Denervation aggravates renal ischemia reperfusion injury via BMAL1-mediated Nrf2/ARE pathway

Area of Science:

• Circadian Biology
• Renal Physiology
• Molecular Medicine

Background:

• The circadian rhythm of clock genes influences renal function and susceptibility to injury.
• Renal ischemia-reperfusion (IR) injury is a significant clinical concern, particularly when occurring at specific times of day.
• The role of renal denervation (RDN) in modulating circadian rhythms and IR injury is not fully understood.

Purpose of the Study:

• To investigate how renal denervation affects clock gene rhythms.
• To determine the impact of altered clock gene rhythms on renal function and oxidative stress during IR injury.
• To elucidate the underlying mechanisms involving the Nrf2 pathway.

Main Methods:

• Mice underwent sham surgery, RDN, IR, or RDN + IR at either 7 AM or 7 PM.
• Renal function was assessed via histology, serum creatinine, urea nitrogen, and neutrophil gelatinase-associated lipocalin.
• Oxidative stress, inflammation, and clock gene (BMAL1, CLOCK) and Nrf2 pathway gene (Nrf2, HO-1) expression were measured using biochemical assays and molecular techniques (qPCR, Western Blot).

Main Results:

• RDN disrupted the kidney's rhythm of BMAL1, CLOCK, and Nrf2, but did not significantly alter baseline renal function.
• RDN exacerbated renal IR injury, oxidative stress, and inflammation, especially during nighttime injury.
• Nocturnal IR in RDN kidneys showed the worst injury with the highest BMAL1, Nrf2, and HO-1 expression, suggesting impaired Nrf2 activation.

Conclusions:

• Renal denervation disrupts the BMAL1-mediated rhythm of Nrf2 accumulation in the kidney.
• This disruption reduces the kidney's capacity to resist oxidative stress and inflammation during nighttime IR injury.
• The impaired activation of the Nrf2/ARE pathway contributes to aggravated renal injury following RDN and IR.