Abstract: SA-PO100
Renal Organic Anion and Cation Transporters Are Downregulated in Ischemia/Reperfusion and Cisplatin-Induced AKI Models, but Not in Cecal Slurry-Induced AKI
Session Information
- AKI: Mechanisms - III
November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Qi, Jenson, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
- Frikke-Schmidt, Henriette, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
- Albarazanji, Kamal, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
- Skrypnyk, Nataliya, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
- Ma, Li-Jun, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
- D'Aquino, Katharine, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
- Camacho, Raul, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
- Guo, Lili, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
- Steffen, Janos, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
- Chen, Tao, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
- Nawrocki, Andrea R., Janssen Research and Development LLC, Spring House, Pennsylvania, United States
- Lee, Seunghun Paul, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
- Pocai, Alessandro, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
Group or Team Name
- Cardiovascular & Metabolic Research
Background
Renal proximal tubules excrete metabolites through unidirectional solute transport systems facilitating active secretion of organic ions into urine. We explored 3 classes of transporters: (1) organic anion transporters (OAT), (2) organic cation transporters (OCT), and (3) aquaporins (AQP). We then investigated the effects of acute kidney injury (AKI) induced by ischemia/reperfusion (I/R), cisplatin, or cecal slurry (CS) on the expression of these transporters.
Methods
Male SD rats had bilateral renal ischemia or sham-surgery. Kidneys were harvested at 24h. Male C57BL/6N mice were IP dosed with a single injection of cisplatin. Kidneys were harvested at 96h. In the CS model, male C57BL/6N mice were IP dosed with vehicle or cecal slurry and sacrificed at 8 or 24h.
Results
SD rats express high levels of renal OAT1/3, OCT2, and AQP1 mRNAs. I/R rats with 33 min of bilateral renal ischemia showed significant decrease of renal OAT1, OAT3, OCT2, and AQP1 mRNAs (76%, 92%, 90%, and 61% reduction, respectively). 40 min I/R led to further decrease of these mRNAs. In C57BL/6N mice, OAT2/3, OCT1/2, and AQP1 are highly expressed in the kidney. We also observed significant decrease of these genes in kidney in I/R mice. In cisplatin-induced mouse nephrotoxic AKI, renal OAT2/3, OCT1/2, mRNAs were significantly reduced (>80%), while AQP1 mRNA was down by 65%. In contrast, no reduction of renal OAT2/3 and OCT1/2 mRNAs, nor any increase of kidney injury marker KIM1 were observed at 8 or 24 in CS mouse AKI. Unlike IR induced-tubular necrosis in the renal outer medulla, CS induced vacuolation and tubule dilation in the cortex. We detected low expression of OATs/OCTs in human renal primary proximal epithelial cells which renders it difficult to assess their regulation in vitro.
Conclusion
Our data show significant downregulation of renal OATs and OCTs in I/R and cisplatin-induced AKI. These reductions might lead to decreased transport activities in the proximal tubule and further deterioration of renal function after injury. The lack of downregulation of renal OATs and OCTs in the CS mouse AKI suggests that the injury of the renal tubule epithelial cells is less in this model.
Funding
- Commercial Support –