Dual therapy with an angiotensin receptor blocker and a JAK1/2 inhibitor attenuates dialysate-induced angiogenesis and preserves peritoneal membrane structure and function in an experimental CKD rat model

• Published in: Peritoneal dialysis international Vol. 43; no. 2; pp. 159 - 167
• Main Authors: Zhang, Pei, Miyata, Kana N, Nast, Cynthia C, LaPage, Janine A, Mahoney, Madisyn, Nguyen, Sonny, Khan, Kamran, Wu, Qiaoyuan, Adler, Sharon G, Dai, Tiane
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01-03-2023
• Subjects: Angiotensin Receptor Antagonists - metabolism; Angiotensin Receptor Antagonists - pharmacology; Angiotensin-Converting Enzyme Inhibitors - metabolism; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Angiotensin-Converting Enzyme Inhibitors - therapeutic use; Angiotensins - metabolism; Angiotensins - pharmacology; Animals; Dialysis Solutions - metabolism; Fibrosis; Glucose - metabolism; Losartan - metabolism; Losartan - pharmacology; Peritoneal Dialysis - adverse effects; Peritoneum - metabolism; Rats; Renal Insufficiency, Chronic - metabolism; Angiogenesis; JAK inhibitor; fibrosis; peritoneal dialysis; peritoneal membrane
• ISSN: 0896-8608; 1718-4304
• DOI: 10.1177/08968608221116956

Background:
Peritoneal dialysis (PD) is limited by reduced efficacy over time. We previously showed that a Janus kinase 1/2 inhibitor (JAK1/2i) reduced inflammation, hypervascularity and fibrosis induced by 4.25% dextrose dialysate (4.25%D) intraperitoneally (IP) infused for 10 days in rats with normal kidney function. JAK/STAT signalling mediates inflammatory pathways, including angiotensin signalling. We now tested the effect of long-term JAK1/2i and/or an angiotensin receptor blocker (ARB) on peritoneal membrane (PM) in polycystic kidneys (PCK) rats infused with 4.25%D.
Methods:
Except for controls, all PCK rats had a tunnelled PD catheter: (1) no infusions; (2) 4.25%D; (3) 4.25%D + JAK1/2i (5 mg/kg); (4) 4.25%D +losartan (5 mg/kg); and (5) 4.25%D + losartan +JAK1/2i (5 mg/kg each) IP BID × 16 weeks (N = 5/group). PM VEGFR2 staining areas and submesothelial compact zone (SMCZ) width were morphometrically measured. Peritoneal equilibration testing measured peritoneal ultrafiltration (UF) by calculating dialysate glucose at time 0 and 90 min (D/D0 glucose).
Results:
4.25%D caused hypervascularity, SMCZ widening, fibrosis and UF functional decline in PCK rats. Angiogenesis was significantly attenuated by JAK1/2i ± ARB but not by ARB monotherapy. Both treatments reduced SMCZ area. UF was preserved consistently by dual therapy (p < 0.05) but with inconsistent responses by monotherapies.
Conclusion:
Long-term JAK1/2i ± ARB reduced angiogenesis and fibrosis, and the combination consistently maintained UF. In clinical practice, angiotensin inhibition has been advocated to maintain residual kidney function. Our study suggests that adding JAK1/2i to angiotensin inhibition may preserve PM structure and UF.