Kidney Week

Abstract: SA-OR011

Alpha 2 Adrenergic Receptor Blockade Prevents AKI to CKD Transition

Session Information

• AKI: Inflammation and Regeneration
  October 27, 2018 | Location: 6B, San Diego Convention Center
  Abstract Time: 04:30 PM - 04:42 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Jang, Hee-Seong, University of Nebraska Medical Center, Omaha, Nebraska, United States

Hee-Seong Jang, PhD



I am a renal pathophysiologist investigating pathogenesis of kidney diseases. My research interest is on cellular and molecular mechanism of acute kidney injury (AKI) and AKI to chronic kidney disease (CKD) transition, as well as organ crosstalk, such as cardio-renal syndrome. After finishing Ph.D course at Kyungpook National University School of Medicine under supervision of Dr. Kwon Moo Park, I moved to Dr. Babu Padanilam’s lab at University of Nebraska Medical Center for postdoc training. In 2018, I joined the faculty of College of Medicine, University of Nebraska, as instructor and continued to study regarding molecular and cellular mechanism of kidney injury and repair.

• Padanilam, Babu J., University of Nebraska Medical Center, Omaha, Nebraska, United States

Babu J. Padanilam,

Background

Increased sympathetic nerve activity and norepinephrine (NE) levels are of importance in the onset and the early development of end stage renal disease. We reported that renal denervation (DNx) can prevent renal fibrosis and inflammation in renal fibrogenesis models. However, the underlying mechanism by which renal denervation prevents the long-term sequelae of acute kidney injury (AKI) remains to be elucidated.

Methods

Based on our data, we hypothesized that NE mediates its effect through activation of alpha 2 adrenergic receptors (α2ARs). In this study, we investigated whether genetic or pharmacological inhibition of α2ARs prevents ischemia/reperfusion injury (IRI)-induced CKD progression.

Results

IRI resulted in severe kidney fibrosis in medullary region over 2 weeks with tubular cast and atrophy and massive macrophage infiltration. Renal DNx and pharmacological inhibition of α2AR did not affect renal functional and histological damage in the acute phase of the IRI. However, renal tubular damage, inflammation, and fibrosis progression was suppressed 2 weeks post-IRI by renal DNx and pharmacological inhibition of α2AR with downregulation of downstream targets of NE-α2AR axis, including angiotensinogen, fibrogenic factors and inflammatory cytokines. Similar with results in pharmacological inhibition of α2A-AR subtype, blockage of α2C-AR subtype by pharmacological or genetic manipulation prevented the long-term sequelae of IRI, including renal tubular atrophy, inflammation and fibrosis progression.

Conclusion

Collectively, inhibition of α2AR subtypes prevents IRI-induced AKI to CKD transition through inhibition of persistent renal tubular injury and inflammation, and fibrosis progression, suggesting that targeting α2ARs may be a potential therapeutic strategy to prevent long-term sequelae of ischemic AKI.

Funding

• Private Foundation Support