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논문분류	춘계학술대회 초록집
제목	αKlotho protects podocyte injury by upregulated calcium channels in diabetic nephropathy
저자	Ji-Hee Kim
출판정보	2023; 2023(1):
키워드
초록	Objectives: αKlotho is mainly expressed in the renal tubules and protects the kidney filter via regulating renal Ca2+ ion channels. The abnormal activation of Orai1 and TRPC5/6 channels in podocyte disorganizes actin-cytoskeleton and leads to proteinuria in diabetic nephropathy (DN). It is still unknown whether and how αKlotho regulates multiple podocyte Ca2+ channels to protect DN. Here we demonstrated that αKlotho ameliorates podocytes injury by stabilizing Orai1 and TRPC5/6 channels-mediated Ca2+ signaling to prevent DN. Methods: Type 2 diabetic db/db mice received i.p. injections of Klotho protein three times a week. Live-cell imaging and immunocytochemistry were performed in immortalized mouse podocytes. Results: The mice were administered with recombinant αKlotho peptide through i.p. injections. αKlotho was reduced along with podocyte markers such as synaptopodin and nephrin, while Orai1, and TRPC5/6 were overexpressed in early and late periods in db/db mice, respectively. Administration of αKlotho protein ameliorated podocyte foot process disruption and proteinuria in db/db mice with decreased expression of channel proteins and the dissolution of synaptopodin. In vitro, αKlotho suppressed Orai1- and TRPC5/6-mediated Ca2+ entry in cultured murine podocytes via inhibiting growth factors and/or insulin signaling. Mechanistically, αKlotho acutely reduced cell-surface abundance of Orai1 by suppressing phosphoinositide-3-kinase-dependent trafficking of the channel, whereas TRPC5/6 channels were slowly decreased by inhibiting growth factor-driven SGK1 activation. All the total channel proteins were reduced in long-term treatment (~24 h) of αKlotho. Functionally, exacerbated actin remodeling by Orai1 and TRPC6 activation was ameliorated by αKlotho. Conclusions: Taken together, our results reveal an underlying mechanism by which αKlotho protects proteinuria and podocyte actin remodeling through stabilizing Ca2+ signaling mediated by Orai1 and TRPC5/6, and offer a new potential therapeutic strategy for the treatment of DN. This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF-2017R1A5A2015369, 2022R1C1C2009853 & 2022R1A2C2011079).
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