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Klotho plays a protective role against glomerular hypertrophy in a cell cycle-dependent manner in diabetic nephropathy
- Klotho plays a protective role against glomerular hypertrophy in a cell cycle-dependent manner in diabetic nephropathy
- Oh, Hyung Jung; Nam, Bo Young; Wu, Meiyan; Kim, Seonghun; Park, Jimin; Kang, Sukyung; Park, Jung Tak; Yoo, Tae-Hyun; Kang, Shin-Wook; Han, Seung Hyeok
- Ewha Authors
- Issue Date
- Journal Title
- AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
- AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY vol. 315, no. 4, pp. F791 - F805
- diabetic nephropathy; klotho; peroxisome proliferator-activated receptor-gamma; podocytes
- AMER PHYSIOLOGICAL SOC
- SCI; SCIE; SCOPUS
- Document Type
- There are few studies on the effect of klotho on podocytes in diabetic nephropathy. Thus, we tested whether klotho exerts a protective effect against glomerular injury in diabetes. Mouse podocytes were cultured in media containing 5.6 or 30 mM glucose(HG) with or without 200 pM of recombinant klotho (rKL). Additionally, 32 mice were injected intraperitoneally with either diluent(n = 16, C) or with streptozotocin (n = 16, DM). Control and diabetic mice underwent sham operation and unilateral nephrectomy, respectively. Eight mice from each control and DM group were treated daily with 10 mu g.kg(-1).day(-1) of rKL, using an osmotic minipump. Klotho was expressed in podocytes, and its expression was dependent on peroxisome proliferator-activateed receptor-gamma (PPAR gamma). HG treatment increased the expression of cell cycle-related and apoptotic markers, and these were significantly attenuated by rKL; rKL inhibited the extracellular signal-regulated protein kinase-1/2 and p38 signaling pathways in HG-induced podocyte injury. However, siRNA against klotho gene in HG-treated podocytes failed to aggravate cell cycle arrest and apoptosis. When HG-treated podocytes were incubated in the high-klotho-conditioned medium from tubular epithelial cells, cell injury was significantly attenuated. This effect was not observed when klotho was inhibited by siRNA. In vivo, the expressions of cell cycle-related and apoptotic markers were increased in diabetic mice compared with controls, which were significantly decreased by rKL. Glomerular hypertrophy (GH) and increased profibrotic markers were significantly alleviated after rKL administration. These results showed that klotho was expressed in glomerular podocytes that and its expression was regulated by PPAR gamma. Additionally, administration of rKL attenuated GH via a cell cycle-dependent mechanism and decreased apoptosis.
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