Abstract: SA-PO331
Semaphorin3A-Inhibitor Ameliorates Podocytopathy and Tubular Fibrosis in Adriamycin-Induced Renal Injury
Session Information
- Cellular Crosstalk in Glomerular Diseases - II
October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 1903 CKD (Non-Dialysis): Mechanisms
Authors
- Sang, Yizhen, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Scineces, Okayama, Japan
- Tsuji, Kenji, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Scineces, Okayama, Japan
- Inoue-Torii, Akiko, Eiju General Hospital, Tokyo, Japan
- Fukushima, Kazuhiko, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Scineces, Okayama, Japan
- Kitamura, Shinji, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Scineces, Okayama, Japan
- Wada, Jun, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Scineces, Okayama, Japan
Background
Semaphorin3A (SEMA3A) is a guidance protein that regulates angiogenesis, cell motility, immune cell regulation and cancer progression. In the mammalian adult kidneys, SEMA3A and its receptor, neuropilin-1 (NRP1) are expressed in podocytes, tubular cells and collecting ducts. However, the pathophysiological roles of the SEMA3A in renal diseases are still unclear. Here we analyzed the role of the SEMA3A-NRP1 signaling using the adriamycin (ADR)-induced podocytopathy mouse model and examined the therapeutic effect of SEMA3A-inhibitor.
Methods
Wild-type male Balb/c mice (10-week old) were assigned into three groups (n=5): ADR group (single injection of 10 mg/kg ADR by tail vein), ADR+SEMA3A-I group (ADR injection + daily intraperitoneal injection of 20 μg SEMA3A-inhibitor) and control group (saline injection by tail vein). All the mice were sacrificed 2 weeks after the ADR injection, and the expression of SEMA3A and NRP1, proteinuria, tubular injury and renal fibrosis were analyzed. We also examined the effect of recombinant SEMA3A and SEMA3A-inhibitor on immortalized mouse podocytes and proximal tubular cells (mProx24 cells) in vitro.
Results
The expression of SEMA3A in podocyte and NRP1 in proximal tubular cells were dramatically increased in ADR group compared to control group. SEMA3A-inhibitor significantly attenuated ADR-induced albuminuria (urinary albumin / creatinine ratio (mg/gCr): ADR group vs. ADR+SEMA3A-I group; 626.5±102.9 vs. 66.0±7.4, p<0.05), tubular injury and tubular fibrosis as well as the cell apoptosis in both podocytes and tubular cells. In vitro, SEMA3A caused the cell apoptosis in cultured podocytes and proximal tubular cells as well as the increase of TGF-β1 expression. In addition, the treatment with TGF-β1 increased NRP1 mRNA expression in the podocytes (5.2-fold) and proximal tubular cells (1.7-fold) compared to the control, implying SEMA3A-NRP1 signaling is associated with tubular fibrosis. Taken together, increased SEMA3A expression in podocytes induced by ADR might cause podocytopathy and proximal tubular injury by accelerating cell apoptosis and renal fibrosis.
Conclusion
SEMA3A-inhibitor ameliorates podocytopathy and tubular fibrosis in ADR-induced renal injury. It would be the therapeutic target for preventing the progression of the renal injury.
Funding
- Government Support - Non-U.S.