Low-Dose IL-17 Therapy Prevents and Reverses Diabetic Nephropathy, Metabolic Syndrome, and Associated Organ Fibrosis.
Diabetes is the leading cause of kidney failure, accounting for >45% of new cases of dialysis. Diabetic nephropathy is characterized by inflammation, fibrosis, and oxidant stress, pathologic features that are shared by many other chronic inflammatory diseases. The cytokine IL-17A was initially implicated as a mediator of chronic inflammatory diseases, but recent studies dispute these findings and suggest that IL-17A can favorably modulate inflammation. Here, we examined the role of IL-17A in diabetic nephropathy. We observed that IL-17A levels in plasma and urine were reduced in patients with advanced diabetic nephropathy. Type 1 diabetic mice that are genetically deficient in IL-17A developed more severe nephropathy, whereas administration of low-dose IL-17A prevented diabetic nephropathy in models of type 1 and type 2 diabetes. Moreover, IL-17A administration effectively treated, prevented, and reversed established nephropathy in genetic models of diabetes. Protective effects were also observed after administration of IL-17F but not IL-17C or IL-17E. Notably, tubular epithelial cell-specific overexpression of IL-17A was sufficient to suppress diabetic nephropathy. Mechanistically, IL-17A administration suppressed phosphorylation of signal transducer and activator of transcription 3, a central mediator of fibrosis, upregulated anti-inflammatory microglia/macrophage WAP domain protein in an AMP-activated protein kinase-dependent manner and favorably modulated renal oxidative stress and AMP-activated protein kinase activation. Administration of recombinant microglia/macrophage WAP domain protein suppressed diabetes-induced albuminuria and enhanced M2 marker expression. These observations suggest that the beneficial effects of IL-17 are isoform-specific and identify low-dose IL-17A administration as a promising therapeutic approach in diabetic kidney disease.
Department of Medicine and Vascular Biology Center, Georgia Regents University, Augusta, Georgia; and.
Riyaz
R
Mohamed
Department of Medicine and Vascular Biology Center, Georgia Regents University, Augusta, Georgia; and.
Calpurnia
C
Jayakumar
Department of Medicine and Vascular Biology Center, Georgia Regents University, Augusta, Georgia; and.
Feng
F
Chen
Department of Medicine and Vascular Biology Center, Georgia Regents University, Augusta, Georgia; and.
David
D
Fulton
Department of Medicine and Vascular Biology Center, Georgia Regents University, Augusta, Georgia; and.
David
D
Stepp
Department of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Ron T
RT
Gansevoort
Department of Medicine and Vascular Biology Center, Georgia Regents University, Augusta, Georgia; and gramesh@gru.edu.
Ganesan
G
Ramesh
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000419:Albuminuria / Q000652:urine; D000818:Animals; D018501:Antirheumatic Agents; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics; D003928:Diabetic Nephropathies / Q000209:etiology / Q000517:prevention & control*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D005919:Glomerular Filtration Rate; D006801:Humans; D020381:Interleukin-17 / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D007678:Kidney Glomerulus / Q000473:pathology*; D007684:Kidney Tubules / Q000166:cytology; D008264:Macrophages / Q000378:metabolism; D008297:Male; D024821:Metabolic Syndrome / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism; D008894:Milk Proteins / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D050199:Podocytes / Q000473:pathology; D020033:Protein Isoforms / Q000008:administration & dosage* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013311:Streptozocin; D015854:Up-Regulation / Q000187:drug effects
D018501:Antirheumatic Agents; D020381:Interleukin-17; D008894:Milk Proteins; D020033:Protein Isoforms; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C024471:whey acidic proteins; D013311:Streptozocin; D055372:AMP-Activated Protein Kinases
chronic kidney disease; cytokines; diabetic; diabetic nephropathy; glomerulopathy