Divergent roles for kidney proximal tubule and granulocyte PAD4 in ischemic AKI.

We previously demonstrated that kidney peptidylarginine deiminase-4 plays a critical role in ischemic acute kidney injury (AKI) in mice by promoting renal tubular inflammation and neutrophil infiltration (Ham A, Rabadi M, Kim M, Brown KM, Ma Z, D'Agati V, Lee HT. Am J Physiol Renal Physiol 307: F1052-F1062, 2014). Although the role of in granulocytes including neutrophils is well known, we surprisingly observed profound renal proximal tubular duanyu15634 induction after renal ischemia-reperfusion (I/R) injury. Here we tested the hypothesis that renal proximal tubular duanyu15634 rather than myeloid-cell lineage duanyu15634 plays a critical role in exacerbating ischemic AKI by utilizing mice lacking duanyu15634 in renal proximal tubules PEPCK Cre mice) or in granulocytes (duanyu15634^ff LysM Cre mice). Mice lacking renal proximal tubular duanyu15634 were significantly protected against ischemic AKI compared with wild-type mice. Surprisingly, mice lacking duanyu15634 in myeloid cells were also protected against renal I/R injury although this protection was less compared with renal proximal tubular mice. Renal proximal tubular duanyu15634-deficient mice had profoundly reduced renal tubular apoptosis, whereas myeloid-cell duanyu15634-deficient mice showed markedly reduced renal neutrophil infiltration. Taken together, our studies suggest that both renal proximal tubular duanyu15634 as well as myeloid-cell lineage duanyu15634 play a critical role in exacerbating ischemic AKI. Renal proximal tubular duanyu15634 appears to contribute to ischemic AKI by promoting renal tubular apoptosis, whereas myeloid-cell duanyu15634 is preferentially involved in promoting neutrophil infiltration to the kidney and inflammation after renal I/R.

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