Long- and short-term treatment with imatinib attenuates the development of chronic kidney disease in experimental anti-glomerular basement membrane nephritis
Long- and short-term treatment with imatinib attenuates the development of chronic kidney disease in experimental anti-glomerular basement membrane nephritis
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DOI：
10.1093/ndt/gfs414
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发表时间：
2013-03-01
影响因子：
6.1
通讯作者：
Akizawa, Tadao
中科院分区：
文献类型：
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作者：
Iyoda, Masayuki;Shibata, Takanori;Akizawa, Tadao
Akizawa及其同事提供了强有力的实验证据，证明PDGF信号抑制在两种看似无关的肾小球疾病（RPGN和FSGS）中的有益作用。伊马替尼是一种选择性酪氨酸激酶抑制剂，可以阻断血小板衍生生长因子（PDGF）受体的活性。伊马替尼也被称为消炎剂。我们研究了长期或短期伊马替尼治疗Wistar-Kyoto （WKY）大鼠抗肾小球基底膜（GBM）肾炎的疗效。采用肾毒性血清法（NTS）诱导WKY大鼠第0天肾炎。长期治疗组从第7天至第49天，短期治疗组从第7天至第13天，每天通过腹腔注射给予伊马替尼或代药；第50天处死所有大鼠。在长期治疗中，伊马替尼表现出明显的肾保护作用；伊马替尼抑制蛋白尿，改善肾功能，减轻肾小球硬化和小管间质损伤的发展，降低肾皮质I型胶原和转化生长因子- β (TGF-)的表达水平。本研究的主要发现是，伊马替尼短期治疗也显著减轻了肾损伤的发展，直到第50天，尽管肾脏保护程度略低于长期治疗。这些结果表明，伊马替尼是限制肾小球肾炎（GN）进展到终末期肾功能衰竭的一种有希望的策略。特别是，在GN早期阶段进行短期治疗，与持续和长期治疗相比，在成本效益和减少不良反应方面更有利。
Akizawa and co-workers have provided strong experimental evidence for beneficial effects of PDGF signaling inhibition in two seemingly unrelated glomerular diseases (RPGN and FSGS).Imatinib is a selective tyrosine kinase inhibitor that can block platelet-derived growth factor (PDGF) receptor activity. Imatinib is also known as an anti-inflammatory agent. We examined the therapeutic effects of long- or short-term imatinib treatment in Wistar-Kyoto (WKY) rats with established anti-glomerular basement membrane (GBM) nephritis.Nephrotoxic serum (NTS) nephritis was induced in WKY rats on day 0. Groups of animals were given either imatinib or vehicle daily by intraperitoneal injection, from day 7 to day 49 in the long-term treatment study, and from day 7 to 13 in the short-term treatment study; all rats were sacrificed at day 50.In long-term treatment, imatinib showed marked renoprotective effects; imatinib suppressed proteinuria, improved renal function, attenuated the development of glomerulosclerosis and tubulointerstitial injury and reduced the expression levels of collagen type I and transforming growth factor-beta (TGF-) in renal cortex. The key finding of the present study was that short-term treatment with imatinib also significantly attenuated the development of renal injury until day 50, although the degree of renoprotection was slightly inferior to that of long-term treatment.These results suggest that administration of imatinib is a promising strategy for limiting the progression of glomerulonephritis (GN) to end-stage renal failure. In particular, a short period of treatment at an early stage of GN is more beneficial in terms of cost-effectiveness and reduction of adverse effects in comparison to a continuous and long period of treatment.