RESUMEN
COL4A3/A4/A5 mutations have been identified as critical causes of Alport syndrome and other genetic chronic kidney diseases. However, the underlying pathogenesis remains unclear, and specific treatments are lacking. Here, we constructed a transgenic Alport syndrome mouse model by generating a mutation (Col4a3 p.G799R) identified previously from one large Alport syndrome family into mice. We observed that the mutation caused a pathological decrease in intracellular and secreted collagen IV α3α4α5 heterotrimers. The mutant collagen IV α3 chains abnormally accumulated in the endoplasmic reticulum and exhibited defective secretion, leading to persistent endoplasmic reticulum stress in vivo and in vitro. RNA-seq analysis revealed that the MyD88/p38 MAPK pathway plays key roles in mediating subsequent inflammation and apoptosis signaling activation. Treatment with tauroursodeoxycholic acid, a chemical chaperone drug that functions as an endoplasmic reticulum stress inhibitor, effectively suppressed endoplasmic reticulum stress, promoted secretion of the α3 chains, and inhibited the activation of the MyD88/p38 MAPK pathway. Tauroursodeoxycholic acid treatment significantly improved kidney function in vivo. These results partly clarified the pathogenesis of kidney injuries associated with Alport syndrome, especially in glomeruli, and suggested that tauroursodeoxycholic acid might be useful for the early clinical treatment of Alport syndrome.
Asunto(s)
Apoptosis , Autoantígenos , Colágeno Tipo IV , Modelos Animales de Enfermedad , Estrés del Retículo Endoplásmico , Ratones Transgénicos , Mutación , Nefritis Hereditaria , Ácido Tauroquenodesoxicólico , Proteínas Quinasas p38 Activadas por Mitógenos , Animales , Ácido Tauroquenodesoxicólico/farmacología , Ácido Tauroquenodesoxicólico/uso terapéutico , Estrés del Retículo Endoplásmico/efectos de los fármacos , Nefritis Hereditaria/genética , Nefritis Hereditaria/tratamiento farmacológico , Nefritis Hereditaria/patología , Colágeno Tipo IV/genética , Colágeno Tipo IV/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Autoantígenos/genética , Autoantígenos/metabolismo , Apoptosis/efectos de los fármacos , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/metabolismo , Humanos , Transducción de Señal/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Masculino , Riñón/patología , Riñón/efectos de los fármacos , Riñón/metabolismoRESUMEN
Background: This study investigates the link between genetic variants associated with kidney function and immunoglobulin A (IgA) nephropathy (IgAN) progression. Methods: We recruited 961 biopsy-proven IgAN patients and 651 non-IgAN end-stage renal disease (ESRD) patients from Ruijin Hospital. Clinical and renal pathological data were collected. The primary outcome was the time to ESRD. A healthy population was defined as estimated glomerular filtration rate >60 mL/min/1.73 m2 without albuminuria or hematuria. Fifteen single-nucleotide polymorphisms (SNPs) were selected from a genome-wide association study of kidney function and genotyped by the SNaPshot. Immunohistochemistry in renal tissue and ELISA in urine samples were performed to explore the potential functions of genetic variations. Results: The rs77924615-G was independently associated with an increased risk for ESRD in IgAN patients after adjustments for clinical and pathologic indices, and treatment (adjusted hazard ratio 2.10; 95% confidence interval 1.14-3.88). No significant differences in ESRD-free survival time were found among different genotypes in non-IgAN ESRD patients (log-rank, P = .480). Moreover, rs77924615 exhibited allele-specific enhancer activity by dual-luciferase reporter assay. Accordingly, the urinary uromodulin-creatinine ratio (uUCR) was significantly higher in healthy individuals with rs77924615 AG or GG than in individuals with AA. Furthermore, uromodulin expression in tubular epithelial cells was higher in patients with rs77924615 AG or GG. Finally, we confirmed that an increased uUCR (P = .009) was associated with faster IgAN progression. Conclusion: The SNP rs77924615, which modulates the enhancer activity of the UMOD gene, is associated with renal function deterioration in IgAN patients by increasing uromodulin levels in both the renal tubular epithelium and urine.