KIAA1199 and hyaluronic acid signaling: a promising therapeutic approach for glomerular disease

肾小球硬化（继发性FSGS）是大多数肾脏疾病导致慢性进行性肾衰竭（CKD）的常见最终途径。它影响着全球5-10%的人口。CKD是心血管并发症和过早死亡最重要的独立危险因素之一。在我们之前的工作中，我们证明了在继发性FSGS的情况下，CKD主要是由激活的壁细胞介导的，因此我们提出了激活这些细胞作为新的治疗靶点。在临床前研究中，几个国际和独立的研究小组已经表明，抑制胶原受体DDR1可以非常有效地预防FSGS。然而，开发一种特定的DDR1抑制剂在技术上是困难的/不可能的。因此，在我们初步的联合工作中，我们进一步研究了DDR1在肾脏中的可能作用机制。我们证明DDR1激活诱导透明质酸酶KIAA1199的表达。我们发现这种酶产生的透明质酸片段具有特定的和不寻常的分子长度约为50 kDa（即中间HA = intHA）。我们的初步数据表明，这些intHA片段最有可能在介导FSGS中发挥关键作用-可能通过激活顶叶上皮细胞。这里的合作要求汇集了一个跨学科的专家团队：一个晶体学家来识别高度特异性的小分子抑制剂（A.C.）。在透明质酸（J.S.）生物学方面有多年经验的基础科学家。FSGS的人类医生和专家，具有转基因动物模型（h.h., h.s.， M.M.）和肾脏病理学家（S.M.）的专业知识，用于人类活组织检查的临床前实验。最后，一位在DDR1通路和药物开发（mp）方面有长期经验的药理学家。我们广泛的初步工作是在密切的科学交流中产生的。这表明了我们联盟的高附加值，我们希望这个项目能对理解透明质酸在肾小球疾病中的生物学作用做出重大贡献。我们相信，我们的研究团队将成功地将一种已知且高效的信号通路（DDR1）用于FSGS和CKD的临床应用（直接转化应用）。

Glomerulosclerosis (secondary FSGS) is the common final pathway of most kidney diseases leading to chronic progressive renal failure (CKD). It affects 5-10% of the population worldwide. CKD is one of the most important independent risk factors for cardiovascular complications and premature death. In our previous work, we demonstrated that CKD is predominantly mediated by activated parietal cells in the context of secondary FSGS, and we therefore proposed activation of these cells as a novel therapeutic target. In preclinical studies, it has been shown by several international and independent research groups that inhibition of the collagen receptor DDR1 can prevent FSGS very effectively. However, the development of a specific DDR1 inhibitor has proven to be technically difficult/impossible. Therefore, in our preliminary joint work, we further investigated the possible mechanism of action of DDR1 in the kidney. We demonstrated that DDR1 activation induces the expression of the hyaluronidase KIAA1199. We show that this enzyme generates hyaluronic acid fragments with a specific and unusual molecular length of approximately 50 kDa (i.e. intermediate HA = intHA). Our pilot data suggest that these intHA fragments most likely play a key role in mediating FSGS - potentially via activation of parietal epithelial cells. The collaborative effort requested here brings together an interdisciplinary team of specialists: A crystallographer to identify highly specific small-molecule inhibitors (A.C.). A basic scientist with many years of experience in the biology of hyaluronic acids (J.S.). Human physicians and experts in FSGS with expertise in transgenic animal models (H.H., H.S., M.M.) and a nephropathologist (S.M.) for preclinical experiments on human biopsies. And finally, a pharmacologist with long experience in the DDR1 pathway and drug development (M.P.).Our extensive preliminary work has been generated in close scientific exchange. This demonstrates the high added value of our consortium and we hope that a significant contribution to the understanding of the biology of hyaluronic acid in glomerular diseases can be expected from this project. We are confident that our consortium will succeed in making an already known and highly effective signaling pathway (DDR1) accessible for clinical application in FSGS and CKD (direct translational application).