Low-dose IL-17 therapy prevents and reverses diabetic nephropathy, metabolic syndrome, and associated organ fibrosis

Riyaz Mohamed, Calpurnia Jayakumar, Feng Chen, David J Fulton, David W Stepp, Ron T. Gansevoort, Ganesan Ramesh

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

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 inmodels 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-17Aadministration suppressed phosphorylation of signal transducer and activator of transcription 3, a central mediator of fibrosis, upregulated anti-inflammatory microglia/macrophageWAP 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.

Original languageEnglish (US)
Pages (from-to)745-765
Number of pages21
JournalJournal of the American Society of Nephrology
Volume27
Issue number3
DOIs
StatePublished - Mar 1 2016

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Interleukin-17
Diabetic Nephropathies
Fibrosis
Therapeutics
AMP-Activated Protein Kinases
Microglia
Chronic Disease
Inflammation
STAT3 Transcription Factor
Albuminuria
Dissent and Disputes
Genetic Models
Type 1 Diabetes Mellitus
Oxidants
Type 2 Diabetes Mellitus
Renal Insufficiency
Dialysis
Protein Isoforms
Oxidative Stress
Anti-Inflammatory Agents

ASJC Scopus subject areas

  • Nephrology

Cite this

Low-dose IL-17 therapy prevents and reverses diabetic nephropathy, metabolic syndrome, and associated organ fibrosis. / Mohamed, Riyaz; Jayakumar, Calpurnia; Chen, Feng; Fulton, David J; Stepp, David W; Gansevoort, Ron T.; Ramesh, Ganesan.

In: Journal of the American Society of Nephrology, Vol. 27, No. 3, 01.03.2016, p. 745-765.

Research output: Contribution to journalArticle

Mohamed, Riyaz ; Jayakumar, Calpurnia ; Chen, Feng ; Fulton, David J ; Stepp, David W ; Gansevoort, Ron T. ; Ramesh, Ganesan. / Low-dose IL-17 therapy prevents and reverses diabetic nephropathy, metabolic syndrome, and associated organ fibrosis. In: Journal of the American Society of Nephrology. 2016 ; Vol. 27, No. 3. pp. 745-765.
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