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

Abstract

BackgroundGdf15 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.MethodsWe used genome editing to generate a Gdf15nuGFP-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.ResultsGdf15 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.ConclusionsGdf15 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.

Prognostic Value of Growth Differentiation Factor 15 in Kidney Donors and Recipients

“…This is consistent with observations by others who found that CKD in all age cohorts leads to a significant increase of GDF15 [12,13,15,21]. In addition, GDF15 can also increase in response to acute kidney injuries [10,11]. Furthermore, the dialysis vintage and possibly the duration of CKD appear to play an important role in the extent of GDF15 values, as GDF15 levels before transplantation were significantly associated with the dialysis vintage in our patients.…”

“…In the context of acute kidney injury, the TGF-ß family member GDF15 is rapidly upregulated [11]. Further upregulation of TGF-β promotes endothelial-to-mesenchymal transition and causes fibrosis in kidneys and other organs [22].…”

“…In diabetic mice, genetic deletion of GDF15 led to increased damage in the tubules and interstitium but not in glomeruli, hinting towards a tissue-protective effect of GDF15 in kidneys [9]. Interestingly, the kidney itself expresses GDF15 in response to different injuries including ischemic and toxic damage [10,11].…”

Increased levels of the cardiovascular disease risk biomarkers GDF15 and myostatin in patients with chronic lymphocytic leukemia

“…Interestingly, in vivo results from an experimental study comparing wild-type and GDF15-deficient mice, showed that GDF15 is strongly upregulated following cardiac infarction, and it is suggested to have a cardioprotective effect in regard to ischemia and reperfusion injury (Kempf et al 2006) since the size of the area injured by the ischemia was significantly larger in GDF15 deficient mice. Recently, a similar protective effect of GDF15 regarding ischemia and reperfusion injury in acute kidney disease was proposed (Liu et al 2020). These conflicting data on GDF15 are indeed intriguing.…”

Growth Differentiation Factor 15: A Biomarker with High Clinical Potential in the Evaluation of Kidney Transplant Candidates

“…The levels of this biomarker seem to highly decrease after transplantation compared to dialysis, in line with the reduction of cardiovascular risk and mortality [ 27 , 28 , 29 ]. GDF-15 has also been related to anemia in kidney transplant recipients [ 30 ] and the degree of ischemia reperfusion injury after transplant [ 31 ].…”