Gut-kidney axis in IgA nephropathy: Role on mesangial cell metabolism and inflammation

Abstract

IgA Nephropathy (IgAN) is the commonest primary glomerular disease around the world and represents a significant cause of end-stage renal disease. IgAN is characterized by mesangial deposition of IgA-immune complexes and mesangial expansion. The pathophysiological process includes an abnormally glycosylated IgA1, which is an antigenic target. Autoantibodies specifically recognize galactose-deficient IgA1 forming immune complexes that are amplified in size by the soluble IgA Fc receptor CD89 leading to deposition in the mesangium through interaction with non-classical IgA receptors. The local production of cytokines promotes local inflammation and complement system activation, besides the stimulation of mesangial proliferation. The spectrum of clinical manifestations is quite variable from asymptomatic microscopic hematuria to rapidly progressive glomerulonephritis. Despite all the advances, the pathophysiology of the disease is still not fully elucidated. The mucosal immune system is quoted to be a factor in triggering IgAN and a "gut-kidney axis" is proposed in its development. Furthermore, many recent studies have demonstrated that food intake interferes directly with disease prognosis. In this review, we will discuss how mucosal immunity, microbiota, and nutritional status could be interfering directly with the activation of intrinsic pathways of the mesangial cells, directly resulting in changes in their function, inflammation and development of IgAN.

Keywords: IgA nephropathy; gut-kidney axis; kidney; mesangial cells; microbiota.

FIGURE 1

Intestinal-derived factors interfering with mesangial cell-intrinsic pathways activation. Diet-derived molecules and bacterial products from the gut of IgAN patients work as antigens, promoting immune cell activation. After a gut-barrier break, these molecules reach the bloodstream and can be recognized directly by the mesangial cells through specific receptors. Other important factors involved in the activation of mesangial cells are cytokines, which are produced during mucosal activation and can act systemically, reaching the mesangial cells at the glomeruli. At the cellular level, the ligands can promote not only a metabolic shift but also increase the responsiveness regarding inflammatory products by the mesangial cells. This, besides the Gd-IgA1 established model for IgAN, can precede the unique mesangial cell features shown by many IgAN patients, justifying the onset of the disease earlier than the IgA complexes deposition. PDGF: Platelet-derived growth factor; GLUTs: Glucose transporters; NF-κB: Nuclear factor-κB; STATs: Signal transducer and activator of transcription; MAPK: Mitogen-activated protein kinase; ERK: Extracellular signal-regulated kinase; PI3K: phosphoinositide 3-kinase; AKT: protein kinase B; JAK: Janus kinase; COX2: Cyclooxygenase-2; PGE2: Prostaglandin E2; iNOS: Inducible nitric oxide synthase; NO: Nitric oxide; IGF-1R: Insulin-like growth factor 1 receptor; TGF-β: Transforming growth factor beta; IgAN: IgA Nephropathy. Created with BioRender.com.