Endothelial Marker Expressing Stromal Cells Play a Critical Role in Recovery Following Acute Kidney Injury

Abstract

BackgroundAcute Kidney Injury (AKI) is characterized by an abrupt decrease in renal function that can lead to renal failure, thus contributing to high percentages of morbidity and mortality. The kidney contains a complex and high degree of vascularization making it susceptible to ischemic injury, particularly the peritubular capillaries. We have identified a subset of endothelial marker expressing stromal (EMES) cells that contribute to the peritubular capillary endothelium. Subsequently, we hypothesize that EMES cells are important contributors to kidney recovery after AKI.MethodsWe confirmed the importance of EMES following ischemia reperfusion injury (IRI) via lineage tracing, using a TdTomato reporter (permanently labeling all EMES cells) and interrogated the percentage of EMES cells that were present in the IRI and contralateral control kidneys. Furthermore, we generated mice with a conditional deletion of Flk1 (Vegfr2, essential for vascular development) in the Foxd1cre positive renal stroma (Flk1ST−/−), and evaluated the tissue after both blood flow dependent AKI, utilizing ischemia reperfusion injury (IRI), and blood flow independent or nephrotoxic AKI utilizing the chemotherapy agent cisplatin and focused on the recovery phase (7, or 28 days) post injury.ResultsWe determined in control mice following IRI that developmental stromal genes were re‐expressed suggesting that the stroma may be undergoing de‐differentiation and subsequently driving EMES proliferation. Furthermore, using lineage tracing we found that EMES preferentially increase during the repair phase (7 days) of IRI. To evaluate the role of EMES cells following AKI, we used Flk1ST−/− animals subjected to IRI, and found that mutants had less perfusion and an increase in hypoxia and increased expression of hypoxia inducible factor 1a (HIF1a) at 7 days. The hypoxic environment caused exasperated kidney damage in the mutant animals. Furthermore, when animals were allowed to recover for 28 days, there was significant fibrosis, and damage in the injured kidney compared to the contralateral control. When these animals were subjected to cisplatin injections we found that while perfusion of the kidneys appeared unaffected, HIF1a was similarly increased and the stromal genes were re‐expressed.ConclusionsTaken together we determined that for repair after AKI the renal stroma requires de‐differentiation and re‐expression of developmental markers prior to proliferation and re‐differentiation. This cellular reprogramming event also requires EMES cell proliferation, which play an important role in mediating vascular perfusion, reestablishing normal oxygen concentrations and regulating HIF signaling to modulate repair and recovery.Support or Funding InformationF32 DK111165‐01K01 DK096996