Abstract
Aging is associated with increased fat mass and elevated serum leptin levels (hyperleptinemia), causing proinflammation in the kidneys where it plays a primary role in the removal of endogenous leptin from the circulation. Lymphocyte-specific kinase (Lck) is a positive regulator of inflammatory signaling and a potential treatment target for age-related diseases, but its role in leptin signaling is unknown. Here, we investigated how Lck influences hyperleptinemia-induced inflammation in kidney tissues from 6- and 21-month-old rats. Results indicate that Lck expression and activation increased significantly in aged rat kidneys, especially at renal tubules. Furthermore, we identified interactions between Lck and short leptin-receptor isoforms, suggesting that Lck is a protein tyrosine kinase regulating leptin signaling. We further investigated whether increased Lck expression in renal tubular epithelial cells and macrophage infiltration are associated with leptin-induced inflammation. We then demonstrated that leptin activates Lck and proinflammatory transcription factors (STAT3 and NF-κB), while Lck knockdown modulates the expression of both transcription factors. Collectively, these data implicate that Lck leads to development of leptin-induced renal inflammation during aging. Inhibition of this protein tyrosine kinase may therefore be an appropriate therapeutic option for protection against age-related hyperleptinemia.
Highlights
Aging is associated with increased fat mass and elevated serum leptin levels, causing proinflammation in the kidneys where it plays a primary role in the removal of endogenous leptin from the circulation
We focused on a novel mechanism of Lymphocyte-specific kinase (Lck)-signal transducer and activator of transcription 3 (STAT3)/nuclear factor-κB (NF-κB) pathways implicated in leptin-induced renal inflammation
Serum leptin increased by over five-fold in old rats compared with young rats (Fig. 1A), implying that aging results in leptin resistance leading to hyperleptinemia
Summary
Aging is associated with increased fat mass and elevated serum leptin levels (hyperleptinemia), causing proinflammation in the kidneys where it plays a primary role in the removal of endogenous leptin from the circulation. Results indicate that Lck expression and activation increased significantly in aged rat kidneys, especially at renal tubules. We identified interactions between Lck and short leptin-receptor isoforms, suggesting that Lck is a protein tyrosine kinase regulating leptin signaling. We further investigated whether increased Lck expression in renal tubular epithelial cells and macrophage infiltration are associated with leptin-induced inflammation. We demonstrated that leptin activates Lck and proinflammatory transcription factors (STAT3 and NF-κB), while Lck knockdown modulates the expression of both transcription factors These data implicate that Lck leads to development of leptin-induced renal inflammation during aging. Inhibition of this protein tyrosine kinase may be an appropriate therapeutic option for protection against age-related hyperleptinemia. Kidneys express significantly more short isoforms [13], and their precise biological functions are unclear, some data suggest an involvement of leptin’s inflammatory effects [14]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
