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vWF levels in vivo and in vitro. vWF mediates adhesion of sickle RBCs to endothelial cells, inducing oxidant stress, and increasing expression of ICAM-1, VCAM and E- selectin.47 Indeed, RONi treatment in SCD mice was asso- ciated with reduced vWF levels in glomerular capillaries, and decreased RBC adhesion and ICAM-1 levels. Therefore, the mechanism of RON inhibition may be associated with prevention of glomerular capillary conges- tion, leading to improvement of renal hemodynamics. A correlation between an alteration of renal hemodynamics and a renal histological injury has been demonstrated in a model of renal ischemia in SCD.48 In addition, our results demonstrate that MSP1 treatment of glomeruli isolated from control mice significantly increased albumin perme- ability that was effectively prevented by RON inhibition. Hyperfiltration is associated with glomerular hypertrophy and glomerulosclerosis.49 We demonstrate a significant reduction in glomerular size in SCD mice after treatment with RON inhibitors, suggesting a possible change in hyperfiltration. Reduction of glomerular size after 14-day treatment with RONi is unlikely to be due to structural remodeling or reduced proliferation of endothelial cells. To the best of our knowledge, this is the first study demonstrating function of MSP1/RON in the glomerular endothelial cells. Future studies will clarify the mechanism of MSP1-associated endothelial cell activation and its role
in the development of glomerular injury.
The present study established for the first time that
inhibition of RON kinase significantly ameliorates SCD renal pathology in mice. Short-term inhibition of RON kinase reduced endothelial injury in young SCD mice dur- ing the early stage of renal disease before the onset of albuminuria. We do not know how long this effect per- sists after RONi withdrawal. Whether short-term inhibi- tion of RON kinase will ameliorate already developed renal disease in older mice is currently under investigation. Future studies will elucidate a role of Ron kinase in renal disease in SCD patients. These findings also highlight a new potential therapeutic target for CKD in SCD. A recent pre-clinical study50 and Phase 1 clinical trial (clinical- trials.gov identifier: 01721148) of BMS-777607 RON inhibitor for treatment of human cancers demonstrated its safety and good tolerability, providing a proof of principal for the potential use of this pharmacological approach.
Funding
This work was supported in part by CHaRM pilot grant awarded to MJ through NIH grant 1P50HL118006 (to SN) and NIH grants 1R01HL125005 (to SN), 5G12MD007597 (to SN), and R41MD008829-01 (to ZMQ). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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