Effects of Atrasentan on Kidney Gene Transcription, Mesangial Cell Proliferation, and Proteinuria in IgA Nephropathy

KEY POINTS: In human renal mesangial cells stimulated with endothelin-1, atrasentan reduced mesangial cell proliferation and matrix expansion. Atrasentan reduced kidney injury in two preclinical models of IgA nephropathy. These findings support the therapeutic potential of atrasentan to treat IgA nephropathy; clinical studies of atrasentan are ongoing. BACKGROUND: IgA nephropathy (IgAN) is the leading cause of primary GN and carries a high risk of progression to ESKD. Endothelin-1 type A (ET A ) receptor activation may be a key driver of proteinuria, inflammation, and fibrosis in patients with kidney diseases. Atrasentan, a highly potent and highly selective antagonist of the ET A receptor, demonstrated a statistically significant and clinically meaningful proteinuria reduction of 36.1% (95% confidence interval, 26.4% to 44.6%; P < 0.001) relative to placebo, at week 36 in the ongoing Atrasentan in Patients With IgA Nephropathy (ALIGN) phase 3 trial. Based on these data, atrasentan is indicated to reduce proteinuria in adults with primary IgAN at risk of rapid disease progression. METHODS: We explored the biologic effects and changes in gene transcription with atrasentan in cultured human renal mesangial cells, grouped ddY mouse model of IgAN, and Wistar rats injected with anti-Thy1.1 (CD90) antibody to induce mesangial injury and mesangioproliferative GN. The effect of atrasentan on proteinuria and kidney gene transcriptome was evaluated in both animal models, and histologic and morphometric assessments of rat kidneys were conducted. RESULTS: In separate transcriptomics analyses of all three models, atrasentan reversed gene expression changes related to cell proliferation, proinflammatory, and profibrotic signatures. In human renal mesangial cells stimulated with endothelin-1, atrasentan reduced mesangial cell proliferation and matrix expansion. After 7 days, atrasentan treatment in the mesangioproliferative GN rat model diminished renal mesangial hypercellularity and matrix expansion, decreased glomerular and tubulointerstitial structural alterations, and significantly reduced proteinuria. In grouped ddY mice, atrasentan treatment for 4 days significantly reduced mean albuminuria by >60%. CONCLUSIONS: The acute mechanistic effects of atrasentan demonstrated in vitro and in vivo support the therapeutic potential of atrasentan in IgAN. The ongoing Atrasentan in Patients With Proteinuric Glomerular Diseases (AFFINITY) and Randomized, Double-blind, Placebo-controlled, Crossover Study of Atrasentan in Subjects With IgA Nephropathy (ASSIST) phase 2 trials, and the ALIGN phase 3 trial in patients with IgAN will further evaluate the translation of these mechanistic effects to the clinical efficacy and safety of atrasentan.