Pathologic mechanisms and therapeutic strategies to progressive renal disease by calcineurin inhibitor

我们先前报道，抑制促炎症转录因子-核因子-κB可以减轻钙调神经磷酸酶抑制剂、环孢素A和他克莫司引起的肾间质炎症和纤维化。间质炎症反应的存在并不是药物诱导的肾纤维化所特有的，而是任何形式的肾纤维化都常见的。阻断这种炎症反应可抑制肾纤维化。口服吸附剂抑制尿毒症毒素的肠道吸收，减轻肾组织核因子-kB的活化和炎症，从而抑制肾大部切除后慢性尿毒症模型的肾纤维化。姜黄素可减轻单侧输尿管梗阻后的肾脏炎症，进而改善肾纤维化。我们认为抑制核因子-kB可能是其作用机制之一。我们还表明，抑制单核细胞趋化蛋白-1(MCP-1)的增强表达和巨噬细胞在肾脏内的渗透可能是这些药物发挥作用的下游机制。由于Rho-Kinase在炎症中发挥作用，我们接下来阐明了Rho-Kinase在两种不同的操作方式--他克莫司给药和输尿管阻断引起的肾脏炎症和纤维化中的作用。Rho-Kinase抑制剂法舒地尔部分减轻了输尿管闭塞后的肾炎症，但在慢性他克莫司肾毒性中观察不到。这些结果可能表明，Rho-Kinase不是肾纤维化发生的常见机制。需要进一步的研究来阐明Rho-Kinase在肾纤维化发病机制中的确切作用。

We previously reported that inhibition of proinflammatory transcription factor, nuclear factor kappaB (NF-κB) attenuated renal interstitial inflammation and fibrosis elicited by calcineurin inhibitors, cyclosporin A and tacrolimus. The existence of interstitial inflammatory responses are not unique to drug-induced renal fibrosis but are common to any form of renal fibrosis. Blockade of this inflammatory response led to inhibition of renal fibrosis. Oral adsorbent that inhibited intestinal absorption of uremic toxin attenuated renal NF-kB activation and inflammation that resulted in inhibition of renal fibrosis in chronic uremic model following subtotal nephrectomy. Curcumin attenuated renal inflammation and subsequently ameliorated renal fibrosis following unilateral ureteral obstruction. We showed that inhibition of NF-kB is a likely mechanism. We also showed that inhibition of enhanced expression of monocyte chemoattractant protein-1 (MCP-1) and macrophage infiltration within the kidney are possible downstream mechanisms by which these drugs acted.As Rho-kinase play a role in inflammation, we next elucidated the role of Rho-kinase in renal inflammation and fibrosis elicited by two different maneuver, tacrolimus administration and ureteral occlusion. Rho-kinase inhibitor, fasudil partially attenuated renal inflammation following ureteral occlusion but not that observed in chronic tacrolimus nephrotoxicity. These results may indicate that Rho-kinase is not a common mechanism by which renal fibrosis develops. Further study is required to clarify the precise role of Rho-kinase in the pathogenesis of renal fibrosis.