Klotho attenuates high glucose-induced fibronectin and cell hypertrophy via the ERK1/2-p38 kinase signaling pathway in renal interstitial fibroblasts.
Although exogenous klotho attenuates renal fibrosis, it is not known if exogenous klotho attenuates diabetic nephropathy (DN). Thus, we studied the anti-fibrotic mechanisms of klotho in terms of transforming growth factor-β (TGF-β) and signaling pathways in high glucose (HG, 30 mM)-cultured renal interstitial fibroblast (NRK-49F) cells. We found that HG increased klotho mRNA and protein expression. HG also activated TGF-β Smad2/3 signaling and activated extracellular signal-regulated kinase (ERK1/2) and p38 kinase signaling. Exogenous klotho (400 pM) attenuated HG-induced TGF-β bioactivity, type II TGF-β receptor (TGF-βRII) protein expression and TGF-β Smad2/3 signaling. Klotho also attenuated HG-activated ERK1/2 and p38 kinase. Additionally, klotho and inhibitors of ERK1/2 or p38 kinase attenuated HG-induced fibronectin and cell hypertrophy. Finally, renal tubular expression of klotho decreased in the streptozotin-diabetic rats at 8 weeks. Thus, exogenous klotho attenuates HG-induced profibrotic genes, TGF-β signaling and cell hypertrophy in NRK-49F cells. Moreover, klotho attenuates HG-induced fibronectin expression and cell hypertrophy via the ERK1/2 and p38 kinase-dependent pathways.
Department of Biological Science and Technology, Chung Hwa University of Medical Technology, Tainan, Taiwan.
Jau-Shyang
JS
Huang
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Chao-Tang
CT
Chuang
Department of Biochemistry, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Mei-Hsin
MH
Liu
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Sheng-Hsuan
SH
Lin
Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address: guhjy@kmu.edu.tw.
Jinn-Yuh
JY
Guh
Department of Biochemistry, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address: layech@kmu.edu.tw.
Lea-Yea
LY
Chuang
D000818:Animals; D002460:Cell Line; D003094:Collagen / Q000096:biosynthesis; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism*; D015870:Gene Expression; D005947:Glucose / Q000502:physiology*; D005966:Glucuronidase / Q000502:physiology*; D006984:Hypertrophy / Q000378:metabolism; D007672:Kidney Cortex / Q000378:metabolism / Q000473:pathology; D000090265:Klotho Proteins; D020935:MAP Kinase Signaling System; D008297:Male; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D005353:Fibronectins; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; C497784:Smad2 protein, rat; D051900:Smad3 Protein; C497787:Smad3 protein, rat; D016212:Transforming Growth Factor beta; D003094:Collagen; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D005966:Glucuronidase; D000090265:Klotho Proteins; D005947:Glucose
Cell hypertrophy; Diabetic nephropathy; Klotho; Renal fibrosis; Transforming growth factor-β