c­Jun N­terminal kinase/transforming growth factor­ß/Smad3 pathway: Is it associated with endoplasmic reticulum stress­mediated renal interstitial fibrosis?

The present study investigated the role of the c­Jun N­terminal kinase (JNK)/transforming growth factor­ß (TGF­ß)/Smad3 pathway in endoplasmic reticulum stress (ERS)­mediated renal interstitial fibrosis, which would be beneficial for chronic kidney disease (CKD) therapy. In human renal biopsy tissue, the expression levels of glucose­regulated protein 78 (GRP78) and phosphorylated (p)­JNK were examined by immunohistochemical analysis. In renal tubular HK­2 cells, tunicamycin (TM) was used to induce ERS, and the cells were then treated with the chemical ERS inhibitor 4­phenylbutyrate (4­PBA) or the chemical JNK pathway inhibitor SP600125, respectively. Western blotting was then performed in the cells to determine the expression levels of GRP78 and p­JNK proteins, as well as TGF­ß/Smad3 pathway­associated proteins, including TGF­ß1, p­Smad3, connective tissue growth factor and α­smooth muscle actin. The results revealed that GRP78 and p­JNK were evidently expressed in the renal tissues of patients with CKD, and these expression levels were significantly higher in renal tissues with severe interstitial fibrosis compared with glomerular minor lesion tissues (P<0.01 and P<0.05, respectively). Furthermore, ERS and JNK pathway inhibition decreased the expression levels of TGF­ß/Smad3 pathway signals in cells incubated with TM. ERS pathway inhibition also attenuated the expression levels of p­JNK in HK­2 cells. In conclusion, ERS was observed to serve an important role in the pathogenesis of CKD and may induce renal interstitial fibrosis via the JNK/TGF­ß/Smad3 pathway.

Clinical and pathological analysis of IgA nephropathy with chronic renal failure.

OBJECTIVE: To investigative clinical and pathological characteristics of IgA nephropathy with chronic renal failure. METHOD: Clinical and pathological findings from 65 cases of IgA nephropathy with chronic renal failure were reviewed. Pathological characteristics of all the cases were analyzed according to WHO definition and Oxford Classification. Evaluating the severity of pathological lesions by the Katafuchi R semiquantitative scoring system, and analyzing their relationship with clinical indexes of renal function. RESULTS: Of all 65 cases the male and female ratio was 1.4, and the mean age was 37 ± 13 years old. Levels of systolic pressure, mean arterial pressure (MAP), blood urea nitrogen (BUN), serum creatinine (Scr), uric acid (UA), album (Alb), serum IgG and 24 h urinary protein were related with eGRF level (p < 0.05, respectively). The most common pathological type was proliferative sclerosis glomerulonephritis (PSGN) and M1S1E0T0 according to WHO definition and Oxford Classification, respectively, and most of the 65 cases had glomerulosclerosis. Simple IgA deposition was the most common immunopathologic type. Of all the cases, 44.6% accompanied with C3 while 4.6% with C1q. Further analysis revealed there were no relationships between severity of pathological lesion and levels of clinical indexes (Scr and eGRF) (p > 0.05). CONCLUSION: IgA nephropathy with chronic renal failure usually occurred in young adults, and it had severe clinical condition and pathological changes, while there was no significant relationship between them.

[A novel mutation of WFS1 gene in Chinese patients with Wolfram syndrome].

OBJECTIVE: Wolfram syndrome is an autosomal recessive disorder characterized by early-onset diabetes mellitus, diabetes insipidus, optic atrophy and deafness. The aim of this study was to scan the WFS1 gene mutations in a Chinese Wolfram syndrome pedigree. METHODS: Eight exons and flanking introns of WFS1 gene were screened using PCR-DNA direct sequencing. Effects of the mutation on the structure and function of the WFS1 gene product, Wolframin, were evaluated by bioinformatics. RESULTS: A novel mutation, F417del, in the WFS1 gene was identified. The patient was homozygous of this mutation and the consanguineous parents were heterozygous. The mutation causes the lose of a non-polar amino acid, which was located in the transmembrane domain of the protein product. Bioinformatics predicted that the mutation altered the secondary structure of the transmembrane domain and decreased the hydrophobicity of F417del protein. CONCLUSIONS: This study identified a novel mutation of WFS1 gene and represented the first cause of molecular characterization of Chinese Wolfram syndrome patients.