Irbesartan ameliorates kidney injury and anemia in a Col4a5-mutant mouse model of Alport syndrome with CKD pathology

Alport syndrome, caused by mutations in type IV collagen genes, leads to progressive proteinuria, anemia, and glomerulosclerosis, ultimately resulting in renal failure. It also shares pathological features with chronic kidney disease (C KD). Previous knockout models of Col4a3 or Col4a5 recapitulated renal disease but were less translatable to the human condition, which arises from specific genetic variants rather than complete gene loss. To address this limitation, we established a Col4a5 R471* mutant mouse carrying a clinically relevant mutation and evaluated its responsiveness to the angiotensin receptor blocker (ARB) irbesartan as a benchmark for translational utility in ameliorating kidney injury and anemia. Col4a5 R471* mutant mice exhibited significant increases in the urine albumin–creatinine ratio (UACR) and blood urea nitrogen, along with age-dependent decreases in glomerular filtration rate. In addition, changes in anemia-related factors—such as red blood cell count, hemoglobin level, and hematocrit value—were observed. Irbesartan treatment significantly reduced UACR and urinary neutrophil gelatinase–associated lipocalin levels and improved anemia-related factors and proinflammatory transcript expression. These results provide the first preclinical evidence that an ARB can improve kidney injury and anemia in Col4a5 R471* mutant mice, highlighting the model’s translational relevance for CKD drug evaluation.