Re-understanding Of Glomerular Filtration Barrier And Related Diseases

The nephron is the basic unit of the kidney to perform its function, and the glomerular filtration barrier is an important line of defense for its normal physiological function. Glomerular endothelial cells, glomerular basement membrane (GBM) and glomerular podocytes constitute an organic whole of the filtration barrier. In view of this, diseases caused by damage to its constituent components have become one of the important fields of kidney disease research, and concepts such as podocyte disease, GBM-related diseases, and type IV collagen-related diseases have also been proposed. With the rapid development of genetic testing technology and the discovery of more and more genes that cause abnormal glomerular filtration barrier function, while improving our understanding of the nature of the disease, it is also reshaping the glomerular filtration barrier and its related Disease awareness. The interaction of cells with the extracellular matrix in the glomerular filtration barrier can be further illustrated by the effect of associated genetic variants on its function. Type IV collagen and laminin are important components of GBM, which are secreted by endothelial cells and podocytes during the development of the glomerulus. It has a loose structure and is easily hydrolyzed by proteolytic enzymes, resulting in increased permeability and layered deformation of the structure, which not only loses its original barrier support function, but also directly affects its adjacent podocytes and endothelial cells, manifested as Podocyte foot process fusion and other lesions. And podocytes are the main secretory cells of type IV collagen and laminin, and their functional defects will affect the formation and function of the normal structure of GBM. Thinning, delamination and tearing. Mutations in the podocyte INF2 gene can also cause similar lesions. Alport syndrome is one of the representative diseases caused by the above abnormalities, and its in-depth analysis will help us to re-understand this kind of disease from the level of the glomerular filtration barrier.

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Understanding the complexity of genetic variation in glomerular filtration barrier-related diseases Our understanding of Alport syndrome can be traced back to 1875, from the first systematic description of the syndrome by Dr. Changes, and then it is clear that the lack of type IV collagen is the cause of the disease, until the gene mutation of type IV collagen is the elucidation of the underlying cause of the disease, which has experienced a course of continuous deepening for nearly a hundred years. Type IV collagen is composed of six α chains (α1 to α6), and the related genes are located on chromosome 13, chromosome 2 and chromosome X, respectively. The six α chains constitute three different heterotrimeric protomers, namely α1α1α2, α3α4α5 and α5α5α6, of which α1α1α2 is distributed in all basement membranes of the body; α3α4α5 is distributed in GBM, glomerular cyst, eye, and cochlea. α5α5α6 is distributed in the basement membrane of skin epidermis, glomerular cyst wall, distal tubule and collecting duct basement membrane. The above characteristics constitute the diversity of clinical phenotypes caused by different type IV collagen gene mutations. The genetic pattern of Alport syndrome directly affects the clinical phenotypic characteristics and prognosis of patients. COL4A5 mutation causes X-linked Alport syndrome (XLAS). Male patients are more severely ill, and the probability of progression to end-stage renal disease (ESKD) before the age of 30 is 70% of female patients had relatively mild disease, and the probability of progression to ESKD before age 40 was 12%. COL4A3-COL4A4 mutations cause autosomal recessive Alport syndrome (ARAS) and autosomal dominant Alport syndrome (ADAS), respectively. ARAS patients have a poor prognosis, while ADAS patients have a relatively good prognosis. The type of Alport syndrome gene variant also has an impact on the clinical phenotype and prognosis of patients. In male patients with XLAS, those with nonsense mutations have a 90% probability of developing ESKD before the age of 30, and the probability of splicing mutations is 70%. 50% of sense mutants. For patients with truncating mutations, the age at onset of ESKD was 22 years, and for those with non-truncating mutations, it was 39 years. The National Center for Clinical Medicine of Renal Diseases performed whole-exome gene sequencing on 570 patients with Alport syndrome diagnosed by renal biopsy, and the results showed that 58% were XLAS, 18% were ARAS, 19% were ADAS, and 5% had COL4A dual genes. Mutation (COL4A3/COL4A4/COL4A5). In addition, chimeric mutations, combined with laminin (LAMA5) gene mutations, and podocyte-related gene mutations (including ACTN4, INF2, TRPC6, MYO1E, and NPHS1, etc.) were detected in this group of Alport syndrome patients. The above findings suggest that the thinning and stratified GBM, structural variation and concomitant podocyte lesions observed in Alport syndrome may be caused by mutations in type IV collagen genes (including the laminin gene), or podocyte-related result of genetic mutation.

Recognizing the diversity of glomerular filtration barrier-related diseases Pierson syndrome is an autosomal recessive genetic disorder caused by mutations in the laminin beta 2 (LAMB2) gene. Mutations in LAMB2 result in impaired GBM maturation with podocyte damage and massive proteinuria. The clinical manifestations are mostly nephrotic syndrome, with neurodevelopmental abnormalities (eg, hypotonia, muscle weakness) and ocular abnormalities. Kidney biopsy showed increased mesangial stroma under light microscope, which may be accompanied by focal segmental glomerulosclerosis (FSGS)-like lesions, tubulointerstitial atrophy and fibrosis; LAMB2 deletion was seen in typical cases by fluorescence detection; mesangium under electron microscope Increased stroma, diffuse foot process fusion of podocytes, and irregular thickening and thinning of GBM with stratification of the GBM dense layer. 

Such diseases may cause clinical missed diagnosis and misdiagnosis if only the type IV collagen gene is detected. It is worth noting that LAMB2/LAMA5 gene mutations have also been detected in some Alport syndrome patients, and some studies have shown that the combination of LAMB2/LAMA5 gene mutations can accelerate the progression of Alport syndrome. Focal segmental glomerulosclerosis (FSGS) FSGS is a group of diseases characterized by focal segmental sclerosis of the glomeruli on renal biopsy. In addition to the more prominent podocyte lesions, the pathological manifestations are often accompanied by changes in GBM. The clinical manifestations are highly heterogeneous and the etiology is unknown. The role of podocyte-related gene mutations in its pathogenesis has been supported by animal experiments and clinical studies, and podocyte-related gene testing for these patients, especially those who are resistant to hormone therapy, has begun to receive attention. A recent study found that in 135 cases of sporadic adult hormone-resistant nephrotic syndrome (SRNS) patients with targeted gene sequencing, podocyte-related genes accounted for 56.3% of the detected pathogenic mutations, and type IV collagen gene mutations. It accounted for 43.7%, and the detection rates of the two were almost evenly divided.

Another study also found that whole-exome sequencing of 193 adult patients with FSGS from 179 families identified pathogenic variants in 20 families (11% genetic diagnosis rate), of which type IV collagen gene mutations accounted for 55%. %, podocyte-related gene mutations accounted for 40%, and type IV collagen gene mutations dominated. These results suggest that the formation of lesions such as FSGS may be caused by the type IV collagen gene, podocyte-related gene mutations in kidney structure and function abnormalities, and the heterogeneity of its clinical phenotype may be related to the type and type of gene mutation. Recognizing this, further strengthening relevant basic and clinical research is of great significance to improving the level of disease diagnosis and treatment, at least at this stage, it can help such patients avoid the side effects caused by unnecessary high-dose immunosuppressive therapy.

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