Vectus Biosystems, North Ryde, Australia.
Vectus Biosystems, North Ryde, Australia.
Eur J Pharmacol. 2020 Apr 15;873:172979. doi: 10.1016/j.ejphar.2020.172979. Epub 2020 Jan 31.
Dialysis requiring renal failure is a silent epidemic. Despite an annual mortality of 24% the dialysis population has increased by 1-4% per annum. Regardless of the initial injury, tubulointerstitial fibrosis is a feature of the renal pathology and it inversely correlates with declining renal function. Current agents display little efficacy against tubulointerstitial fibrosis. Clearly, therapies effective against tubulointerstitial fibrosis and able to preserve kidney function are needed. Vasoactive intestinal peptide (VIP) has been shown to reverse pre-existing cardiac fibrosis. We sought to determine whether VIP is effective in tubulointerstitial fibrosis. Spontaneous hypertensive rats (SHR) on a 2.2% salt diet were randomised to zero time control, 4 week infusion of VIP (5 pmol/kg/min) or vehicle control infusion. A fourth group, to match the blood pressure reduction achieved in the VIP infused group was included. Fibrosis was quantitated by computerised histomorphometry, changes in pro-fibrotic mediators were measured by quantitative rt-PCR and macrophage activation assessed by cyclic adenosine monophosphate (c-AMP) response to incubation with VIP. Tubulointerstitial fibrosis in the VIP treated rats was significantly lower than the zero time control (P < 0.0005), the vehicle infused control (P < 0.0005) and the blood pressure matched group (P < 0.01). Although all six profibrotic mediators increased over the 4 week experimental period VIP infusion only decreased tumour necrosis alpha (TNFα) expression significantly (P < 0.001). Incubation of RAW264 macrophages with VIP significantly increased c-AMP (P < 0.01). We conclude that VIP infusion reversed existing tubulointerstitial fibrosis suggesting a possible therapeutic role for a VIP based therapy in chronic kidney disease.
肾衰竭需要透析是一种无声的流行疾病。尽管每年的死亡率为 24%，但透析人群的数量仍以每年 1-4%的速度增长。无论最初的损伤是什么，肾小管间质纤维化都是肾脏病理的一个特征，它与肾功能下降呈反比。目前的药物对肾小管间质纤维化的疗效甚微。显然，需要有针对肾小管间质纤维化并能保持肾功能的治疗方法。血管活性肠肽 (VIP) 已被证明可逆转已存在的心脏纤维化。我们试图确定 VIP 是否对肾小管间质纤维化有效。给予自发性高血压大鼠 (SHR) 2.2%盐饮食，并将其随机分为零时间对照、4 周 VIP（5 pmol/kg/min）输注组或载体对照输注组。还包括第四组，以匹配 VIP 输注组的血压降低幅度。纤维化通过计算机组织形态计量学进行定量，通过定量 RT-PCR 测量促纤维化介质的变化，并通过环磷酸腺苷 (c-AMP) 对 VIP 孵育的反应评估巨噬细胞激活。与零时对照组（P < 0.0005）、载体输注对照组（P < 0.0005）和血压匹配组（P < 0.01）相比，VIP 治疗组的肾小管间质纤维化明显降低。虽然所有六种促纤维化介质在 4 周的实验期间均增加，但 VIP 输注仅显著降低肿瘤坏死因子α (TNFα) 的表达（P < 0.001）。VIP 孵育 RAW264 巨噬细胞可显著增加 c-AMP（P < 0.01）。我们得出结论，VIP 输注逆转了现有的肾小管间质纤维化，这表明 VIP 为基础的治疗在慢性肾病中可能具有治疗作用。
