ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005


The Latest on Twitter

Kidney Week

Abstract: SA-PO138

Reduction of H3K27Me3 and Metabolic Memory Associated Inflammation in Podocytes

Session Information

Category: Diabetes

  • 503 Diabetes Mellitus and Obesity: Translational


  • Dieter, Brad, Providence Sacred Heart , Spokane, Washington, United States
  • Meek, Rick L., Providence Sacred Heart , Spokane, Washington, United States
  • Anderberg, Robert J., Providence Sacred Heart , Spokane, Washington, United States
  • Cooney, Sheryl K., Providence Sacred Heart , Spokane, Washington, United States
  • Tuttle, Katherine R., Providence Sacred Heart , Spokane, Washington, United States

Poor glycemic control, even with subsequent periods of well-controlled glycemia, increases risk for diabetic complications. This phenomenon, known as metabolic memory, may cause epigenetic changes such as reduction of histone 3 lysine 27 trimethylation (H3K27Me3), which increases expression of inflammatory mediators including serum amyloid A (SAA) in the diabetic kidney. The aim of this study was to determine if a sustained inflammatory response to metabolic memory may be mediated by increased SAA expression due to H3K27Me3 demethylation near the SAA promoter in podocytes, a cell centrally involved in diabetic kidney disease.


SAA knockout podocytes were generated using CRISPR-Cas9. In experiments to model metabolic memory, wild type and SAA knockout mouse podocytes were differentiated for 8-10 days, then exposed to advanced glycation end products (AGE, 300 μg/ml) for 7 days, followed by AGE removal and ongoing culture in control conditions for 7 more days. Chromatin immunoprecipitation measured H3K27Me3 near the SAA promoter. qRT-PCR was used to measure mRNA expression of inflammatory mediators: SAA, CXCL5, CCL2, and CCL5. Podocytes were exposed to AGE (300 μg/ml) for 1 day while H3K27Me3 demethylation was prevented by inhibiting the H3K27me3 specific demethylase, jmjd3, with GSK-J1 (20 μM).


In metabolic memory experiments conducted in podocytes (n=6), histone H3K27Me3 near the SAA promoter was markedly reduced (95%) at day 14, while SAA mRNA increased (17±6-fold, p=0.025), as were SAA-dependent inflammatory mediators: CXCL5 (18.5±12-fold, p=0.004), CCL2 (2.0±0.7-fold, p=0.001), and CCL5 (1.6±0.6-fold, p=0.026). SAA knockout in podocytes reduced expression of CXCL5, CCL2, and CCL5 by >60% (p<0.05 for all) in metabolic memory experiments. jmjd3 inhibition reduced AGE-induced expression of SAA and each of the SAA-dependent inflammatory mediators by >60% (p<0.05 for all) in podocytes.


Short term exposure of podocytes to hyperglycemia-related perturbations causes sustained H3K27Me3 demethylation and increased SAA expression, leading to a sustained SAA-dependent inflammatory response.


  • Private Foundation Support