Kidney Week

Abstract: SA-PO930

Transcriptomic Analysis of PCK Rat Peritoneum After Long -Term Infusion of Dialysate with Mono or Dual Therapy of a JAK1/2 Inhibitor and/or Losartan

Session Information

• Dialysis: Peritoneal Dialysis - III
  October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Dialysis

• 703 Dialysis: Peritoneal Dialysis

Authors

• Nguyen, Sonny Truong, Los Angeles Biomedical Research institute at Harbor-UCLA Medical Center, Torrance , California, United States

Sonny Truong Nguyen,

• Adler, Sharon G., Los Angeles Biomedical Research institute at Harbor-UCLA Medical Center, Torrance , California, United States

Sharon G. Adler,

• Miyata, Kana N., Los Angeles Biomedical Research institute at Harbor-UCLA Medical Center, Torrance , California, United States

Kana N. Miyata,

• Zhang, Pei, The First Affiliated Hospital of Anhui Medical University, Anhui, He Fei, China

Pei Zhang,

• La page, Janine A., Los Angeles Biomedical Research institute at Harbor-UCLA Medical Center, Torrance , California, United States

Janine A. La page,

• Dai, Tiane, Los Angeles Biomedical Research institute at Harbor-UCLA Medical Center, Torrance , California, United States

Tiane Dai,

Background

Peritoneal dialysis (PD) is limited by reduced efficacy over time. Peritoneal membrane (PM) injury is characterized by inflammation, hypervascularity, and fibrosis. JAK/STAT signaling mediates inflammatory pathways, including angiotensin signaling. Our previous work showed in rats with polycystic kidneys (PCK) chronically infused with 4.25% Dianeal x 16 wks, treatments with JAK1/2 inhibitor (JAK1/2i), losartan, or both preserved PM structure; JAK1/2i conferred better structural preservation vs losartan. Monotherapy with either JAK1/2i or losartan failed to consistently preserve PM function; dual infusion consistently preserved PM function. In order to elucidate mechanism at the transcriptomic level, we performed RNAseq analysis on PCK rat peritoneum.

Methods

PCK rats received dialysate infusions BID via an implanted subcutaneous port in the neck tunneled to the intraperitoneal cavity for 16 wks in the following groups: (1) 4.25% Dianeal; (2) 4.25% Dianeal + JAK1/2i (5mg/kg BID); (3) 4.25% Dianeal + Losartan (5mg/kg BID); and (4) 4.25% Dianeal + Losartan +JAK1/2i (5mg/kg BID each). PM with muscle was sampled for RNAseq. Total RNA was used, cDNA libraries were single-end sequenced (50bp) on an Illumina HiSeq 3000. Differentially expressed genes are defined as at least 2-fold change and p<0.05.

Results

Compared to PCK rats receiving Dianeal only, concomitant infusion of Dianeal and JAK1/2i or losartan up- or downregulated expression of 88 genes in 132 canonical pathways and 36 genes in 55 pathways respectively. Combination treatment with JAK1/2i and losartan caused differential expression of 29 genes in 65 pathways. When comparing PCK rats that received JAK1/2i to losartan, 38 genes in 98 pathways were differentially expressed. 12 genes were regulated by either JAK1/2i or losartan with a similar pattern, of which, only three were similarly regulated when both JAK1/2i and losartan were infused.

Conclusion

The differentially expressed gene pattern may explain superior morphologic protection in the JAK1/2i group and the functional preservation in the dual therapy group that we previously showed in our study. The transcriptomic analysis in this study provides gene differential expression profiles of JAK1/2i and losartan that helps explain different treatment effects.

Funding

• Commercial Support – Renal Research Institute