Silencing of Central (Pro)renin Receptor Ameliorates Salt-Induced Renal Injury in Chronic Kidney Disease.

Abstract

Aims: A high-salt diet can aggravate oxidative stress, and renal fibrosis via the brain and renal renin-angiotensin system (RAS) axis in chronic kidney disease (CKD) rats. (Pro)renin receptor (PRR) plays a role in regulating RAS and oxidative stress locally. However, whether central PRR regulates salt-induced renal injury in CKD remains undefined. Here, we hypothesized that the reduction of central PRR expression could ameliorate central lesions and thereby ameliorate renal injury in high-salt-load CKD rats. Results: We investigated RAS, sympathetic nerve activity, oxidative stress, inflammation, and tissue injury in subfornical organs and kidneys in high-salt-load 5/6 nephrectomy CKD rats after the silencing of central PRR expression by intracerebroventricular lentivirus-RNAi. We found that the sympathetic nerve activity was reduced, and the levels of inflammation and oxidative stress were decreased in both brain and kidney. Renal injury and fibrosis were ameliorated. To explore the mechanism by which central inhibition of PRR expression ameliorates kidney damage, we blocked central MAPK/ERK1/2 and PI3K/Akt signaling pathways as well as angiotensin converting enzyme 1-angiotensin II-angiotensin type 1 receptors (ACE1-Ang II-AT1R) axis. Salt-induced overexpression of renal RAS, inflammation, oxidative stress, and fibrosis in CKD rats were prevented by central blockade of the pathways. Innovation: This study provides new insights into the mechanisms underlying salt-induced kidney damage. Targeting central PRR or PRR-mediated signaling pathway may be a novel strategy for the treatment of CKD. Conclusions: These results suggested that the silencing of central PRR expression ameliorates salt-induced renal injury in CKD through Ang II-dependent and -independent pathways.

• Authors: Jiawen Li, Min Liang, Tao Zeng, Minzi Qiu, Mengbi Zhang, Shaoling Jiang, Lishan Tan, Aiqing Li
• Journal: Antioxidants & redox signaling (Antioxid Redox Signal) Vol. 35 Issue 2 Pg. 93-112 (07 10 2021) ISSN: 1557-7716 [Electronic] United States
• PMID: 32757619 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Cell Surface
• Sodium, Dietary
• Angiotensin II
• ATP6AP2 protein, rat
• Vacuolar Proton-Translocating ATPases

Topics

• Angiotensin II (metabolism)
• Animals
• Disease Models, Animal
• Gene Expression Regulation (drug effects)
• Gene Silencing
• Genetic Vectors (administration & dosage, genetics)
• Infusions, Intraventricular
• Lentivirus (genetics)
• MAP Kinase Signaling System (drug effects)
• Male
• Nephrectomy (adverse effects)
• RNA Interference
• Rats
• Rats, Sprague-Dawley
• Receptors, Cell Surface (antagonists & inhibitors, genetics, metabolism)
• Renal Insufficiency, Chronic (chemically induced, genetics, metabolism, therapy)
• Renin-Angiotensin System (drug effects)
• Sodium, Dietary (adverse effects)
• Vacuolar Proton-Translocating ATPases (antagonists & inhibitors, genetics, metabolism)