scholarly journals Diabetic Kidney Disease Alters the Transcriptome and Function of Human Adipose-Derived Mesenchymal Stromal Cells but Maintains Immunomodulatory and Paracrine Activities Important for Renal Repair

2021 ◽  
Author(s):  
LaTonya J. Hickson ◽  
Alfonso Eirin ◽  
Sabena M. Conley ◽  
Timucin Taner ◽  
Xiaohui Bian ◽  
...  
Keyword(s):  
Growth Factor ◽  
Kidney Disease ◽  
Stromal Cells ◽  
Diabetic Kidney Disease ◽  
Transforming Growth Factor ◽  
Inflammatory Marker ◽  
Patient Characteristics ◽  
Rna Seq ◽  
Diabetic Kidney

<a>Mesenchymal stem/stromal cells (MSC) facilitate repair in experimental diabetic kidney disease (DKD). However, the hyperglycemic and uremic milieu may diminish regenerative capacity of patient-derived therapy. We hypothesized that DKD reduces human MSC paracrine function. Adipose-derived MSC from 38 DKD participants and 16 controls were assessed for cell surface markers, tri-lineage differentiation, RNA-sequencing (RNA-seq), <i>in vitro</i> function (co-culture or conditioned medium experiments with T cells and human kidney cells [HK-2]), secretome profile, and cellular senescence abundance. The direction of association between MSC function and patient characteristics were also tested. RNA-seq analysis identified 353 differentially expressed genes and downregulation of several immunomodulatory genes/pathways in DKD- <i>vs</i>. Control-MSC. DKD-MSC phenotype, differentiation, and tube formation capacity were preserved but migration was reduced. DKD-MSC with and without interferon-γ priming inhibited T-cell proliferation greater than Control-MSC. DKD-MSC-medium contained higher levels of anti-inflammatory cytokines (indoleamine 2,3-deoxygenase-1 and prostaglandin-E2) and pro-repair factors (hepatocyte growth factor and stromal cell-derived factor-1) but lower Interleukin-6 vs. Control-MSC-medium. DKD-MSC-medium protected high glucose plus transforming growth factor-β-exposed HK-2 cells by reducing apoptotic, fibrotic and inflammatory marker expression. Few DKD-MSC functions were affected by patient characteristics including age, gender, body mass index, hemoglobin A1c, kidney function or urine albumin excretion. However, senescence-associated-β-galactosidase activity was lower in DKD-MSC from participants on metformin therapy. Therefore, while </a><a>DKD altered the transcriptome and migratory function of culture-expanded MSC, DKD-MSC functionality, trophic factor secretion and immunomodulatory activities contributing to repair remained intact. </a>These observations support testing patient-derived MSC therapy and may inform preconditioning regimens in DKD clinical trials.

scholarly journals Diabetic Kidney Disease Alters the Transcriptome and Function of Human Adipose-Derived Mesenchymal Stromal Cells but Maintains Immunomodulatory and Paracrine Activities Important for Renal Repair

2021 ◽  
Author(s):  
LaTonya J. Hickson ◽  
Alfonso Eirin ◽  
Sabena M. Conley ◽  
Timucin Taner ◽  
Xiaohui Bian ◽  
...  
Keyword(s):  
Growth Factor ◽  
Kidney Disease ◽  
Stromal Cells ◽  
Diabetic Kidney Disease ◽  
Transforming Growth Factor ◽  
Inflammatory Marker ◽  
Patient Characteristics ◽  
Rna Seq ◽  
Diabetic Kidney

<a>Mesenchymal stem/stromal cells (MSC) facilitate repair in experimental diabetic kidney disease (DKD). However, the hyperglycemic and uremic milieu may diminish regenerative capacity of patient-derived therapy. We hypothesized that DKD reduces human MSC paracrine function. Adipose-derived MSC from 38 DKD participants and 16 controls were assessed for cell surface markers, tri-lineage differentiation, RNA-sequencing (RNA-seq), <i>in vitro</i> function (co-culture or conditioned medium experiments with T cells and human kidney cells [HK-2]), secretome profile, and cellular senescence abundance. The direction of association between MSC function and patient characteristics were also tested. RNA-seq analysis identified 353 differentially expressed genes and downregulation of several immunomodulatory genes/pathways in DKD- <i>vs</i>. Control-MSC. DKD-MSC phenotype, differentiation, and tube formation capacity were preserved but migration was reduced. DKD-MSC with and without interferon-γ priming inhibited T-cell proliferation greater than Control-MSC. DKD-MSC-medium contained higher levels of anti-inflammatory cytokines (indoleamine 2,3-deoxygenase-1 and prostaglandin-E2) and pro-repair factors (hepatocyte growth factor and stromal cell-derived factor-1) but lower Interleukin-6 vs. Control-MSC-medium. DKD-MSC-medium protected high glucose plus transforming growth factor-β-exposed HK-2 cells by reducing apoptotic, fibrotic and inflammatory marker expression. Few DKD-MSC functions were affected by patient characteristics including age, gender, body mass index, hemoglobin A1c, kidney function or urine albumin excretion. However, senescence-associated-β-galactosidase activity was lower in DKD-MSC from participants on metformin therapy. Therefore, while </a><a>DKD altered the transcriptome and migratory function of culture-expanded MSC, DKD-MSC functionality, trophic factor secretion and immunomodulatory activities contributing to repair remained intact. </a>These observations support testing patient-derived MSC therapy and may inform preconditioning regimens in DKD clinical trials.

How to inhibit transforming growth factor beta safely in diabetic kidney disease

2020 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Yuxin Yang ◽  
Kexin Shi ◽  
Devang M. Patel ◽  
Fang Liu ◽  
Tieqiao Wu ◽  
...  
Keyword(s):  
Growth Factor ◽  
Kidney Disease ◽  
Transforming Growth Factor Beta ◽  
Diabetic Kidney Disease ◽  
Transforming Growth Factor ◽  
Diabetic Kidney ◽  
Growth Factor Beta

scholarly journals Aliskiren and perindopril reduce the levels of transforming growth factor-β in patients with non-diabetic kidney disease

2012 ◽  
Vol 25 (6) ◽  
pp. 636-639 ◽  
Author(s):  
Sławomir Lizakowski ◽  
Leszek Tylicki ◽  
Marcin Renke ◽  
Przemysław Rutkowski ◽  
Zbigniew Heleniak ◽  
...  
Keyword(s):  
Growth Factor ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Diabetic Kidney

scholarly journals Klotho prevents epithelial–mesenchymal transition through Egr-1 downregulation in diabetic kidney disease

2021 ◽  
Vol 9 (1) ◽  
pp. e002038
Author(s):  
Yang Li ◽  
Meng Xue ◽  
Fang Hu ◽  
Yijie Jia ◽  
Zongji Zheng ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Signaling Pathway ◽  
Diabetic Kidney Disease ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Diabetic Kidney ◽  
Mesenchymal Transition ◽  
Hk2 Cells ◽  
Tgf Β1

IntroductionAs a key event leading to tubulointerstitial fibrosis in diabetic kidney disease (DKD), epithelial–mesenchymal transition (EMT) has drawn increasing attention from researchers. The antiaging protein Klotho attenuates renal fibrosis in part by inhibiting ERK1/2 signaling in DKD. Early growth response factor 1 (Egr-1), which is activated mainly by ERK1/2, has been shown to play an important role in EMT. However, whether Klotho prevents EMT by inhibiting ERK1/2-dependent Egr-1 expression in DKD is unclear.The aim of this study was to investigate whether Klotho prevents EMT through Egr-1 downregulation by inhibiting the ERK1/2 signaling pathway in DKD.Research design and methodsMale C57BL/6J mice fed an high-fat diet for 4 weeks received 120 mg/kg streptozotocin (STZ), which was injected intraperitoneally. Klotho and Egr-1 expression was detected in the renal cortices of these mice on their sacrifice at 6 and 12 weeks after STZ treatment. In In vitro studies, we incubated HK2 cells under high-glucose (HG) or transforming growth factor-β1 (TGF-β1) conditions to mimic DKD. We then transfected the cells with an Klotho-containing plasmid, Klotho small interfering RNA.ResultsKlotho expression was significantly decreased in the renal cortices of mice with diabetes mellitus (DM) compared with the renal cortices of control mice at 6 weeks after treatment and even more significantly decreased at 12 weeks. In contrast, Egr-1 expression was significantly increased in mice with DM compared with control mice only at 12 weeks. We also found that Klotho overexpression downregulated Egr-1 expression and the (p-ERK1/2):(ERK1/2) ratio in HG-treated or TGF-β1-treated HK2 cells. Conversely, Klotho silencing upregulated Egr-1 expression and the (p-ERK1/2):(ERK1/2) ratio in HG-treated or TGF-β1-treated HK2 cells. Moreover, the effects of si-Klotho were abolished by the ERK1/2 inhibitor PD98059.ConclusionsKlotho prevents EMT during DKD progression, an effect that has been partially attributed to Egr-1 downregulation mediated by ERK1/2 signaling pathway inhibition.

scholarly journals Development of the Diabetic Kidney Disease Mouse Model Culturing Embryos in α-Minimum Essential Medium In Vitro, and Feeding Barley Diet Attenuated the Pathology

2021 ◽  
Vol 12 ◽  
Author(s):  
Shiori Ishiyama ◽  
Mayu Kimura ◽  
Takao Nakagawa ◽  
Yuka Fujimoto ◽  
Kohei Uchimura ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Mouse Model ◽  
Transforming Growth Factor Beta ◽  
Diabetic Kidney Disease ◽  
Transforming Growth Factor ◽  
Control Diet ◽  
Renal Tubules ◽  
Minimum Essential Medium ◽  
Diabetic Kidney

Diabetic kidney disease (DKD) is a critical complication associated with diabetes; however, there are only a few animal models that can be used to explore its pathogenesis. In the present study, we established a mouse model of DKD using a technique based on the Developmental Origins of Health and Disease theory, i.e., by manipulating the embryonic environment, and investigated whether a dietary intervention could ameliorate the model’s pathology. Two-cell embryos were cultured in vitro in α-minimum essential medium (MEM; MEM mice) or in standard potassium simplex-optimized medium (KSOM) as controls (KSOM mice) for 48 h, and the embryos were reintroduced into the mothers. The MEM and KSOM mice born were fed a high-fat, high-sugar diet for 58 days after they were 8 weeks old. Subsequently, half of the MEM mice and all KSOM mice were fed a diet containing rice powder (control diet), and the remaining MEM mice were fed a diet containing barley powder (barley diet) for 10 weeks. Glomerulosclerosis and pancreatic exhaustion were observed in MEM mice, but not in control KSOM mice. Renal arteriolar changes, including intimal thickening and increase in the rate of hyalinosis, were more pronounced in MEM mice fed a control diet than in KSOM mice. Immunostaining showed the higher expression of transforming growth factor beta (TGFB) in the proximal/distal renal tubules of MEM mice fed a control diet than in those of KSOM mice. Pathologies, such as glomerulosclerosis, renal arteriolar changes, and higher TGFB expression, were ameliorated by barley diet intake in MEM mice. These findings suggested that the MEM mouse is an effective DKD animal model that shows glomerulosclerosis and renal arteriolar changes, and barley intake can improve these pathologies in MEM mice.

Diabetic kidney disease: impact of puberty

2002 ◽  
Vol 283 (4) ◽  
pp. F589-F600 ◽  
Author(s):  
Pascale H. Lane
Keyword(s):  
Diabetes Mellitus ◽  
Growth Factor ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Transforming Growth Factor ◽  
Microvascular Complications ◽  
Renin Angiotensin System ◽  
Redox Systems ◽  
Renal Hypertrophy ◽  
Diabetic Kidney

Puberty accelerates microvascular complications of diabetes mellitus, including nephropathy. Animal studies confirm a different renal hypertrophic response to diabetes before and after puberty, probably due to differences in the production of transforming growth factor-β (TGF-β). Many of the complex physiological changes during puberty could affect potentially pathogenic mechanisms of diabetic kidney disease. Increased blood pressure, activation of the growth hormone-insulin-like growth factor I axis, and production of sex steroids could all play a role in pubertal susceptibility to diabetic renal hypertrophy and nephropathy. These factors may influence the effects of hyperglycemia and several systems that ultimately control TGF-β production, including the renin-angiotensin system, cellular redox systems, the polyol pathway, and protein kinase C. These phenomena may also explain gender differences in kidney function and incidence of end-stage renal disease. Normal changes during puberty, when coupled with diabetes and superimposed on a genetically susceptible milieu, are capable of accelerating diabetic hypertrophy and microvascular lesions. A better understanding of these processes may lead to new treatments to prevent renal failure in diabetes mellitus.

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