AT1 receptor antagonism before ischemia prevents the transition of acute kidney injury to chronic kidney disease.
Despite clinical recovery of patients from an episode of acute kidney injury (AKI), progression to chronic kidney disease (CKD) is possible on long-term follow-up. However, mechanisms of this are poorly understood. Here, we determine whether activation of angiotensin-II type 1 receptors during AKI triggers maladaptive mechanisms that lead to CKD. Nine months after AKI, male Wistar rats develop CKD characterized by renal dysfunction, proteinuria, renal hypertrophy, glomerulosclerosis, tubular atrophy, and tubulointerstitial fibrosis. Renal injury was associated with increased oxidative stress, inflammation, α-smooth muscle actin expression, and activation of transforming growth factor β; the latter mainly found in epithelial cells. Although administration of losartan prior to the initial ischemic insult did not prevent or reduce AKI severity, it effectively prevented eventual CKD. Three days after AKI, renal dysfunction, tubular structural injury, and elevation of urinary biomarkers were present. While the losartan group had similar early renal injury, renal perfusion was completely restored as early as day 3 postischemia. Further, there was increased vascular endothelial growth factor expression and an early activation of hypoxia-inducible factor 1 α, a transcription factor that regulates expression of many genes that help reduce renal injury. Thus, AT1 receptor antagonism prior to ischemia prevented AKI to CKD transition by improving early renal blood flow recovery, lesser inflammation, and increased hypoxia-inducible factor 1 α activity.
Roxana
R
Rodríguez-Romo
Kenia
K
Benítez
Jonatan
J
Barrera-Chimal
Rosalba
R
Pérez-Villalva
Arturo
A
Gómez
Diana
D
Aguilar-León
Jesús F
JF
Rangel-Santiago
Sara
S
Huerta
Gerardo
G
Gamba
Norma
N
Uribe
Norma A
NA
Bobadilla
D058186:Acute Kidney Injury / Q000150:complications* / Q000517:prevention & control; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D004353:Drug Evaluation, Preclinical; D007668:Kidney / Q000098:blood supply / Q000187:drug effects; D019808:Losartan / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D017208:Rats, Wistar; D051436:Renal Insufficiency, Chronic / Q000209:etiology / Q000517:prevention & control*; D015427:Reperfusion Injury / Q000150:complications* / Q000517:prevention & control
D047228:Angiotensin II Type 1 Receptor Blockers; D019808:Losartan