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.
Highlights
The renin-angiotensin system (RAS), including the intrarenal (Zhuo et al, 1998) and cerebral (Burkhalter et al, 2001; Davisson, 2003; Wright and Harding, 2011) entities, is activated during progression of chronic kidney disease (CKD) (Crowley and Coffman, 2012; Cao et al, 2015; VillarCheda et al, 2017)
The dCSF-CNs could act as a link between the cerebrospinal fluid and the brain for signal transmission in the development of kidney injury
CB-HRP could not pass through the ependyma, and no CB-labeled cells were found in the subfornical organ (SFO) or OVLT that lack the blood-brain barrier, making it a reliable substance to trace dCSF-CNs (Xing et al, 2015)
Summary
The renin-angiotensin system (RAS), including the intrarenal (Zhuo et al, 1998) and cerebral (Burkhalter et al, 2001; Davisson, 2003; Wright and Harding, 2011) entities, is activated during progression of chronic kidney disease (CKD) (Crowley and Coffman, 2012; Cao et al, 2015; VillarCheda et al, 2017). Intracerebroventricular injection of angiotensin receptor blockers (ARBs) or dCSF-CNs Contribute to Renal Fibrosis antioxidants dramatically alleviates the intrarenal RAS, oxidative stress, and sympathetic nerve activity, resulting in the alleviation of renal fibrosis (Cao et al, 2015) and prevention of ongoing ischemia-reperfusion renal damage (Cao et al, 2017). Accumulating evidence indicates that nuclei, such as SFO, PVN, hippocampus, and RVLM, affect the activation of cerebral and renal RAS during disease progression in rats with CKD, which were administered high salt diet (Cao et al, 2015), as well as in mice with ischemia-reperfusion injury (Cao et al, 2017). By transmitting and integrating the cerebrospinal fluid signals, the dCSF-CNs plays an important role in neuropathic pain and sodium homeostasis (Liu et al, 2014; Xing et al, 2015)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
