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

Glomerulosclerosis (secondary FSGS) is the common final pathwayof most kidney diseases leading to chronic progressive renal failure(CKD). It affects 5-10% of the population worldwide. CKD is one ofthe most important independent risk factors for cardiovascularcomplications and premature death. In our previous work, wedemonstrated that CKD is predominantly mediated by activatedparietal cells in the context of secondary FSGS, and we thereforeproposed activation of these cells as a novel therapeutic target. Inpreclinical studies, it has been shown by several international andindependent research groups that inhibition of the collagen receptorDDR1 can prevent FSGS very effectively. However, the developmentof a specific DDR1 inhibitor has proven to be technicallydifficult/impossible. Therefore, in our preliminary joint work, we furtherinvestigated the possible mechanism of action of DDR1 in the kidney.We demonstrated that DDR1 activation induces the expression of thehyaluronidase KIAA1199. We show that this enzyme generateshyaluronic acid fragments with a specific and unusual molecularlength of approximately 50 kDa (i.e. intermediate HA = intHA). Ourpilot data suggest that these intHA fragments most likely play a keyrole in mediating FSGS - potentially via activation of parietal epithelialcells. The collaborative effort requested here brings together aninterdisciplinary team of specialists: A crystallographer to identifyhighly specific small-molecule inhibitors (A.C.). A basic scientist withmany years of experience in the biology of hyaluronic acids (J.S.).Human physicians and experts in FSGS with expertise in transgenicanimal models (H.H., H.S., M.M.) and a nephropathologist (S.M.) forpreclinical experiments on human biopsies. And finally, apharmacologist with long experience in the DDR1 pathway and drugdevelopment (M.P.). Our extensive preliminary work has beengenerated in close scientific exchange. This demonstrates the highadded value of our consortium and we hope that a significantcontribution to the understanding of the biology of hyaluronic acid inglomerular diseases can be expected from this project. We areconfident that our consortium will succeed in making an alreadyknown and highly effective signaling pathway (DDR1) accessible forclinical application in FSGS and CKD (direct translational application).