Abstract: TH-PO1090
Deletion of p38 MAPK in Podocytes Aggravates Glomerular Injury by Aldosterone in Podocyte-Specific GC-A Knockout Mice
Session Information
- Glomerular Diseases: Podocyte Biology - I
November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1204 Podocyte Biology
Authors
- Sugioka, Sayaka, Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Kato, Yukiko, Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Ishii, Akira, Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Mori, Keita P., TMK Project, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
- Osaki, Keisuke, Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Tokudome, Takeshi, Department of Biochemistry, National Cerebral and Cardiovascular Research Institute, Osaka, Japan
- Matsusaka, Taiji, Department of Basic Sciences, Tokai University School of Medicine, Isehara, Japan
- Yanagita, Motoko, Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Yokoi, Hideki, Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Background
Previously, we demonstrated that uninephrectomized aldosterone-infused, high salt-fed podocyte-specific guanylyl cyclase-A (natriuretic peptide receptor 1) conditional KO (pod-GC-A cKO) mice exhibited glomerular injury and that pharmacological inhibition of p38 MAPK ameliorates podocyte damage. However, the effects of genetic deletion of p38 MAPK in podocytes of pod-GC-A cKO mice have been unknown.
Methods
We generated p38 MAPK(fl/fl);Nephrin-Cre (pod-p38 MAPK cKO) mice and p38 MAPK(fl/fl);GC-A(fl/fl);Nephrin-Cre (pod-p38MAPK/GC-A DKO) mice. For induction of glomerular injury, we treated them with aldosterone and high salt at 2 months of age for 3 weeks without nephrectomy (B-ALDO). In vitro, we examined the effect of p38 MAPK inhibitor in cultured human podocytes transfected with GC-A siRNA.
Results
B-ALDO-treated pod-p38 MAPK/GC-A DKO mice resulted in significant elevation of serum Cr (0.29 ± 0.04 mg/dl), massive albuminuria (42,660 ± 20,200 mg/mgCr) and severe foot process effacement in addition to intracapillary fibrin thrombi which indicated endothelial damage. Vehicle-treated DKO mice, B-ALDO-treated pod-GC-A cKO mice, and B-ALDO-treated pod-p38 MAPK cKO showed normal serum Cr levels (0.14 ± 0.01, 0.18 ± 0.02, 0.20 ± 0.01 mg/dl, respectively), mild increase of albuminuria (223 ± 6.5, 1496 ± 592, 649 ± 303 mg/mgCr, respectively) and only segmental foot process effacement. Blood pressure was not elevated in either mutant mice compared with that of B-ALDO control mice. Furthermore, glomerular mRNA expressions of MCP-1, PAI-1, and FN were upregulated and that of VEGF-A was downregulated in DKO mice. Consistent with this, suppression of GC-A mRNA expression by siRNA in combination with p38 MAPK inhibitor downregulated VEGF mRNA in human cultured podocytes.
Conclusion
Genetic p38 MAPK deletion in GC-A-nul podocytes exacerbated aldosterone-induced glomerular endothelial cell injury as well as podocytes, and resulted in renal dysfunction, probably through VEGF downregulation. These results suggest p38 MAPK in podocytes is necessary to protect endothelial and epithelial cells from aldosterone-induced injury.