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

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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).