Loss of the Protein Cystathionine β-Synthase During Kidney Injury Promotes Renal Tubulointerstitial Fibrosis

Abstract

Background/Aims: Renal tubulointerstitial fibrosis (TIF) is the common pathway of progressive chronic kidney disease. Inflammation has been widely accepted as the major driving force of TIF. Cystathionine β-synthase (CBS) is the first and rate-limiting enzyme in the transsulfuration pathway. CBS is considered to play protective role in liver and pulmonary fibrosis, but its role in TIF remains unknown. The purpose of this study was to investigate the potential role and mechanism of CBS in renal inflammation and TIF. Methods: Renal function, tubulointerstitium damage index score, extracellular matrix (ECM) deposition, and the expressions of collagen I, collagen III, fibronectin, CD3, CD68, IL-1β, TNF-α were measured in sham operation and unilateral ureteral obstruction (UUO) rats. Proteomics and gene array analysis were performed to screen differentially expressed molecules in the development of renal inflammation and TIF in UUO rats. The expression of CBS was detected in patients with obstructive nephropathy and UUO rats. We confirmed the expression of CBS using western blot and real-time PCR in HK-2 cells. Overexpression plasmid and siRNA were transfected specifically to study the possible function of CBS in HK-2 cells. Results: Abundant expression of CBS, localized in renal tubular epithelial cells, was revealed in human and rat renal tissue, which correlated negatively with the progression of fibrotic disease. Expression of CBS was dramatically decreased in the obstructed kidney from UUO rats as compared with the sham group (SHM). In addition, knocking down CBS exacerbated extracellular matrix (ECM) deposition, whereas CBS overexpression attenuated TGF-β1-induced ECM deposition in vitro. Inflammatory and chemotactic factors were also increased in CBS knockdown HK-2 cells stimulated by IL-1β.

Roles of Hydrogen Sulfide Donors in Common Kidney Diseases

“…In addition, 3-MPST is localized in the proximal tubular epithelium (Nagahara et al, 1998). The deficiency of H 2 S-producing enzymes and H 2 S levels has been reported in human patients and rat models, which can be correlated with the severity of kidney diseases (Yuan et al, 2017). The above evidence indicates that the kidneys are enriched with all three enzymes and confirm their potential roles in kidney function.…”

“…With respect to H 2 S, the expression of CBS is reduced in renal tissues of patients with obstructive nephropathy compared to the normal ones (Yuan et al, 2017). Further analysis reveals that the knockdown of CBS in HK-2 human proximal tubular derived cells results in the elevation of proinflammatory markers while its overexpression shows opposite effects (Yuan et al, 2017). Moreover, both CSE and CBS negatively regulate Hcy levels via transsulfuration pathway; hence, their deficiency can cause the elevation of Hcy and the corresponding activation of proinflammatory responses leading to the progression of fibrosis (Chiku et al, 2009;Shastry and James, 2009;Yang et al, 2016).…”

“…In addition, 75% of the renal cells and 87% of endothelial cells express the enzymes. On the other hand, CBS is highly expressed in renal proximal tubular cells (Yuan et al, 2017). Similarly, in mice kidneys, CBS and CSE proteins are well expressed with the former reported to be predominantly in the outer renal cortex (mainly in the proximal convoluted tubule) and the later in the inner cortex and medulla (specifically in the proximal straight tubule) (House et al, 1997).…”

“…Moreover, the serum levels of several proinflammatory cytokines including interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor-α (TNF-α) are also reported to be increased (Goldstein et al, 2006). With respect to H 2 S, the expression of CBS is reduced in renal tissues of patients with obstructive nephropathy compared to the normal ones (Yuan et al, 2017). Further analysis reveals that the knockdown of CBS in HK-2 human proximal tubular derived cells results in the elevation of proinflammatory markers while its overexpression shows opposite effects (Yuan et al, 2017).…”

Identification of a genome-wide serum microRNA expression profile as potential noninvasive biomarkers for chronic kidney disease using next-generation sequencing

“…As one of seven target genes (Table 5), cystathionine beta synthase (CBS) was reported to be an inhibitor in renal fibrosis. 29 Because renal fibrosis is one of the histopathological hallmarks for CKD, miR-483-5p was predicted to regulate target genes that were enriched in pathways that are related to fibrosis. 25 However, whether miR-483-5p plays a role in the development of CKD via regulating CBS or other fibrosis-related genes remains unknown.…”