Renal tubular collagen IV a345 expression and implications for Alport syndrome
Wissenschaftliches Arbeitsprogramm:
People with Alport Syndrome (AS) have a significant risk of kidney failure due to mutations in COL4A3/4/5 genes. Recent genetic studies suggest AS is more prevalent than previously recognized, leading to atypical clinical presentations resembling other kidney diseases. While previous studies primarily focused on glomerular expression, collagen IV a345 molecule shows equally strong expression in the distal renal tubule, where its disruption may drive kidney disease progression.
Cultivation of human urinary primary tubular cells (huPTCs) from urine is established in our laboratory, these cells have shown to produce the collagen IV a345 molecule. ELX-02 is a gentamycin derivate known for its translational readthrough effect and has recently been studied in genetic diseases caused by premature stop codons. We plan to assess the impact of ELX-02 on collagen IV a345 molecule expression in huPTCs obtained from AS patients with COL4A5 variants leading to premature translational termination. AS patient-derived huPTCs will be used to establish tubular organoids (tubuloids), providing a 30 model for examining basement membrane characteristics and
collagen IV a345 expression. Kidneys obtained from Col4a3 knockout mice will be employed for immunohistochemical studies of tubular collagen IV a345 expression and tubulointerstitial inflammation, as well as electron-microscopic examination of variability in tubular basement membrane thickness. These experiments can help clarify the pathophysiological contribution of tubular collagen IV a345 expression in Alport syndrome.