Abstract P2045: Genetic Disruption of Npr1 Depletes T Regulatory Cells and Provokes High Levels of Proinflammatory Cytokines and Fibrosis in the Kidneys of Female Mutant Mice

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 74; no. Suppl_1
• Main Authors: Gogulamudi, Venkateswara R, Mani, Indra, Subramanian, Umadevi, Pandey, Kailash N
• Format: Journal Article
• Language: English
• Published: 01.09.2019
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/hyp.74.suppl_1.P2045

Abstract only The aim of the present study was to determine the effects of gene-knockout of guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) on immunogenic responses affecting kidney function and blood pressure (BP) in Npr1 (coding for GC-A/NPRA) null mutant mice. We used female Npr1 gene-disrupted ( Npr1 -/- , 0-copy), heterozygous ( Npr1 +/- , 1-copy), wild-type ( Npr1 +/+ , 2-copy) and gene-duplicated ( Npr1 ++/++ , 4-copy) mice. Expression levels of Toll-like receptor 2/4 (TLR2/TLR4) mRNA were increased 4- to 5-fold in 1-copy mice and 6- to 10-fold in 0-copy mice; protein levels were increased 2.5- to 3-fold in 1-copy mice and 4- to 5-fold in 0-copy mice. Expression of proinflammatory cytokines and BP was significantly elevated in 1-copy and 0-copy mice compared with 2-copy and 4-copy mice. In addition, 0-copy and 1-copy mice exhibited drastic reductions in T regulatory cells (Tregs). After rapamycin treatment, Tregs were increased by 17% ( P < 0.001) in 0-copy mice and 8% ( P < 0.001) in 1-copy mice. Renal mRNA and protein levels of TLR2 and TLR4 were decreased by 70% in 0-copy mice and 50% in 1-copy mice. There were significantly higher levels of Tregs and very low levels of TLR2/TLR4 expression in 4-copy mice (p < 0.001). These findings indicate that the disruption of Npr1 in female mice triggers renal immunogenic pathways, which transactivate the expression of proinflammatory cytokines and renal fibrosis with elevated BP in mutant animals. The data suggest that rapamycin treatment attenuates proinflammatory cytokine expression, dramatically increases anti-inflammatory cytokines, and substantially reduces BP and renal fibrosis in mutant animals.