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

医学 氯沙坦 内分泌学 纤维化 腹膜透析 血管紧张素II 肾功能 内科学 缬沙坦 药理学 泌尿科 受体 血压
作者
Pei Zhang,Kana N. Miyata,Cynthia C. Nast,Janine LaPage,Madisyn Mahoney,Sonny Nguyen,Kamran Khan,Qiaoyuan Wu,Sharon G. Adler,Tiane Dai
出处
期刊:Peritoneal Dialysis International [SAGE]
卷期号:43 (2): 159-167 被引量:1
标识
DOI:10.1177/08968608221116956
摘要

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.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).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.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.

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