Pro-inflammatory/Th1 gene expression shift in high glucose stimulated mesangial cells and tubular epithelial cells

Abstract

Diabetic nephropathy (DN) is a major cause of end stage kidney disease and a strong risk factor for cardiovascular diseases. Growing data show chronic inflammation plays an important role for the progression of DN. As for the immune cells, anti-inflammatory leukocytes as well as pro-inflammatory leukocytes play an important role in DN. In addition to leukocytes, renal resident cells contribute to the inflammatory process of DN. However, precise functions, phenotypes and immune balance of renal resident cells remain to be explored. Therefore, we hypothesized that the aberrant immune balance of renal resident cells contributes to the pathogenesis of DN. To explore this possibility, we performed genome-wide transcriptome profiling in mesangial cells and tubular epithelial cells (TECs), which were stimulated by high glucose (HG) and detected the expression of inflammation associated genes. HG increased the mRNA expression of oxidative stress, inflammasome and mammalian target of rapamycin (mTOR) related genes in mesangial cells. Pro-inflammatory/Th1 gene expression was upregulated, but Th2 related gene expression was downregulated in mesangial cells. In TECs, HG stimulation increased pro-inflammatory/Th1/Th2 gene expression. Phosphorylation of signaling proteins shifted towards pro-inflammatory phenotype with suppressed phosphorylation of Th2 related signaling in TECs. The data taken together indicate that HG shifts the immune balance toward pro-inflammatory/Th1 phenotype in mesangial cells and TECs, which might initiate and/or prolong inflammation, thereby resulting in diabetic nephropathy.

Helper T‐cell signaling and inflammatory pathway lead to formation of calcium phosphate but not calcium oxalate stones on Randall's plaques

“…A study reported that Th1 cells drove the pro‐inflammatory and Th2 the anti‐inflammatory response in atherosclerosis, which has similar calcification lesions on the vascular endothelial cells as urolithiasis . Interestingly, the pro‐inflammatory/Th1 phenotype is reportedly predominant in renal mesangial cells and tubular epithelial cells under diabetic nephropathy, which is in line with the results of our previous studies showing that the renal tissues of kidney stone patients and crystal‐forming mice shifted towards pro‐inflammatory and M1 macrophage phenotypes. In the present study, both the Th1‐ and Th2‐related pathways were upregulated in RP‐containing tissues of CaP SFs; however, validation of the expressions of these genes using PCR could not distinguish the tendency of either the Th1 or Th2 polarization between the papillary tissues of CaOx SFs and CaP SFs.…”

Erythropoietin signal protected human umbilical vein endothelial cells from high glucose‐induced injury

“…In a prior study, we reported that HG stimulation disrupts immune balance toward triggering pro-inflammatory reaction in nephrogenic cells such as mesangial cells, which in turn causes cell damage. 11 The results of the present study suggest the possibility that a similar mechanism may come into play not only in nephrogenic cells but also in vascular endothelial cells, which are distributed throughout the body, thereby causing angiopathy. We believe these findings to be important in conducting future research on proinflammatory reaction in vascular endothelial cells as well as cytopathy and ensuing systemic organ failure.…”

“…We observed that HG stimulation increased the gene expressions of pro‐inflammatory/Th1/Th17‐related molecules and decreased those of Th2‐related molecules. In a prior study, we reported that HG stimulation disrupts immune balance toward triggering pro‐inflammatory reaction in nephrogenic cells such as mesangial cells, which in turn causes cell damage . The results of the present study suggest the possibility that a similar mechanism may come into play not only in nephrogenic cells but also in vascular endothelial cells, which are distributed throughout the body, thereby causing angiopathy.…”

“…The disruption of glycocalyx and dysregulation of angiogenic factors/cytokines may lead to dysfunction of endothelial cells . We have ascertained that as hyperglycemic damage progresses, nephrogenic cells act on the pro‐inflammatory system and disrupt its balance with the immunosuppression system . In the present study, we focused on the immune balance in vascular endothelial cells under high‐glucose (HG) conditions, as well as the involvement of EPO signals in this process.…”

“…10 We have ascertained that as hyperglycemic damage progresses, nephrogenic cells act on the pro-inflammatory system and disrupt its balance with the immunosuppression system. 11 In the present study, we focused on the immune balance in vascular endothelial cells under high-glucose (HG) conditions, as well as the involvement of EPO signals in this process. In other words, we hypothesized that EPO signals in vascular endothelial cells function to protect cells and organs by regulating immune balance under HG conditions, and performed exhaustive genetic analysis to verify this hypothesis.…”