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

Significance Statement The endoplasmic reticulum (ER) stress response and the maladaptive and cell-death?promoting transcription factor C/EBP homologous protein (CHOP) have been linked with diabetic kidney disease (DKD). Specific therapies targeting maladaptive ER stress signaling are lacking. We show that an antisense oligonucleotide (ASO)?based approach reducing CHOP expression ameliorates DKD in mice, providing renal protection on top of ACE inhibition. CHOP inhibition improves both glomerular and tubular damage. ASO-based therapies are a potentially new approach to target maladaptive ER stress signaling and improve DKD. Background Maladaptive endoplasmic reticulum stress signaling in diabetic kidney disease (DKD) is linked to increased glomerular and tubular expression of the cell-death?promoting transcription factor C/EBP homologous protein (CHOP). Here, we determined whether locked nucleic acid (LNA)?modified antisense oligonucleotides (ASOs) targeting CHOP ameliorate experimental DKD. Methods We determined the efficacy of CHOP-ASO in the early and late stages of experimental DKD (in 8- or 16-week-old db/db mice, respectively) alone or with an angiotensin-converting enzyme inhibitor (ACEi), after an in vivo dose-escalation study. We used renal functional parameters and morphologic analyses to assess the effect of CHOP-ASO and renal gene-expression profiling to identify 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 DKD at the 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. CHOP-ASO affected a significantly larger number of genes and disease pathways, including reduced sodium-glucose transport protein 2 (Slc5a2) and PROM1 (CD133). Human CHOP-ASOs efficiently reduced glucose-induced CHOP and prevented death of human kidney cells in vitro. Conclusions The ASO-based approach efficiently reduced renal CHOP expression in a diabetic mouse model, providing an additional benefit to an ACEi, particularly at later timepoints. These studies demonstrate that ASO-based therapies efficiently reduce maladaptive CHOP expression and ameliorate experimental DKD.

Automated summary

The study demonstrates that an ASO-based approach reducing CHOP expression can ameliorate DKD in mice, providing renal protection on top of ACE inhibition. Inhibition of CHOP not only improves glomerular damage, but also tubular damage. ASO therapies are a potential new approach to target maladaptive ER stress signaling and improve DKD.