation is manifest even in the early clinical stages of chronic kidney disease and is directly related to disease severity. A role for renal nerves in renal interstitial fibrogenesis in the setting of ischemia reperfusion injury has not been studied. In male 129S1/SvImJ mice, ischemia reperfusion injury induced tubulointerstitial fibrosis as indicated by collagen deposition and profibrotic protein expression 4 to 16 days after the injury.. Leukocyte influx, proinflammatory protein expression, oxidative stress, apoptosis, and cell cycle arrest at G2/M phase were enhanced after ischemia reperfusion injury. Renal denervation at the time of injury or up to 1 day post-injury improved histology, decreased proinflammatory/profibrotic responses and apoptosis, and prevented G2/M cell cycle arrest in the kidney. Treatment with afferent nerve-derived calcitonin gene-related peptide (CGRP) or efferent nerve-derived norepinephrine in denervated and ischemia reperfusion injury-induced kidneys mimicked innervation, restored inflammation and fibrosis, induced G2/M arrest, and enhanced TGF-β1 activation. Blocking norepinephrine or CGRP function using respective receptor blockers prevented these effects. Consistent with the in vivo study, treatment with either norepinephrine or CGRP induced G2/M cell cycle arrest in HK-2 proximal tubule cells, whereas antagonists against their respective receptors prevented G2/M arrest. Thus, renal nerve stimulation is a primary mechanism and renal nerve-derived factors drive epithelial cell cycle arrest and the inflammatory cascade causing interstitial fibrogenesis after ischemia reperfusion injury.

Targeting neural reflex circuits in immunity to treat kidney disease

“…Experimental evidence suggests that VNS and therapeutic ultrasound protect the kidney from acute ischaemic injury by stimulating the CAP 13,67–69 . Furthermore, data suggest that neural pathways mediate inflammation and hyper tension 124 as well as kidney fibrosis 99,100 , and that stimulation of C1 neurons in the brainstem activates the CAP 76 . C1 neurons respond to a variety of stimuli, including danger signals, and could be a central component of the immune reflex circuit.…”

“…In animal models, renal denervation prevented the development of renal fibrosis after unilateral ureteral obstruction 99 or IRI 100 . Fibrotic and inflammatory responses in these denervated kidneys were, however, observed following local infusion of noradrenaline (which is found in sympathetic efferents) or CGRP (which is found in sensory afferents).…”

Renal Allograft Fibrosis: Biology and Therapeutic Targets

“…Renal denervation was suggested as a potential treatment for resistant hypertension, albeit recent clinical studies were inconclusive (218). In various models of tubulointerstitial fibrosis, renal denervation exerts potent blood-pressure-independent anti-fibrotic effects, but this was only effective if performed before fibrosis was induced (219,220). The potential clinical applicability is yet unknown, in particular since experimental studies suggested that effective reinnervation takes place in kidneys after denervation (221).…”

Exogenous spermidine ameliorates tubular necrosis during cisplatin nephrotoxicity

“…Renal function was then assessed by determining the concentration of plasma creatinine using a QuantiChrom Creatinine kit (Bio-Assay Systems, Hayward, CA, USA) [22, 23]. …”