Neural and central mechanisms of kidney fibrosis after relief of ureteral obstruction

Huanjuan Su; Zhichen Yang; Ying Zhang; Bihui Yang; Zhanmei Zhou; Cailing Su; Wei Cao

doi:10.1016/j.isci.2023.106338

Neural and central mechanisms of kidney fibrosis after relief of ureteral obstruction

iScience. 2023 Mar 5;26(4):106338. doi: 10.1016/j.isci.2023.106338. eCollection 2023 Apr 21.

Authors

Huanjuan Su¹, Zhichen Yang^{1

2}, Ying Zhang³, Bihui Yang¹, Zhanmei Zhou¹, Cailing Su¹, Wei Cao¹

Affiliations

¹ Division of Nephrology, Nanfang Hospital, Southern Medical University, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Nephrology, 1838 North Guangzhou Avenue, Guangzhou 510515, P. R. China.
² Division of Nephrology, The Third Affiliated Hospital of Southern Medical University, 183 West Zhongshan Avenue, Guangzhou 510630, P. R. China.
³ Division of Nephrology, The Second Affiliated Hospital of Guangzhou Medical University, Changgang East Road, Guangzhou 510260, P. R. China.

Abstract

Obstructive uropathy from nephrolithiasis remains a leading cause of end-stage kidney disease. Mechanisms of kidney fibrosis after relief of ureteral obstruction represent opportunities for therapeutic intervention. Here, in mouse models of ureteral obstruction, we have combined methods of virus tracing and optogenetic techniques to identify an overactive central pathway in the paraventricular nucleus (PVN)-rostral ventrolateral medulla (RVLM) that determines the fibrotic fate of kidney after relief of the obstruction. The overactive pathway is driven by kidney afferent nerves that activate angiotensin II signaling in RVLM-projecting PVN neurons to drive sympathetic discharge back to the kidney. This causes the kidney to undergo fibrosis with loss of function. Blockade of sympathetic traffic or deletion of AT1a in PVN preserves the structure of the post-obstructed kidney. Human post-obstructed kidneys also demonstrate evidence of increased sympathetic nerve activity associated with a fibrotic outcome. Manipulating these neural elements is a potential treatment strategy.

Keywords: Biological sciences; Neuroscience; Systems neuroscience.