Activation of GPR120 in podocytes ameliorates kidney fibrosis and inflammation in diabetic nephropathy

Diabetic nephropathy (DN) is one of the most common causes of end-stage renal disease worldwide. omega 3-Fatty acids (omega 3FAs) were found to attenuate kidney inflammation, glomerulosclerosis, and albuminuria in experimental and clinical studies of DN. As G protein-coupled receptor 120 (GPR120) was firstly identified as the receptor of omega 3FAs, we here investigated the function of GPR120 in DN. We first examined the renal biopsies of DN patients, and found that GPR120 expression was negatively correlated with the progression of DN. Immunofluorescence staining analysis revealed that GPR120 protein was mainly located in the podocytes of the glomerulus. A potent and selective GPR120 agonist TUG-891 (35 mg center dot kg(-1) center dot d(-1), ig) was administered todb/dbmice for 4 weeks. We showed that TUG-891 administration significantly improved urinary albumin excretion, protected against podocyte injury, and reduced collagen deposition in the glomerulus. Indb/dbmice, TUG-891 administration significantly inhibited the mRNA and protein expression of fibronectin, collagen IV, alpha-SMA, TGF-beta 1, and IL-6, and downregulated the phosphorylation of Smad3 and STAT3 to alleviate glomerulosclerosis. Similar results were observed in high-glucose-treated MPC5 podocytes in the presence of TUG-891 (10 mu M). Furthermore, we showed that TUG-891 effectively upregulated GPR120 expression, and suppressed TAK1-binding protein-1 expression as well as the phosphorylation of TAK1, IKK beta, NF-kappa B p65, JNK, and p38 MAPK indb/dbmice and high-glucose-treated MPC5 podocytes. Knockdown of GPR120 in MPC5 podocytes caused the opposite effects of TUG-891. In summary, our results highlight that activation of GPR120 in podocytes ameliorates renal inflammation and fibrosis to protect against DN.

Automated summary

Activation of GPR120 in podocytes plays a crucial role in ameliorating renal inflammation and fibrosis to protect against DN.