Abstract: FR-PO096
Mucin 1 Prevents Accelerated Shedding of Kidney Injury Molecule-1 Following Ischemic Renal Injury
Session Information
- AKI: Tubules, Metabolism, New Models
October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Al-bataineh, Mohammad M., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Kinlough, Carol L., Department of Medicine University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Mi, Zaichuan, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Jackson, Edwin Kerry, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Hughey, Rebecca P., Dept Medicine-Renal Electrolyte Division, Pittsburgh, Pennsylvania, United States
Background
Kidney injury molecule-1 (KIM-1) is a type I transmembrane glycoprotein that is rapidly induced after kidney injury in the proximal tubule (PT). The ectodomain of KIM-1 is cleaved and thereby constitutively shed into the urine providing a sensitive biomarker for kidney injury. It was reported recently that a transcription factor STAT3 is phosphorylated by extracellular signal-regulated kinases 1 and 2 (ERK1/2) and/or checkpoint kinase 1 (ChK1) following kidney injury and thereby upregulates KIM-1. KIM-1 also has anti-inflammatory role as it mediates phagocytosis of apoptotic and necrotic cells (efferocytosis) following kidney injury. However, the accelerated shedding of KIM-1 regulated by p38 MAPK blocks efferocytosis as the excess soluble KIM-1 acts as a decoy to cell-associated KIM-1. Mucin 1 (Muc1) is a transmembrane glycoprotein found primarily in the distal nephron that is also induced in the PT following kidney injury. We previously published data showing that Muc1 plays a protective role during ischemia-reperfusion injury (IRI) by stabilizing both HIF-1a and b-catenin.
Methods
More recently, using our hanging-weight protocol of 20 min ischemia and 48 h recovery, we observed a significant two-fold higher level of urinary KIM-1 as well as more severe kidney injury in Muc1 KO mice when compared to wild-type (WT) littermates. There was no significant difference in the levels of neutrophil gelatinase-associated lipocalin (the distal tubule injury biomarker NGAL) between Muc1 KO and WT littermates. Based on these findings, we tested the hypothesis that Muc1 plays a protective role during IRI by modulating the pathways known to regulate PT KIM-1 activity.
Results
Immunoblots of kidney tissue revealed that levels of both ERK1/2 and ChK1 were significantly higher in Muc1 KO mice when compared to WT littermates. Furthermore, the cytoplasmic and nuclear levels of active STAT3 were significantly higher and thus KIM-1 levels in Muc1 KO mice when compared to WT littermates. Moreover, levels of phosphorylated p38 MAPK are significantly higher in Muc1 KO mice when compared to WT littermates which enhances KIM-1 shedding, and consequently more severe kidney injury.
Conclusion
These results support the likelihood that Muc1 regulates KIM-1 function by regulating both its expression and shedding following kidney injury.
Funding
- NIDDK Support