Key result
Genetic angiotensinogen inhibition fails to prevent kidney injury and fibrosis in mice with ureteral obstruction.
Why the study?
The precise role of tissue-specific angiotensinogen in kidney fibrosis independent of blood pressure remains to be fully understood.
Does genetic inhibition of proximal tubule or liver angiotensinogen prevent kidney injury and fibrosis in a unilateral ureteral obstruction model?
Does genetic inhibition of proximal tubule or liver angiotensinogen prevent kidney injury and fibrosis in a unilateral ureteral obstruction model?
Genetic deletion of angiotensinogen in the liver or proximal tubules does not prevent kidney injury and fibrosis in an obstructive nephropathy model, suggesting complex compensatory mechanisms.
Genetic angiotensinogen inhibition does not prevent obstructive kidney injury in mice; leaves open compensatory mechanisms and requires validation in other models.
BACKGROUND/AIM: Angiotensinogen (AGT), a precursor of angiotensin II (AngII), contributes to regulating (patho)physiological conditions, including blood pressure changes, inflammation, and kidney fibrosis. However, the precise role of tissue-specific AGT in kidney fibrosis independent of blood pressure remains to be fully understood. This study investigated the source of intrarenal AGT and its role in kidney injury and fibrosis during obstructive nephropathy. MATERIALS AND METHODS: Proximal tubule- (PT, major source secreting AGT in the kidney; PKO) or liver- (major source of circulating AGT; LKO) AGT knockout (KO) mice were subjected to unilateral ureteral obstruction (UUO), a blood pressure-independent fibrosis model. RESULTS: UUO increased AGT mRNA and protein levels in the kidneys. PKO decreased AGT mRNA, but LKO enhanced it in UUO kidneys compared with the control. In contrast, the intrarenal protein levels of AGT increased in PKO, but not in LKO in UUO kidneys, indicating that the liver is a major source of intrarenal AGT protein. Expression of megalin, a PT receptor involved in the uptake of circulating AGT, was down-regulated in UUO kidneys and was independent of PKO or LKO. However, none of these changes prevented UUO-induced tubular injury and kidney fibrosis. CONCLUSION: Hepatic and proximal tubule AGT play distinct roles in contributing to intrarenal AGT levels during UUO, and their genetic inhibitions fail to prevent kidney injury and fibrosis, suggesting a highly complicated signaling pathway of the renin-angiotensin system and an associated compensatory mechanism in obstructive nephropathy.
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Jang et al. (2024) studied Obstructive nephropathy. Proximal tubule- or liver-specific AGT knockout vs. Control was evaluated on Kidney injury and fibrosis. Genetic inhibition of hepatic or proximal tubule angiotensinogen failed to prevent kidney injury and fibrosis in mice subjected to unilateral ureteral obstruction.
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