How do the ET-1- and Ang II-Mediated Signalling Pathways Work in Tandem in the Pathophysiology and Progression of IgA Nephropathy?

Immunoglobin A (IgA) nephropathy is the most common glomerulonephritis. It occurs from a process wherein the kidneys suffer systemic damage. Synthesis and binding of antibodies directed against galactose deficient IgA1 cause the formation of immune complexes; a formation which activates mesangial cells, inducing proliferation and secretion of the extracellular matrix, cytokines, and chemokines, which results in kidney injury.

The endothelial (ET) family consists of three 21 amino acid peptides (ET-1, ET-2, and ET-3). ET-1 plays the biggest role in kidney functionality and disease because its binding effects, specifically the receptor isoform ET_B, promotes tissue injury and scarring. Similarly, angiotensin II (ANG II), a primary active peptide of the renin-angiotensin-aldosterone system (RAAS), has well established actions in the kidney and plays a critical role in renal pathophysiology. ET-1 signalling works in concert with ANG II signalling to amplify the ongoing inflammatory cytokine response and worsen glomerular injury and proteinuria, driving further tubular damage, which results in a progressive decline in kidney function.

ANG II stimulates ET-1 release and expression in renal cells, while ET-1 mediates certain actions of ANG II. ANG II-dependent increases in ET-1 contribute to the vasoconstrictor effects of ANG II in vitro in isolated vascular preparations, while ET receptor blockade can inhibit the acute vasoconstrictor responses to ANG in vivo. Despite their obvious tandem role, it remains unclear whether ET-1 stimulates ANG II in nonvascular and renal cells.

The major impact of ET-1 and ANG II includes glomerulosclerosis via mesangial cell proliferation, extracellular matrix production, podocyte cytoskeletal alterations, and podocyte loss, leading to increased glomerular permeability and proteinuria, and ultimately causing the progression of IgA nephropathy. Moreover, both pathways augment inflammation and fibrosis in the tubulointerstitial compartment as well as vasoconstriction and endothelial dysfunction of renal blood vessels.

A potential remedy to the effect of ANG II and ET-1 is the development of dual ET_AR and AT₁R as therapeutic targets, a combination of individual receptor blockers. It has been posited that merging the structural elements of these two antagonists may yield a compound with dual activity for both receptors, which in turn may slow IgA nephropathy progression and reduce proteinuria.

References: Benigni A, et al. Pediatr Nephrol 2021; 36: 763–775; Kohan DE & Barton M. Kidney Int 2014; 86:896–904