Klotho attenuates high glucose-induced fibronectin and cell hypertrophy via the ERK1/2-p38 kinase signaling pathway in renal interstitial fibroblasts

• Klotho attenuates high glucose-induced TGF-β, type II receptor and signaling in NRK-49F cells.
• Klotho attenuates high glucose-activated ERK1/2 and p38 kinase.
• Klotho, ERK1/2 and p38 kinase inhibitors attenuated HG-induced fibronectin and cell hypertrophy.

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.