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Previous studies have indicated that Angiopoietin-2 (Angpt2) is upregulated in murine models of progressive kidney disease, particularly in fibrotic kidneys. The renin-angiotensin system (RAS) plays a pivotal role in regulating blood pressure and fluid balance, with Angiotensin Ⅱ (AngⅡ) levels closely associated with Angpt2 expression. Our hypothesis is that inhibiting Angpt2 in combination with high levels of AngⅡ may exacerbate kidney fibrosis.
To investigate this hypothesis, we employed a tamoxifen-inducible system to induce universal Angpt2 deletion in transgenic mice, Tg(UBC-CreERT2);Angpt2F/F. Littermates without the Cre gene served as experimental controls. Adult mice (8 weeks old) received oral gavage of 0.4 mg/g tamoxifen to achieve universal Angpt2 deletion. In addition, adult mice were subjected to a 14-day period of osmotic-infusion pump-based AngⅡ administration at a dosage of 15 ng/min/g.
Our results confirmed the successful use of the tamoxifen-inducible system to induce universal Angpt2 deletion in renal cells. After the surgery involving the infusion of AngⅡ using osmotic pumps, we observed significantly higher expression of fibrosis-related genes, including Acta2, Col1a1, Col3a1, in the kidneys of Tg(UBC-CreERT2);Angpt2F/F transgenic mice compared to littermate controls. Moreover, the deposition of collagen fibrils, as indicated by picrosirius red staining, was significantly greater in Angpt2 knockout mice following AngⅡ administration.
Our findings suggest that inhibiting Angpt2 in combination with high levels of AngⅡ exacerbates kidney fibrosis. Further studies are required to investigate the specific cellular components and the underlying pathogenic mechanisms involved in this process.