Abstract: TH-PO965
Varying AKI Types Affect Parietal Epithelial Cell Function with Different Impact on Tubuloglomerular Cross-Talk
Session Information
- Pathology and Lab Medicine: Basic
October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Pathology and Lab Medicine
- 1501 Pathology and Lab Medicine: Basic
Authors
- Wang, Jiayi, Vanderbilt University Medical School, Nashville, Tennessee, United States
- Li, Xin, The Medicine College of Shanghai JiaoTong University, Shanghai, China
- Zhang, Ming-Zhi, Vanderbilt University Medical School, Nashville, Tennessee, United States
- Harris, Raymond C., Vanderbilt University Medical School, Nashville, Tennessee, United States
- Matsusaka, Taiji, Tokai University School of Medicine, Isehara, KANAGAWA, Japan
- Yang, Haichun, Vanderbilt University Medical School, Nashville, Tennessee, United States
- Fogo, Agnes B., Vanderbilt University Medical School, Nashville, Tennessee, United States
Background
Previously we found that mild tubulointerstitial fibrosis sensitizes the kidney to subsequent glomerular injury. The transition of acute kidney injury (AKI) to chronic kidney disease depends on the severity of AKI. In this study, we explored whether the type of initial proximal tubular (PT) injury impacts the glomerular response to a subsequent injury, and the role of parietal epithelial cells (PECs) in this response.
Methods
We induced AKI by injecting diphtheria toxin (DT) in DTR transgenic mice that express human DT receptor in S2 and S3 PT, or by injecting aristolochic acid (AA) which targets all PT and part of PECs. All mice were mated with NEP25 mice, which express human CD25 on podocytes, and podocyte injury can be induced by immunotoxin (LMB2). Mice underwent LMB2 injection at 6 wks after DT or AA injury, with control mice (PODO) only receiving LMB2 without preceding tubular injury, followed by uninephrectomy 1 wk later and sacrifice 4 wks later. In vitro, PECs were exposed to vehicle or AA for 24h, followed by exposure to supernatant from injured podocytes for 48 hours.
Results
Urinary KIM-1/NGAL recovered to baseline in DT while they remained high in AA mice at wk 6 after injury. AA+LMB2 mice had significantly higher albuminuria than PODO, while DT+LMB2 had no significant increase vs PODO, at 1 wk after LMB2. Columnar PECs may have more stem cell potential vs flat PECs, and columnar/flat PECs ratios were higher in PODO mice and DT+LMB2 than AA+LMB2. Expression of β–catenin and ILK in PECs increased in AA+LMB2, but not in DT+PODO, compared to PODO. WT1+ cell density was decreased in both AA+LMB2 and DT+LMB2 vs PODO. At 4 wks after LMB2, 0/16 PODO and 1/23 DT+LMB2 vs 8/16 AA+LMB2 mice had died. GFR, ACR and glomerulosclerosis were similar among groups in surviving mice. Both DT+LMB2 and AA+LMB2 showed more CD44+/α-SMA+ cells on the glomerular tuft than PODO, suggesting mesenchymal transition of activated PECs. In vitro, AA-treated PECs expressed more ILK and CTGF vs vehicle after cells were exposed to injured podocyte medium.
Conclusion
Tubular injury that involves specific PT segments and PECs, which may serve as stem cells and participate in glomerular rescue after injury, may result in less recovery and increased sensitization of glomeruli to a second hit.
Funding
- NIDDK Support