Renoprotective and Immunomodulatory Effects of GDF15 following AKI Invoked by Ischemia-Reperfusion Injury

Significance Statement Gdf15 , which encodes a signaling factor activated by oxidative stress, DNA damage, and proinflammatory cytokines, is upregulated in the human and mouse kidney within a few hours of ischemia-reperfusion injury. Using novel mouse strains, the authors mapped cellular sites of Gdf15 expression in normal and injured kidney and examined Gdf15 ’s role in ischemia-reperfusion injury. They showed that Gdf15 is expressed within hypoxic regions of the kidney and is predominantly activated within tubular epithelial cells at injury repair sites; loss of Gdf15 exacerbated injury, enhancing the inflammatory response. In an analysis of clinical data, they demonstrated that single nucleotide polymorphisms linked to lower circulating GDF15 levels associate with an increased incidence of biopsy-proven acute rejection. These findings point to modulating GDF15 levels in patients receiving kidney transplant as a possible therapeutic strategy. Background Gdf15 encodes a TGF- β superfamily member that is rapidly activated in response to stress in multiple organ systems, including the kidney. However, there has been a lack of information about Gdf15 activity and effects in normal kidney and in AKI. Methods We used genome editing to generate a Gdf15 nuGFP-CE mouse line, removing Gdf15 at the targeted allele, and enabling direct visualization and genetic modification of Gdf15 -expressing cells. We extensively mapped Gdf15 expression in the normal kidney and following bilateral ischemia-reperfusion injury, and quantified and compared renal responses to ischemia-reperfusion injury in the presence and absence of GDF15. In addition, we analyzed single nucleotide polymorphism association data for GDF15 for associations with patient kidney transplant outcomes. Results Gdf15 is normally expressed within aquaporin 1–positive cells of the S3 segment of the proximal tubule, aquaporin 1–negative cells of the thin descending limb of the loop of Henle, and principal cells of the collecting system. Gdf15 is rapidly upregulated within a few hours of bilateral ischemia-reperfusion injury at these sites and new sites of proximal tubule injury. Deficiency of Gdf15 exacerbated acute tubular injury and enhanced inflammatory responses. Analysis of clinical transplantation data linked low circulating levels of GDF15 to an increased incidence of biopsy-proven acute rejection. Conclusions Gdf15 contributes to an early acting, renoprotective injury response, modifying immune cell actions. The data support further investigation in clinical model systems of the potential benefit from GDF15 administration in situations in which some level of tubular injury is inevitable, such as following a kidney transplant.