Intrarenal extracellular matrix production or kidney fibrosis is a prevalent feature of all forms of chronic kidney disease (CKD). The transforming growth factor-beta (TGFβ) is believed to be a major driver of extracellular matrix production. Nevertheless, anti-TGFβ therapies have consistently failed to reduce extracellular matrix production in CKD patients indicating the need for novel therapeutic strategies. We have previously shown that necroinflammation contributes to acute kidney injury. Here, we show that chronic/persistent necroinflammation drives intrarenal extracellular matrix production during CKD. We found that renal expression of receptor-interacting protein kinase-1 (RIPK1), RIPK3, and mixed lineage kinase domain-like (MLKL) increases with the production of intrarenal extracellular matrix and declined kidney function in both humans and mice. Furthermore, we found that TGFβ exposure induces the translocation of RIPK3 and MLKL to mitochondria resulting in mitochondrial dysfunction and ROS production. Mitochondrial ROS activates the serine-threonine kinase calcium/calmodulin-dependent protein kinases-II (CaMKII) that increases phosphorylation of Smad2/3 and subsequent production of alpha-smooth muscle actin (αSMA), collagen (Col) 1α1, etc. in response to TGFβ during the intrarenal extracellular matrix production. Consistent with this, deficiency or knockdown of RIPK3 or MLKL as well as pharmacological inhibition of RIPK1, RIPK3, and CaMKII prevents the intrarenal extracellular matrix production in oxalate-induced CKD and unilateral ureteral obstruction (UUO). Together, RIPK1, RIPK3, MLKL, CaMKII, and Smad2/3 are molecular targets to inhibit intrarenal extracellular matrix production and preserve kidney function during CKD.

肾内细胞外基质产生或肾纤维化是所有形式的慢性肾病 (CKD) 的普遍特征。转化生长因子-β (TGFβ) 被认为是细胞外基质产生的主要驱动力。然而，抗 TGFβ 疗法一直未能减少 CKD 患者的细胞外基质产生，这表明需要新的治疗策略。我们之前已经表明坏死性炎症会导致急性肾损伤。在这里，我们表明慢性/持续性坏死性炎症在 CKD 期间驱动肾内细胞外基质的产生。我们发现受体相互作用蛋白激酶 1 (RIPK1)、RIPK3、和混合谱系激酶结构域样 (MLK​​L) 随着肾内细胞外基质的产生而增加，并且在人类和小鼠中肾功能下降。此外，我们发现 TGFβ 暴露诱导 RIPK3 和 MLKL 易位至线粒体，导致线粒体功能障碍和 ROS 产生。线粒体 ROS 激活丝氨酸-苏氨酸激酶钙/钙调蛋白依赖性蛋白激酶-II (CaMKII)，从而增加 Smad2/3 的磷酸化和随后产生的α-平滑肌肌动蛋白 (αSMA)、胶原蛋白 (Col) 1α1 等作为响应在肾内细胞外基质产生过程中转化为 TGFβ。与此一致，RIPK3 或 MLKL 的缺乏或敲低以及 RIPK1、RIPK3、CaMKII 可防止草酸盐诱导的 CKD 和单侧输尿管梗阻 (UUO) 中肾内细胞外基质的产生。RIPK1、RIPK3、MLKL、CaMKII 和 Smad2/3 共同是抑制肾内细胞外基质产生并在 CKD 期间保护肾功能的分子靶标。