Mucin 1 Regulates KIM‐1 Function Following Ischemic Renal Injury
Authors: Al‐bataineh Mohammad , Kinlough Carol , Mi Zaichuan , Jackson Edwin , Hughey Rebecca 
Published: June 2021

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 by a disintegrin and metalloproteinase domain 17 (ADAM17) 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 an 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 in humans, and Muc1 in mice) 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. 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. We also found that MUC1 and KIM‐1 are co‐localized in human kidney proximal tubule using immunofluorescence microscopy. Based on these findings, we tested the hypothesis that Muc1 limits kidney injury and enhances recovery during IRI by modulating the pathways known to regulate PT KIM‐1 activity. Immunoblots of kidney tissue revealed that levels of active ERK1/2 were significantly higher in Muc1 KO mice when compared to WT littermates. Though the levels of active p38 MAPK were significantly induced following kidney injury, there was no significant difference between Muc1 KO mice and WT littermates. Using an in vitro cell culture model where MDCK cells were stably transfected with KIM‐1 and transiently transfected with MUC1 or empty vector, we observed a reduction in KIM‐1 expression levels in the presence of MUC1. We also observed in our preliminary data that KIM‐1 shedding was enhanced after treating MDCK cells with PMA (a PKC activator that used to enhance ectodomain shedding of surface proteins such as those mediated by ADAM17) only in the absence of MUC1. As Muc1 is also a substrate for ADAM17, we also hypothesize that the absence of the competing Muc1 substrate after AKI in the Muc1 KO mice, could account for the accelerated shedding of KIM‐1 and consequently more severe kidney injury. These results support the likelihood that Muc1 regulates KIM‐1 function by regulating both its expression and shedding following kidney injury.

Support or Funding Information

This work was supported by the National Institutes of Health (K01 DK109038, and P30‐DK‐079307), Pittsburgh Center for Kidney Research and Dialysis Clinics, Inc. (DCI).

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.