S1P-Mediated Podocyte Injury in Focal Segmental Glomerulosclerosis
Abstract
In the United States, about 37 million adults (15% of the adult population) are estimated to have chronic kidney disease (CKD), making kidney disease a leading cause of death. Approximately 90,000 Americans die from kidney disease each year, more than from breast and prostate cancers combined. One of the Topic Areas of the Peer Reviewed Medical Research Program is Focal and Segmental Glomerulosclerosis (FSGS). FSGS is a protein-spilling disorder that affects the kidney filtration apparatus (glomerulus). About half of the patients diagnosed with FSGS require dialysis or kidney transplantation within 5 years from the time the diagnosis is made. Interestingly, people of West African descent, including African Americans, have a four-fold greater risk than the general population to have FSGS. Researchers believe that this increased risk is due to the presence of a variation (mutation) in a gene called Apolipoprotein (APOL1) in the genome of some African Americans. In addition to APOL1, many other genes were found to be associated with the development of FSGS or with the inability to respond to the initial treatment, which is usually a cortisone-based therapy. Among these mutations, the most common ones in patients that are affected by familiar FSGS and do not respond to cortisone-based therapy are mutations in a gene that makes collagen IV (COL4), an important constituent of the filtration apparatus. Among these FSGS causing mutations, a recently described one causes the accumulation of a form of lipid called sphingosine-1 phosphate (S1P) in the kidney filtration apparatus. While more and more genes and pathways that contribute to FSGS are being investigated, there is an unmet need to understand how these different genetic variations and pathways of injury can amplify each other and are associated with a worse disease prognosis. It is ultimately only through a better understanding of the mechanisms linking known genes variations, pathways of injury and clinical presentation that a definitive cure can be identified. The overall scope of this proposal is to investigate a new mechanism causing protein spillage in FSGS, to understand if this mechanism is responsible for the higher susceptibility to FSGS we see in African Americans and to propose a new therapeutic strategy for affected individuals. We have utilized a unique bedside to bench approach where the research being proposed stem from the clinical observation that in the kidney filtration apparatus of patients with FSGS there is the deficiency of a newly identified protein called Apolipoprotein M, APOM. We generated strong clinical and experimental preliminary data suggesting that reduced APOM expression in patients with FSGS is associated with loss of renal function. We confirmed these findings in an experimental model of FSGS, where administration of APOM was sufficient to reduce protein spillage in the urine and was able to block injury induced by accumulation of S1P in the kidney, confirming that the APOM/S1P pathways are related and suggesting the therapeutic potential of targeting these pathways. Finally, we analyzed cells that were established from the urine of African American patients with FSGS with and without the APOL1 gene variations to demonstrate that patients with the APOL1 risk variations are more susceptible to S1P-dependent injury. Based on these observations, we hypothesize that decreased APOM expression renders kidney filtration cells susceptible to S1P-mediated injury and that the presence of APOL1 gene variations amplifies this pathway of injury. The proposed study is highly feasible, as we have developed all the tools needed to address this hypothesis. The risks associated with our approach to find a cure for FSGS is minimal, as our idea stems from and is supported by strong clinical observations. The proposed study is significant, as experiments proposed herein are likely be sufficient to lead to the clinical development of a new therapeutic a
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310054
Entities
People
- Sandra Merscher
Organizations
- United States Army
- University of Miami