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RARa Deletion Specifically in the Proximal Tubules Leads to Acute Kidney Injury and Fibrosis in Mice
Author(s) -
DiKun Krysta,
Gudas Lorraine,
Tang XiaoHan
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.03985
Subject(s) - fibrosis , acute kidney injury , medicine , kidney , pathology
Chronic Kidney Disease (CKD) is characterized by a gradual loss of kidney function and affects an estimated 15% of adults in the United States. While treatable in its early stages, more than 90% of those effected remain unaware of the disease until it has progressed to later stages and the kidneys have become irreversibly fibrotic. Identifying and targeting genes that ameliorate or reverse renal fibrosis could prevent patients in later stages of CKD from progressing to End Stage Renal Disease (ESRD). Proximal tubule (PT) injury is one of the known drivers of tubulointerstitial fibrosis and normal kidney development is highly influenced by the metabolism and signaling of Retinoic Acid (RA), an agonist for the three types of Retinoic Acid Receptors (RAR a, b, g). RARs act as transcription factors to regulate the expression of genes, such as those involved in fibrosis, apoptosis, inflammation, and differentiation. We are specifically interested in RARa, as its activation has been shown to improve kidney function in a mouse model of HIV‐related kidney. Therefore, we have developed a mouse model that allows the tamoxifen‐induced deletion of RARa specifically in kidney PT cells to elucidate whether RARa has a protective role during kidney injury. Thus far, our data have indicated that mice with RARa deleted from PTs exhibit significant tubulointerstitial fibrosis, a decrease in healthy proximal tubules, an increase in TGFB1 expression, and proteinuria, collectively indicating kidney damage. This phenotype is present without any external stimuli to induce kidney injury. Additionally, this phenotype is more severe in female mice, indicating a potential sex difference in the role of RARa in the kidney. In conclusion, we have identified RARa as a key regulator in the prevention of the development and progression of fibrosis in the kidney. Because there are currently no treatments to combat renal fibrosis, further investigations into the anti‐fibrotic role of RARa could lead to novel treatments against kidney injury.