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Updated: May 2, 2026
Unilateral Ureteral Obstruction Model for Investigating Kidney Interstitial Fibrosis
Published on: April 25, 2025
Increasing cGMP-dependent protein kinase activity attenuates unilateral ureteral obstruction-induced renal fibrosis
Wenpeng Cui1, Hasiyeti Maimaitiyiming, Xinyu Qi
1Graduate Center for Nutritional Sciences, Univ. of Kentucky, Wethington Bldg., Rm. 583, 900 S. Limestone St., Lexington, KY 40536. swang7@uky.edu.
Abstract:
Our previous studies support the protective effect of cGMP and cGMP-dependent protein kinase I (PKG-I) pathway on the development of renal fibrosis. Therefore, in the present studies, we determined whether pharmacologically or genetically increased PKG activity attenuates renal fibrosis in a unilateral ureteral obstruction (UUO) model and also examined the mechanisms involved. To increase PKG activity, we used the phosphodiesterase 5 inhibitor sildenafil and PKG transgenic mice. UUO model was induced in wild-type or PKG-I transgenic mice by ligating the left lateral ureteral and the renal fibrosis was observed after 14 days of ligation. Sildenafil was administered into wild-type UUO mice for 14 days. In vitro, macrophage and proximal tubular cell function was also analyzed. We found that sildenafil treatment or PKG transgenic mice had significantly reduced UUO-induced renal fibrosis, which was associated with reduced TGF-β signaling and reduced macrophage infiltration into kidney interstitial. In vitro data further demonstrated that both macrophages and proximal tubular cells were important sources of UUO-induced renal TGF-β levels. The interaction between macrophages and tubular cells contributes to TGF-β-induced renal fibrosis. Taken together, these data suggest that increasing PKG activity ameliorates renal fibrosis in part through regulation of macrophage and tubular cell function, leading to reduced TGF-β-induced fibrosis.
Insights
Increasing cyclic guanosine monophosphate-dependent protein kinase I (PKG-I) activity protects against kidney fibrosis. Pharmacological or genetic enhancement of PKG-I reduced fibrosis in a unilateral ureteral obstruction model by modulating cellular responses.
Area of Science:
- Nephrology
- Molecular Biology
- Cell Biology
Background:
- The cyclic guanosine monophosphate (cGMP) and cGMP-dependent protein kinase I (PKG-I) pathway demonstrates protective effects against renal fibrosis.
- Understanding the role of PKG-I in mitigating kidney fibrosis is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate whether augmenting PKG activity can attenuate renal fibrosis in a unilateral ureteral obstruction (UUO) model.
- To elucidate the underlying mechanisms by which PKG activity influences renal fibrosis development.
Main Methods:
- Utilized a unilateral ureteral obstruction (UUO) mouse model to induce kidney fibrosis.
- Administered sildenafil (a phosphodiesterase 5 inhibitor) to wild-type mice and employed PKG-I transgenic mice to increase PKG activity.
- Analyzed renal fibrosis, TGF-β signaling, and macrophage infiltration in kidney tissues.
- Assessed macrophage and proximal tubular cell function in vitro.
Main Results:
- Pharmacological (sildenafil) or genetic (transgenic) increase in PKG activity significantly reduced UUO-induced renal fibrosis.
- Reduced renal fibrosis was associated with decreased transforming growth factor-beta (TGF-β) signaling.
- Macrophage infiltration into the kidney interstitial was diminished in groups with increased PKG activity.
- In vitro studies confirmed macrophages and proximal tubular cells as key sources of TGF-β, highlighting their interaction in fibrosis.
Conclusions:
- Elevated PKG activity ameliorates renal fibrosis in the UUO model.
- PKG-I activation modulates macrophage and tubular cell function, thereby reducing TGF-β-driven fibrosis.
- Targeting the PKG pathway represents a potential therapeutic strategy for managing kidney fibrosis.
