المؤلفون: Mishima, Keiichiro, Nakasatomi, Masao, Takahashi, Shunsuke, Ikeuchi, Hidekazu, Sakairi, Toru, Kaneko, Yoriaki, Hiromura, Keiju, Nojima, Yoshihisa, Maeshima, Akito

المصدر: PLoS ONE; 10/9/2019, Vol. 14 Issue 10, p1-15, 15p

مصطلحات موضوعية: RENAL fibrosis, URETERIC obstruction, CALCIUM channels, PROXIMAL kidney tubules, TYROSINE hydroxylase, MICE, MYOFIBROBLASTS, NERVE fibers

مستخلص: The N-type Ca²⁺ channel (Cav2.2) is distributed in sympathetic nerves that innervate the tubules, the vessels, and the juxtaglomerular granular cells of the kidney. However, the role of N-type Ca²⁺ channels in renal disease remains unknown. To address this issue, Cav2.2 knockout mice were utilized. Immunoreactive Cav2.2 was undetectable in normal kidneys of C57BL/6N mice, but it became positive in the interstitial S100-positive nerve fibers after unilateral ureteral obstruction (UUO). There were no significant differences in mean blood pressure, heart rate, and renal function between wild-type littermates and Cav2.2-knockout mice at baseline, as well as after UUO. Cav2.2 deficiency significantly reduced the EVG-positive fibrotic area, alpha-SMA expression, the production of type I collagen, and the hypoxic area in the obstructed kidneys. The expression of tyrosine hydroxylase, a marker for sympathetic neurons, was significantly increased in the obstructed kidneys of wild-type mice, but not in Cav2.2-knockout mice. These data suggest that increased Cav2.2 is implicated in renal nerve activation leading to the progression of renal fibrosis. Blockade of Cav2.2 might be a novel therapeutic approach for preventing renal fibrosis. [ABSTRACT FROM AUTHOR]

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المؤلفون: Nakasatomi, Masao¹, Takahashi, Shunsuke¹, Sakairi, Toru¹, Ikeuchi, Hidekazu¹, Kaneko, Yoriaki¹, Hiromura, Keiju¹, Nojima, Yoshihisa¹, Maeshima, Akito¹ amaesima@jichi.ac.jp

المصدر: PLoS ONE. 3/7/2019, Vol. 14 Issue 3, p1-15. 15p.

مصطلحات موضوعية: *PROXIMAL kidney tubules, *HEPATOCYTE growth factor, *KIDNEY tubules, *PHYSICAL sciences, *EPITHELIAL cells, *ENDOTHELIAL cells

مستخلص: Tubulogenesis, the organization of epithelial cells into tubular structures, is an essential step during renal organogenesis as well as during the regeneration process of renal tubules after injury. In the present study, endothelial cell-derived factors that modulate tubule formation were examined using an in vitro human tubulogenesis system. When human renal proximal tubular epithelial cells (RPTECs) were cultured in gels, tubular structures with lumens were induced in the presence of hepatocyte growth factor (HGF). Aquaporin 1 was localized in the apical membrane of these tubular structures, suggesting that these structures are morphologically equivalent to renal tubules in vivo. HGF-induced tubule formation was significantly enhanced when co-cultured with human umbilical vein endothelial cells (HUVECs) or in the presence of HUVEC-conditioned medium (HUVEC-CM). Co-culture with HUVECs did not induce tubular structures in the absence of HGF. A phospho-receptor tyrosine kinase array revealed that HUVEC-CM markedly enhanced phosphorylation of Ret, glial cell-derived neurotrophic factor (GDNF) receptor, in HGF-induced tubular structures compared to those without HUVEC-CM. HUVECs produced GDNF, and RPTECs expressed both Ret and GDNF family receptor alpha1 (co-receptor). HGF-induced tubule formation was significantly enhanced by addition of GDNF. Interestingly, not only HGF but also GDNF significantly induced phosphorylation of the HGF receptor, Met. These data indicate that endothelial cell-derived GDNF potentiates the tubulogenic properties of HGF and may play a critical role in the epithelial-endothelial crosstalk during renal tubulogenesis as well as tubular regeneration after injury. [ABSTRACT FROM AUTHOR]