Could IL-17A Be a Novel Therapeutic Target in Diabetic Nephropathy?

Abstract

Chronic kidney disease has become a major medical issue in recent years due to its high prevalence worldwide, its association with premature mortality, and its social and economic implications. A number of patients gradually progress to end-stage renal disease (ESRD), requiring then dialysis and kidney transplantation. Currently, approximately 40% of patients with diabetes develop kidney disease, making it the most prevalent cause of ESRD. Thus, more effective therapies for diabetic nephropathy are needed. In preclinical studies of diabetes, anti-inflammatory therapeutic strategies have been used to protect the kidneys. Recent evidence supports that immune cells play an active role in the pathogenesis of diabetic nephropathy. Th17 immune cells and their effector cytokine IL-17A have recently emerged as promising targets in several clinical conditions, including renal diseases. Here, we review current knowledge regarding the involvement of Th17/IL-17A in the genesis of diabetic renal injury, as well as the rationale behind targeting IL-17A as an additional therapy in patients with diabetic nephropathy.

Keywords: IL-17A; cytokines; diabetes mellitus; diabetic nephropathy; immune cells; inflammation; proteinuria; treatment.

Figure 1

Th17 differentiation. Naïve CD4+ T lymphocytes can be differentiated into different T cell subtypes, including Treg or Th17 immune cells. This process is regulated by particular cytokines and activation of specific transcription factors, as indicated. Moreover, mixed phenotypes have also been described.

Figure 2

Proposed mechanism of IL-17A-induced renal damage in diabetic nephropathy. Under diabetic conditions, renal resident cells are activated and can produce different mediators that could contribute to recruit immune cells into the kidney. Infiltrating Th17 cells can locally produce IL-17A in the diabetic kidney. Then, IL-17A acting on IL-17R on resident renal cells can produce additional proinflammatory mediators, contributing to sustained inflammation. Moreover, IL-17A acting on tubular epithelial cells can induce phenotype changes, such as partial epithelial-to-mesenchymal transition (EMT) and secretome changes. By these mechanisms, IL-17A participates in the amplification of the inflammatory response and the progression of renal damage, finally leading to tubulointerstitial fibrosis.

Figure 3

Intracellular mechanisms involved in inflammatory responses of IL-17A in the kidney. IL-17A can binds to its receptors and activates several intracellular mechanisms. The activation of NF-κB pathway and the upregulation of proinflammatory factors, such as MCP-1 can contribute to renal inflammation, as proposed under diabetic conditions. IL-17A can also activate other mechanisms, such as protein kinases and redox processes, but their role in renal damage have not been fully demonstrated.