Abstract: PO0350
Urinary UDP-Glucose as a Novel Actionable Biomarker of Dehydration-Induced AKI
Session Information
- AKI: Mechanisms of Injury
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Battistone, Maria A., Massachusetts General Hospital Division of Nephrology, Boston, Massachusetts, United States
- Mendelsohn, Alexandra, Massachusetts General Hospital Division of Nephrology, Boston, Massachusetts, United States
- Brown, Dennis, Massachusetts General Hospital Division of Nephrology, Boston, Massachusetts, United States
- Breton, Sylvie, Massachusetts General Hospital Division of Nephrology, Boston, Massachusetts, United States
Background
People working in ”extreme” conditions such as sugar cane workers, firefighters, and military personnel are subjected to significant dehydration. Prolonged episodes of dehydration may result in acute kidney Injury (AKI). AKI is associated with inflammation and is usually diagnosed only after the kidneys have gone through significant and often irreversible damage. We showed that the P2Y14 receptor mediates renal inflammation leading to AKI following ischemia-reperfusion-injury. P2Y14 is activated by the danger molecule UDP-glucose (UDP-Glc). Here we hypothesized that UDP-Glc is released by damaged cells throughout the body after dehydration-induced stress. UDP-Glc is filtered by the kidney and concentrated in collecting ducts where it activates P2Y14 in intercalated cells. This would trigger renal inflammation and contribute to dehydration-associated AKI.
Methods
Mice were subjected to water deprivation for 24, 48 and 72 hours. Kidney function was assessed via serum creatinine (SCr), blood urea nitrogen (BUN) and urine albumin. To study proximal tubule (PT) damage, aquaporin 1 (AQP1) localization was analyzed by immunofluorescence (IF). Urinary UDP-Glc concentration was measured by LC-MS, and renal recruitment of immune cells by flow cytometry and IF.
Results
Mice that were subjected to dehydration showed body weight loss. Water deprivation induced elevations in SCr and BUN after 48 and 72 hours, relative to control. Dehydration also promoted albuminuria and the redistribution of AQP1 from the plasma membrane into the PT cell body indicating PT injury. An increase in urinary UDP-Glc concentration, and renal recruitment of macrophages (CD64+F4/80+) were detected at 48 and 72 hours of dehydration. In particular, infiltration of CD11c-positive renal macrophages after dehydration was observed.
Conclusion
This study supports the hypothesis that UDP-Glc, released by damaged cells during severe dehydration, induces the renal recruitment of inflammatory macrophages leading to PT injury. Blocking the UDP-Glc/P2Y14 pathway represents, therefore, a new therapeutic avenue for the attenuation of dehydration-induced renal inflammation and dysfunction. In this context, urinary UDP-Glc is a promising actionable biomarker for dehydration-induced AKI.
Funding
- NIDDK Support –