Targets for Iga Nephropathy

The pathogenesis of IgA Nephropathy (IgAN) is multifactorial, involving immune complex deposition, complement activation, inflammation, and fibrosis. Understanding the molecular targets directly implicated in these processes is critical for elucidating disease mechanisms, identifying therapeutic opportunities, and guiding drug development. The selected targets represent key nodes in pathways such as the renin-angiotensin system, complement cascade, immune signaling, and inflammation. Collectively, these targets provide mechanistic insights into the initiation and progression of glomerular injury in IgAN and highlight potential points for therapeutic intervention. By focusing on those with clear, demonstrable roles in IgAN pathogenesis, this analysis supports the rational design of targeted therapies and the identification of reliable biomarkers for disease monitoring and prognosis.

Complement Activation And Inflammatory Cascade

This category encompasses targets involved in the activation and amplification of the complement system, a central driver of inflammation and tissue damage in IgA Nephropathy. Aberrant activation of the alternative and lectin complement pathways contributes to glomerular injury, recruitment of inflammatory cells, and progression to chronic kidney disease. The targets in this category are directly implicated in the complement-mediated pathogenesis of IgAN.

Complement C3 (C3)

Complement C3 (C3) is the central component of the complement system, serving as a convergence point for the classical, alternative, and lectin pathways. Structurally, C3 is a 187-kDa glycoprotein with an internal thioester bond critical for covalent attachment to target surfaces. Upon activation, C3 is cleaved into C3a and C3b, the latter promoting opsonization and formation of the C5 convertase. In IgA Nephropathy, glomerular deposition of C3 is a hallmark of disease, correlating with the presence of IgA-containing immune complexes and severity of renal injury. C3 activation amplifies local inflammation, recruits leukocytes, and drives membrane attack complex (MAC) formation, leading to cell lysis and tissue damage. C3 levels and activation fragments serve as biomarkers of disease activity. Therapeutic inhibition of C3 (e.g., pegcetacoplan) is under investigation for complement-mediated kidney diseases, including IgAN (NCT05085986), with early evidence suggesting reduction in proteinuria and stabilization of renal function.

Complement C5 (C5)

Complement C5 (C5) is a 190-kDa glycoprotein cleaved by C5 convertase into C5a, a potent anaphylatoxin, and C5b, which initiates the assembly of the membrane attack complex (MAC, C5b-9). C5 activation is a critical effector step in complement-mediated tissue injury. In IgA Nephropathy, glomerular C5 and C5b-9 deposition is frequently observed and correlates with more severe histological lesions and worse renal outcomes. C5a drives neutrophil and macrophage recruitment and activation, amplifying glomerular inflammation. Clinical trials of C5 inhibitors (e.g., eculizumab, ravulizumab) in IgAN have shown variable results, but selective targeting of the terminal complement pathway remains a promising therapeutic strategy, particularly in patients with complement-dependent disease activity.

Complement C5a Receptor 1 (C5AR1)

Complement C5a Receptor 1 (C5AR1, also known as CD88) is a G protein-coupled receptor expressed on myeloid cells, mesangial cells, and other renal cell types. It mediates the pro-inflammatory effects of C5a, including chemotaxis, cytokine release, and oxidative burst. In IgA Nephropathy, C5AR1 expression is upregulated in the glomeruli and tubulointerstitium, correlating with disease activity. Blockade of C5AR1 with small molecules (e.g., avacopan) reduces proteinuria and glomerular injury in experimental models. Clinical trials in complement-driven glomerulopathies, including IgAN, are ongoing (NCT02384317), supporting its role as a therapeutic target.

Complement Factor B (CFB)

Complement Factor B (CFB) is a serine protease essential for the activation and amplification of the alternative complement pathway. It forms the C3 convertase (C3bBb) upon cleavage by factor D, leading to further C3 activation. In IgA Nephropathy, increased alternative pathway activity and glomerular CFB deposition have been documented, particularly in patients with more aggressive disease. Genetic polymorphisms in CFB are associated with susceptibility and progression of IgAN (PMID: 26283675). Targeting CFB or the alternative pathway (e.g., factor B inhibitors) is a rational approach for modulating complement activation in IgAN.

MBL Associated Serine Protease 2 (MASP2)

MBL Associated Serine Protease 2 (MASP2) is a key enzyme in the lectin pathway of complement activation. Upon binding of mannose-binding lectin (MBL) to pathogen- or immune complex-associated carbohydrates, MASP2 cleaves C4 and C2 to form the classical pathway C3 convertase. In IgA Nephropathy, lectin pathway activation has been implicated in glomerular injury, with MASP2 and MBL detected in renal biopsies and associated with worse outcomes (PMID: 20595689). Inhibition of MASP2 (e.g., narsoplimab) is under clinical investigation for IgAN (NCT02682407), with interim data suggesting reduction in proteinuria.

Renin-Angiotensin System And Fibrosis

This category includes targets in the renin-angiotensin system (RAS) that mediate glomerular hemodynamics, inflammation, and fibrogenesis. RAS activation is a key driver of proteinuria and chronic progression in IgA Nephropathy, independent of blood pressure effects. Targeting these molecules has both antiproteinuric and antifibrotic effects.

Angiotensin II Receptor Type 1 (AGTR1)

Angiotensin II Receptor Type 1 (AGTR1) is a G protein-coupled receptor that mediates the vasoconstrictive, pro-inflammatory, and profibrotic effects of angiotensin II. AGTR1 is expressed in glomerular and tubular cells. In IgA Nephropathy, upregulation of AGTR1 signaling promotes mesangial cell proliferation, extracellular matrix deposition, and inflammatory cytokine production. Blockade of AGTR1 with angiotensin receptor blockers (ARBs) is a cornerstone of IgAN therapy, reducing proteinuria and slowing progression to end-stage renal disease. This effect is mediated via inhibition of TGF-β signaling, attenuation of oxidative stress, and reduction of glomerular hypertension. AGTR1 antagonists are clinically validated and recommended in international guidelines for IgAN management.

Endothelin Receptor Type A (EDNRA)

Endothelin Receptor Type A (EDNRA) is a G protein-coupled receptor that binds endothelin-1, a potent vasoconstrictor and profibrotic peptide. EDNRA is upregulated in glomerular and vascular cells in IgA Nephropathy. Activation of EDNRA signaling contributes to glomerular hypertension, mesangial proliferation, and extracellular matrix accumulation. Endothelin receptor antagonists (e.g., sparsentan, atrasentan) are being evaluated in clinical trials for proteinuric kidney diseases, including IgAN (NCT03762850), with evidence of antiproteinuric and antifibrotic effects.

Immune Cell Activation And Inflammatory Signaling

This category comprises targets involved in immune cell activation, cytokine signaling, and the propagation of glomerular inflammation in IgA Nephropathy. These molecules contribute to the recruitment and activation of leukocytes, promotion of inflammatory cytokine networks, and perpetuation of glomerular injury.

Spleen Associated Tyrosine Kinase (SYK)

Spleen Associated Tyrosine Kinase (SYK) is a non-receptor tyrosine kinase that mediates signaling downstream of immunoreceptors, including the IgA receptor (FcαRI/CD89) and B cell receptor. In IgA Nephropathy, SYK is activated in mesangial cells and infiltrating leukocytes upon engagement by IgA-containing immune complexes, leading to pro-inflammatory cytokine production, cell proliferation, and matrix expansion. Inhibition of SYK (e.g., fostamatinib) reduces proteinuria and glomerular injury in preclinical IgAN models (PMID: 29596096). Clinical studies of SYK inhibitors in IgAN are ongoing (NCT03976188).

TNF Superfamily Member 13b (TNFSF13B)

TNF Superfamily Member 13b (TNFSF13B, also known as BAFF) is a cytokine critical for B cell survival, maturation, and immunoglobulin class switching. Elevated serum and renal levels of TNFSF13B are observed in IgA Nephropathy and correlate with increased production of aberrantly glycosylated IgA1, the initiating event in IgAN pathogenesis. TNFSF13B promotes expansion of autoreactive B cells and enhances immune complex formation. BAFF inhibitors (e.g., belimumab) are being explored for their potential to modulate B cell responses in IgAN (NCT04573478).