Acute kidney injury (AKI) is a debilitating syndrome with a poor prognosis and increased mortality rate when it occurs in the setting of intensive hospital care. The increased frequency of occurrence of AKI in the older adults and the lasting impact that it makes in the quality of life and expectancy is a growing concern that needs to be addressed. There is immense interest in identifying molecular and cellular pathways that facilitate efficient renal repair in order to devise new therapeutic strategies against AKI in the elderly population. Several recent studies have demonstrated the activation of developmentally important signaling pathways during injury and regeneration in multiple adult tissue types. Retinoic acid (RA) signaling is one such pathway that is critically important for the proper development of many organs including the embryonic kidney. While there are studies including ours demonstrating the beneficial effects of exogenous administration of RA in multiple kidney injury models including AKI in the young kidneys, there is lack of evidence for a possible protective effect of exogenous RA administration against AKI in the aged kidneys following acute injury / repair. Also there is a lack of mechanistic insights of RA action and importantly, evidence towards the reactivation of endogenous RA signaling/pathway and the renal cell populations that are responsive to exogenous RA. Therefore, an investigation into the plausible reactivation or lack thereof of endogenous RA signaling pathway during kidney injury in the aged kidneys is highly imperative and will be key towards RA based pharmacological intervention in the future. Thus, in this research proposal we seek (i) to understand the protective effects of RA in the aged kidneys during acute injury and the effect of exogenous RA on the important players that determine the outcome of AKI, such as renal tubular epithelial cells and immune cells (ii) to study the exact functional role and status of endogenous RA signaling pathway in the aged kidneys during acute kidney injury / repair using mice models of AKI. A better understanding of the RA signaling pathway in the aged kidneys during AKI will help develop effective retinoid based therapeutic modalities for the prevention and / or treatment of AKI in the older adults.

Public Health Relevance

Acute kidney injury (AKI) is a leading cause of morbidity and mortality in the United States and a recent study indicates that deaths resulting from AKI have doubled in the last ten years in the US. The rate of incidence of AKI and the damage suffered from it are significantly heightened in the elderly population. Despite our increased understanding of the pathophysiology of AKI and clinical diagnosis and care, AKI remains a challenge especially in the older adults. A comprehensive approach to tackle this problem includes identification of novel therapeutic approaches that halt the kidney damage and boost tissue regeneration. The goals of this project are to identify the renoprotective effects of retinoc acid treatment against acute injury during aging and obtain insights into retinoid signaling pathway during injury / repair in the aging kidneys.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AG047412-01A1
Application #
8893593
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Macchiarini, Francesca
Project Start
2015-08-01
Project End
2017-05-31
Budget Start
2015-08-01
Budget End
2016-05-31
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
Kota, Satya K; Roening, Coco; Patel, Nehal et al. (2018) PRMT5 inhibition promotes osteogenic differentiation of mesenchymal stromal cells and represses basal interferon stimulated gene expression. Bone 117:37-46
Kota, Satya K; Kota, Savithri B (2017) Noncoding RNA and epigenetic gene regulation in renal diseases. Drug Discov Today 22:1112-1122
Kota, Satya K; Pernicone, Elizabeth; Leaf, David E et al. (2017) BPI Fold-Containing Family A Member 2/Parotid Secretory Protein Is an Early Biomarker of AKI. J Am Soc Nephrol 28:3473-3478