Why the study?
The liver is the primary source of circulating AGT, but whether hepatocyte-derived AGT regulates renal AGT accumulation remained to be determined.
Does hepatocyte-specific inhibition of AGT using GalNAc AGT ASO reduce renal AGT accumulation in female cynomolgus monkeys?
Does hepatocyte-specific inhibition of AGT using GalNAc AGT ASO reduce renal AGT accumulation in female cynomolgus monkeys?
In nonhuman primates, renal angiotensinogen is predominantly derived from the liver, supporting the concept that the liver regulates renal angiotensin II production in humans.
Caution interpreting urinary AGT as kidney-derived RAS activity; extends rodent evidence to primates but leaves open human studies.
AGT (Angiotensinogen) is the unique substrate of the renin-angiotensin system. Liver is the primary source of circulating AGT. The present study determined whether hepatocyte-derived AGT regulates renal AGT accumulation by injecting ASO (antisense oligonucleotides) targeting hepatocyte-derived AGT (GalNAc AGT ASO) into female cynomolgus monkeys. Hepatocyte-specific inhibition of AGT led to profound reductions of plasma AGT concentrations. AGT protein in S1 and S2 of renal proximal tubules was greatly diminished by GalNAc AGT ASO. Given the similarity between nonhuman primates and human, our findings support the notion that renal AGT is predominantly derived from liver, and liver regulates renal angiotensin II production in humans. Abstract Figure
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Kukida et al. (2021) studied this question.
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