대한신장학회

논문분류	춘계학술대회 초록집
제목	ER stress-induced microtubule disruption accelerates renal fibrosis by regulating TGF-β/Smad signaling.
저자	Noh Mi Ra* 1, Kong Min Jung1, Kim Jee In2, Park Kwon Moo1
출판정보	2016; 2016(1):
키워드	CHOP, ER stress, fibrosis, Microtubules
초록	Background: ER stress facilitates fibrotic remodeling through activation of pro-apoptotic pathways, induction of epithelial–mesenchymal transition (EMT). ER stress affects the dynamics of microtubules which composed of α- and β-tubulin and involved in diverse cellular functions, such as cell division, cell motility and the maintenance of cell shape. Inhibition of microtubule dynamics serves as negative regulator for TGF-β/Smad signaling by forming a complex with endogenous Smad2, Smad3 and Smad4. Herein, we investigated the role of C/EBP homologous protein (CHOP)-related ER stress in kidney fibrosis and an involvement of microtubule dynamics. Methods: The mice were subjected to unilateral ureteral obstruction (UUO) via the ligation of the left ureter near the renal pelvis. Results: UUO induced ER stress; increases of Bip/GRP78 and CHOP expression and apoptosis in the tubule cells. CHOP-gene deletion attenuated UUO-induced collagen deposition and expressions of collagen III and α-smooth muscle actin (α-SMA). The levels of TGF-β and phospho-Smad3 expression increased in UUO mice. These elevations were less in CHOP−/− mice than in CHOP+/+ mice after UUO. Microtubule network presented striped patterns in the cytosol and expressed high density near the nuclear. These patterns weakened and microtubules depolymerized like spot in the cytosol after UUO. The disruption of microtubule was less in CHOP−/− mice, compared with CHOP+/+ mice. UUO decreased acetylation of α-tubulin. The reduction of α-tubulin acetylation was less in CHOP−/− mice than in CHOP+/+ mice after UUO. Acetylation of α-tubulin is one of post-translation modification of α-tubulin and stabilizes microtubules. The expression of α-tubulin acetyltransferase (α-TAT), a mediator of α-tubulin acetylation, decreased after UUO. The reduction of α-TAT was less in CHOP−/− mice than in CHOP+/+ mice after UUO. These results indicate that ER stress accelerates the progression of UUO-induced kidney. Conclusion: The present data collectively suggest that ER stress plays in microtubule disruption via TGF-β/Smad signaling, leading to renal fibrosis.
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