Major Vault Protein Contributes to Tubulo-interstitial Fibrosis in Chronic Kidney Disease

Abstract

Background: Chronic kidney disease (CKD) is a major global issue leading to much morbidity and mortality. Tubulo-interstitial fibrosis is the final pathogenic pathway in the progression of CKD to end-stage renal failure. There is currently no effective treatment for kidney fibrosis. We previously reported that major vault protein (MVP), a key component in the vault complex, contributed to fibrogenesis in HK-2 cells in lupus nephritis. We extended our investigations to other causes of CKD. Methods: MVP expression in renal biopsies from patients with CKD due to various causes was examined with cytochemical staining. Animal studies were carried out using unilateral ureteral obstruction (UUO) model in wild-type (WT) and MVP knockout (KO) mice, with the contralateral unobstructed kidney serving as control. Mice were sacrificed 14 days after UUO, and the kidneys were harvested and examined. The effect of MVP overexpression in HK-2 cells was investigated. Results: Kidney biopsies from patients with IgA nephropathy, diabetic nephropathy, or idiopathic membranous glomerulonephritis with CKD showed markedly increased MVP expression, predominately in proximal tubular epithelial cells, compared with normal kidney specimens. MVP gene expression was negligible in normal mice. UUO significantly induced MVP mRNA expression, accompanied by tubular atrophy, increased tubulo-interstitial inflammatory cell infiltration, and matrix protein accumulation including fibronectin and collagen III. MVP KO in UUO mice was associated with reduced immune cell infiltration and decreased tubulo-interstitial collagen III and fibronectin expression compared with WT. Further data showed that MVP regulated collagen III at transcription level, whereas its effect on fibronectin expression was at the post-transcriptional level. MVP gene editing using CRISPR-Cas9 in HK-2 cells was accompanied by decreased MCP-1 secretion and fibronectin expression. Conclusions: Our data show increased renal tubulo-interstitial MVP expression in CKD irrespective of original cause, which may contribute to inflammatory and fibrotic processes in CKD progression.