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Abstract: TH-PO188

Ferroptotic Tubular Cell Death Is Facilitated in Diabetic Nephropathy in Mice

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic


  • Maremonti, Francesca, Technical University Dresden, Dresden, Saxony, Germany
  • Tonnus, Wulf, Technical University Dresden, Dresden, Saxony, Germany
  • Brucker, Anne Marie, Technical University Dresden, Dresden, Saxony, Germany
  • Himmerkus, Nina, Christian-Albrechts-Universitat zu Kiel, Kiel, Schleswig-Holstein, Germany
  • Gembardt, Florian, Technical University Dresden, Dresden, Saxony, Germany
  • Hugo, Christian, Technical University Dresden, Dresden, Saxony, Germany
  • Linkermann, Andreas, Technical University Dresden, Dresden, Saxony, Germany

Glycaemic dysregulation associated with diabetes mellitus is the cause of diabetic nephropathy (DN). DN progression involves renal tubular necrosis and glomerulosclerosis. Our previous data suggest that tubular damage involves a regulated form of iron-catalyzed necrosis referred to as ferroptosis. GIP (glucose-dependent insulinotropic polypeptide) is an endogenous polypeptide hormone secreted by enteroendocrine K cells of the lower gut. Its receptor, GIPR (GIP receptor) is a G-coupled transmembrane receptor placed on the surface of pancreatic β-cells. GIPR dominant-negative transgenic mice (GIPRdn) are the first murine model that exhibits typical late complications of diabetes such as DN and atherosclerosis.


We employed GIPRdn mice to study the mechanisms and progression of DKD. Besides histological assesment, we detected serum urea and serum creatinine concentrations over the first year of age at 7, 10, 25, 40, and 50 weeks of age. At all time points, kidney tubules were freshly prepared to assess spontaneous tubular death patterns and LDH release assays over 6 hours following isolation. We monitored cell death propagation by live tubular fluorescence microscopy using Sytox Green and performed Fluorescence Lifetime Microscopy (FLIM). We investigated two models of acute kidney injury (AKI) such as ischemia-reperfusion injury (IRI) and cisplatin-induced AKI.


Blood glucose levels and serum concentrations of urea and creatinine of GIPRdn transgenic mice were significantly increased in comparison to littermate controls. The difference reached statistcal significance from 7 weeks of age. LDH release assays alongside with fluorescence live tubular imaging indicated sensitzation to ferroptosis of GIPRdn tubules. In the live imaging and in FLIM analysis of freshly isolated tubules, we detected synchronized regulated necrosis and accelerated cell death propagation between tubular cells in the GIPRdn transgenic mice. In keeping with these observations, we detected strongly increased sensitivity to all AKI models tested.


First, we identify the renal tubule as a primary site of injury in diabetic nephropathy. Second, we conclude that GIPRdn mice and diabetic renal tubules are particularly sensitive to ferroptosis. Third, we identify ferroptosis as a novel drug target for AKI in DN.