1. Figure 4 Mechanisms of leptin function on kidney injury
Figure 4 | Mechanisms of leptin function on kidney injury. Binding of leptin to its receptors (OBR; also known as LEP-R) in the kidney leads to activation of tyrosine-protein kinase JAK2 (JAK2) via phosphorylation, which activates signal transducer and activator of transcription 3 (STAT3) (and in some cases STAT5 (not shown)), which then translocates to the nucleus to regulate the transcription of target genes, including those encoding profibrotic factors. Activation of p38 mitogen-activated protein kinase (MAPK) via tyrosine-protein phosphatase non-receptor type 11 (SHP2; also known as PTPN11) and growth factor receptor-bound protein 2 (GRB2) might also promote STAT3 transcriptional activity. Phosphorylated JAK2 also activates NADPH oxidase and promotes oxidative signalling by generating reactive oxygen species (ROS). Independent of JAK2, leptin also activates the AKT–GSK3β pathway, which stabilizes β-catenin. Combined, these pathways increase the expression of transforming growth factor β-1 (TGFβ1) and other fibrogenic factors, such as collagen type IV (COL IV), fibronectin and vascular cell adhesion protein 1 (VCAM1). In a positive feedback loop, TGFβ1 binds to its receptor, TGFβR, and activates mothers against decapentaplegic homolog 2 (SMAD2) and SMAD3, further enhancing targeted gene expression. As a result, these dysregulated transcriptional programmes lead to inflammation and fibrogenesis in the kidney. High levels of circulating leptin lead to activation of renal mesangial cells and tubular inflammation110. Moreover, leptin regulates kidney endothelial dysfunction, an important process that contributes to the development of kidney fibrosis. AKT, RAC-alpha serine/threonine-protein kinase; GSK3β, glycogen synthase kinase-3-β.
Zhu, Q. & Scherer, P. E. (2017) Immunologic and endocrine functions of adipose tissue: implications for kidney disease
Nat. Rev. Nephrol. doi: /nrneph