Angiotensin II type-2-receptor stimulation ameliorates focal and segmental glomerulosclerosis in mice.

Abstract

Podocyte damage and loss are the early event in the development of focal segmental glomerulosclerosis (FSGS). Podocytes express angiotensin II type-2-receptor (AT2R), which may play a key role in maintaining kidney integrity and function. Here, we examined the effects of AT2R deletion and AT2R agonist compound 21 (C21) on the evolution of FSGS. FSGS was induced by adriamycin (ADR) injection in both male wild-type (WT) and AT2R knockout (KO) mice. C21 was administered to WT-FSGS mice either one day before or 7 days after ADR (Pre-C21 or Post-C21), using two doses of C21 at either 0.3 (low dose, LD) or 1.0 (high dose, HD) mg/kg/day. ADR-induced FSGS was more severe in AT2RKO mice compared with WT-FSGS mice, and included profound podocyte loss, glomerular fibrosis, and albuminuria. Glomerular cathepsin L expression increased more in AT2RKO-FSGS than in WT-FSGS mice. C21 treatment ameliorated podocyte injury, most significantly in the Pre C21-HD group, and inhibited glomerular cathepsin L expression. In vitro, Agtr2 knock-down in mouse podocyte cell line given ADR confirmed the in vivo data. Mechanistically, C21 inhibited cathepsin L expression, which protected synaptopodin from destruction and stabilized actin cytoskeleton. C21 also prevented podocyte apoptosis. In conclusion, AT2R activation by C21 ameliorated ADR-induced podocyte injury in mice by the inhibition of glomerular cathepsin L leading to the maintenance of podocyte integrity and prevention of podocyte apoptosis.

• Authors: Min-Chun Liao, Kana N Miyata, Shiao-Ying Chang, Xin-Ping Zhao, Chao-Sheng Lo, Mohamad-Ali El-Mortada, Junzheng Peng, Isabelle Chenier, Michifumi Yamashita, Julie R Ingelfinger, John S D Chan, Shao-Ling Zhang
• Journal: Clinical science (London, England : 1979) (Clin Sci (Lond)) Vol. 136 Issue 10 Pg. 715-731 (05 27 2022) ISSN: 1470-8736 [Electronic] England
• PMID: 35502764 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: © 2022 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Chemical References

• Imidazoles
• Receptor, Angiotensin, Type 2
• Sulfonamides
• Thiophenes
• Angiotensin II
• Cathepsin L
• compound 21

Topics

• Angiotensin II (metabolism)
• Animals
• Cathepsin L (metabolism, pharmacology)
• Glomerulosclerosis, Focal Segmental (chemically induced, genetics, metabolism)
• Imidazoles
• Kidney Diseases (metabolism)
• Male
• Mice
• Mice, Knockout
• Podocytes (metabolism)
• Receptor, Angiotensin, Type 2 (metabolism)
• Sulfonamides
• Thiophenes