Back to Search
Start Over
Benefit of Mineralocorticoid Receptor Antagonism in AKI: Role of Vascular Smooth Muscle Rac1
- Source :
- Journal of the American Society of Nephrology, Journal of the American Society of Nephrology, American Society of Nephrology, 2017, 28 (4), pp.1216-1226. ⟨10.1681/ASN.2016040477⟩, Journal of the American Society of Nephrology, 2017, 28 (4), pp.1216-1226. ⟨10.1681/ASN.2016040477⟩
- Publication Year :
- 2017
- Publisher :
- HAL CCSD, 2017.
-
Abstract
- International audience; AKI is a frequent complication in hospitalized patients. Unfortunately, there is no effective pharmacologic approach for treating or preventing AKI. In rodents, mineralocorticoid receptor (MR) antagonism prevents AKI induced by ischemia-reperfusion (IR). We investigated the specific role of vascular MR in mediating AKI induced by IR. We also assessed the protective effect of MR antagonism in IR-induced AKI in the Large White pig, a model of human AKI. In mice, MR deficiency in smooth muscle cells (SMCs) protected against kidney IR injury. MR blockade by the novel nonsteroidal MR antagonist, finerenone, or genetic deletion of MR in SMCs associated with weaker oxidative stress production. Moreover, ischemic kidneys had higher levels of Rac1-GTP, required for NADPH oxidase activation, than sham control kidneys, and genetic deletion of Rac1 in SMCs protected against AKI. Furthermore, genetic deletion of MR in SMCs blunted the production of Rac1-GTP after IR. Pharmacologic inhibition of MR also prevented AKI induced by IR in the Large White pig. Altogether, we show that MR antagonism, or deletion of the MR gene in SMCs, limited the renal injury induced by IR through effects on Rac1-mediated MR signaling. The benefits of MR antagonism in the pig provide a rational basis for future clinical trials assessing the benefits of this approach in patients with IR-mediated AKI.
- Subjects :
- 0301 basic medicine
rac1 GTP-Binding Protein
Male
Vascular smooth muscle
Swine
[SDV]Life Sciences [q-bio]
030204 cardiovascular system & hematology
urologic and male genital diseases
Muscle, Smooth, Vascular
ischemia-reperfusion
Mice
0302 clinical medicine
Mineralocorticoid receptor
vascular
Smooth Muscle
Myocyte
Aldosterone
Cells, Cultured
Mineralocorticoid Receptor Antagonists
Kidney
NADPH oxidase
Cultured
biology
Acute kidney injury
General Medicine
Acute Kidney Injury
female genital diseases and pregnancy complications
3. Good health
medicine.anatomical_structure
Nephrology
Reperfusion Injury
Muscle
Smooth
medicine.medical_specialty
Finerenone
Cells
Myocytes, Smooth Muscle
03 medical and health sciences
Internal medicine
medicine
Animals
Myocytes
business.industry
urogenital system
Neuropeptides
medicine.disease
Basic Research
030104 developmental biology
Endocrinology
Oxidative stress
biology.protein
business
Reperfusion injury
Subjects
Details
- Language :
- English
- ISSN :
- 10466673 and 15333450
- Database :
- OpenAIRE
- Journal :
- Journal of the American Society of Nephrology, Journal of the American Society of Nephrology, American Society of Nephrology, 2017, 28 (4), pp.1216-1226. ⟨10.1681/ASN.2016040477⟩, Journal of the American Society of Nephrology, 2017, 28 (4), pp.1216-1226. ⟨10.1681/ASN.2016040477⟩
- Accession number :
- edsair.doi.dedup.....846f24c93fc73bde20a47ab41e920a61