Acute kidney injury (AKI) and chronic kidney disease (CKD) are more prevalent in elderly individuals due to the increased susceptibility to injury and diminished repair capability of the aging kidney. Age-related decline of renal function may reflect multicellular dysfunction that leads to reduced capability of the kidney to repair or regenerate in response to stress. Our group previously identified MG53 as a key component of cell membrane repair, which plays a vital role in protection against AKI. We know that renal proximal tubular epithelia (PTE) contain endogenous MG53 protein. In principle, compromised function of MG53 to repair injury to PTE may be an intrinsic mechanism that contributes to reduced kidney function in aging. We also know that MG53's myokine function in tissue repair is compromised in aging. A loss of the crosstalk from muscle to kidney may constitute an extrinsic mechanism leading to the increased vulnerability of the kidney to function properly during aging. This project is centered on testing the hypothesis that MG53 participates in the multicellular process of aging-related AKI and CKD by maintaining the integrity of PTE cells and facilitating muscle-kidney crosstalk. We have made a novel finding that links MG53's myokine function in control of intracellular Ca signaling to modulation of inflammasome activation associated with kidney injury and fibrosis. Thus, we developed a novel concept that engineering of macrophages with tailored secretion of MG53 can enhance renoprotection via harnessing inflammation and fibrotic remodeling associated with CKD. If proven, these findings can have a significant impact on geriatric medicine research, as chronic inflammation and fibrosis occur during the aging process and can impact the function of many organs including kidney.
Age-related decline of renal function reflects the reduced capability of the kidney to repair or regenerate in response to stress. By defining the fundamental biology that governs the muscle-kidney crosstalk, we aim to translate the basic findings of a novel tissue repair protein named MG53 into treatment of age-related kidney diseases.
