Targeting inflammation in perivascular cells and neuroimmune interactions for treating kidney disease

Abstract

Inflammation plays a crucial role in the pathophysiology of various kidney diseases. Kidney perivascular cells (pericytes/fibroblasts) are responsible for producing proinflammatory molecules, promoting immune cell infiltration, and enhancing inflammation. Vascular adhesion protein-1, expressed in kidney perivascular cells, is an ectoenzyme that catalyzes the oxidative deamination of primary amines with the production of hydrogen peroxide in the extracellular space. Our study demonstrated that blocking this enzyme suppressed hydrogen peroxide production and neutrophil infiltration, thereby reducing renal ischemia-reperfusion injury. Sphingosine 1-phosphate (S1P) signaling was also observed to play an essential role in the regulation of perivascular inflammation. S1P, which is produced in kidney perivascular cells, is transported into the extracellular space via spinster homolog 2, and then binds to S1P receptor-1 expressed in perivascular cells. Upon injury, inflammatory signaling in perivascular cells is enhanced by this pathway, thereby promoting immune cell infiltration and subsequent fibrosis. Furthermore, inhibition of S1P transport by spinster homolog 2 reduces kidney fibrosis. Hypoxia-inducible factor-prolyl hydroxylase inhibitors can restore the capacity for erythropoietin production in kidney perivascular cells. Animal data suggested that these drugs could also alleviate kidney and lipid inflammation although the precise mechanism is still unknown. Neuroimmune interactions have been attracting significant attention due to their potential to benefit patients with inflammatory diseases. Vagus nerve stimulation is one of the most promising strategies for harnessing neuroimmune interactions and attenuating inflammation associated with various diseases, including kidney disease. Using cutting-edge tools, the vagal afferents-C1 neurons-sympathetic nervous system-splenic nerve-spleen-kidney axis responsible for kidney protection induced by vagus nerve stimulation was identified in our study. Further research is required to decipher other crucial systems that control kidney inflammation and to determine whether these novel strategies can be applied to patients with kidney disease.

Keywords: Acute kidney injury; Chronic kidney disease; Fibroblasts; Neuroimmune interactions; Pericytes; Vagus nerve stimulation.

Fig. 1

VAP-1 in pericytes enhances neutrophil infiltration into the injured kidney by generating hydrogen peroxide (H₂O₂). Reprinted from [20], with permission from International Society of Nephrology (Elsevier). VAP-1 expressed in pericytes catalyzes the oxidative deamination of primary amines, resulting in the production of H₂O₂ in the extracellular space. This generates a local H₂O₂ gradient, which in turn enhances the infiltration of neutrophils into the injured kidney, thus worsening the injury

Fig. 2

SphK2/S1P/Spns2/S1P1 axis enhances inflammatory signaling in kidney perivascular cells (reprinted from [27]). S1P, which is predominantly produced by SphK2 in kidney perivascular cells, is transported into the extracellular space through Spns2 and binds to S1P1 in an autocrine manner. This axis enhances inflammatory signaling through production of proinflammatory cytokines/chemokines on injury, which promotes immune cell infiltration and subsequent fibrosis

Fig. 3

The inflammatory reflex. Reprinted from [44], with permission from Elsevier. Please refer to the text for details. DAMPs damage-associated molecular patterns, PAMPs pathogen-associated molecular patterns, PRRs pattern recognition receptors, CNS central nervous system, ChAT choline acetyltransferase, DMV dorsal motor nucleus of the vagus, NTS nucleus tractus solitarius, α7nAChR α7 nicotinic acetylcholine receptor

Fig. 4

Proposed mechanism of kidney protection by vagal afferent stimulation (reprinted from [55]). Please refer to the text for details. NTS nucleus tractus solitaries, IML intermediolateral cell column