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Kidney Week

Abstract: PO0703

CHOP-ASO Ameliorates Glomerular and Tubular Damage on Top of ACE Inhibition in Diabetic Nephropathy

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Shahzad, Khurrum, Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostic, University Hospital, Leipzig, Leipzig, Germany
  • Fatima, Sameen, Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostic, University Hospital, Leipzig, Leipzig, Germany
  • Michel, Sven, Secarna Pharmaceuticals GmbH & Co. KG, Planegg, Germany
  • Jaschinski, Frank, Secarna Pharmaceuticals GmbH & Co. KG, Planegg, Germany
  • Klar, Richard, Secarna Pharmaceuticals GmbH & Co. KG, Planegg, Germany
  • Isermann, Berend Heinrich, Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostic, University Hospital, Leipzig, Leipzig, Germany
Background

Maladaptive ER stress signaling in diabetic nephropathy (dNP) is linked to increased glomerular and tubular expression of the cell death-promoting transcription factor C/EBP homologous protein (CHOP). We determined whether therapy with locked nucleic acid (LNA)-modified antisense oligonucleotides (ASOs) targeting CHOP ameliorates experimental dNP.

Methods

Following an in vivo dose-escalation study, we determined the efficacy of CHOP-ASO in the early and later stages of experimental dNP (8- or 16-week-old db/db mice, respectively) alone or in combination with an angiotensin-converting enzyme inhibitor (ACEi). Renal functional parameters and morphological analyses were used to determine the effects. Renal gene expression profiling was conducted to determine differentially regulated genes and pathways. Several human CHOP-ASOs were tested in hyperglycemia-exposed human kidney cells.

Results

CHOP-ASOs efficiently reduced renal CHOP expression in diabetic mice and reduced markers of dNP at early and late stages. Early combined intervention (CHOP-ASO and ACEi) efficiently prevented interstitial damage. At the later timepoint, the combined treatment reduced indices of both glomerular and tubular damage more efficiently than either intervention alone. A significantly larger number of genes and disease pathways were affected by CHOP-ASO, including reduced Slc5a2 (sodium-glucose transport protein 2). Human CHOP-ASOs efficiently reduced glucose-induced CHOP and SGLT2 expression and prevented cell death of human kidney cells in vitro.

Conclusion

The ASO-based approach efficiently reduced renal CHOP expression in a diabetic mouse model, providing an additional benefit to an ACEi in particular at later timepoints. These studies demonstrate that ASO-based therapies efficiently reduce maladaptive CHOP expression and ameliorate experimental dNP.