Targeted ablation of distal cerebrospinal fluid-contacting nucleus alleviates renal fibrosis in chronic kidney disease

Abstract

The potential function of distal cerebrospinal fluid-contacting nucleus (dCSF-CNs) in chronic kidney disease (CKD) development is poorly understood. We hypothesized that dCSF-CNs might affect the renin-angiotensin system (RAS) in kidney injury progression, with dCSF-CNs ablation potentially alleviating local RAS and renal fibrosis in rats after five-sixths nephrectomy (5/6Nx). Part of rats were randomly administered artificial cerebrospinal fluid (aCSF) intracerebroventricularly (icv), followed by 5/6Nx or sham operation; and other part of rats were administered Cholera toxin B subunit conjugated with saporin (CB-SAP) for dCSF-CNs lesion before 5/6Nx. The effect of CB-SAP on dCSF-CNs ablation was confirmed by double immunofluorescence staining. RAS component, NOX2 and c-fos levels in the subfornical organ (SFO), hypothalamic paraventricular nucleus (PVN) and hippocampus, as well as tyrosine hydroxylase (TH) and c-fos positive cells in rostral ventrolateral medulla (RVLM) were assessed. Next, the levels of RAS components (angiotensinogen [AGT], angiotensin-converting enzyme [ACE], Ang II type 1 receptor [AT1R], angiotensin-converting enzyme 2 [ACE2], and Mas receptor), NADPH oxidases (NOX2 and catalase), inflammatory cytokines (monocyte chemotactic protein 1 [MCP-1] and IL-6), and fibrotic factors (fibronectin and collagen I) were assessed. Less CB-labeled neurons were found in dCSF-CNs of CB-SAP-treated rats compared with 5/6Nx animals. Meanwhile, CB-SAP downregulated AGT, Ang II, AT1R, NOX2, catalase, MCP-1, IL-6, fibronectin, and collagen I, and upregulated ACE2 and Mas receptor, compared with CKD rats. More TH and c-fos positive cells were found in RVLM of 5/6Nx rats but the number decreased after dCSF-CNs ablation. Targeted dCSF-CNs ablation could alleviate renal inflammation and fibrosis in chronic kidney injury by inhibiting cerebral and renal RAS/NADPH oxidase.