The Use of Neutralizing Antibodies to Demonstrate the Role of Transforming Growth Factor-� and Amadori-Glycated Albumin as Mediators of Experimental Diabetic Kidney Disease

2015 ◽  
pp. 188-194 ◽  
Author(s):  
Fuad N. Ziyadeh ◽  
Kumar Sharma
Keyword(s):  
Growth Factor ◽  
Kidney Disease ◽  
Neutralizing Antibodies ◽  
Diabetic Kidney Disease ◽  
Transforming Growth Factor ◽  
Glycated Albumin ◽  
Diabetic Kidney

scholarly journals Role of TGF-alpha in the progression of diabetic kidney disease

2017 ◽  
Vol 312 (6) ◽  
pp. F951-F962 ◽  
Author(s):  
Josef G. Heuer ◽  
Shannon M. Harlan ◽  
Derek D. Yang ◽  
Dianna L. Jaqua ◽  
Jeffrey S. Boyles ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Renal Disease ◽  
Neutralizing Antibodies ◽  
Diabetic Kidney Disease ◽  
Transforming Growth Factor ◽  
Renin Angiotensin System ◽  
Neutralizing Antibody ◽  
Diabetic Kidney

Transforming growth factor-alpha (TGFA) has been shown to play a role in experimental chronic kidney disease associated with nephron reduction, while its role in diabetic kidney disease (DKD) is unknown. We show here that intrarenal TGFA mRNA expression, as well as urine and serum TGFA, are increased in human DKD. We used a TGFA neutralizing antibody to determine the role of TGFA in two models of renal disease, the remnant surgical reduction model and the uninephrectomized (uniNx) db/db DKD model. In addition, the contribution of TGFA to DKD progression was examined using an adeno-associated virus approach to increase circulating TGFA in experimental DKD. In vivo blockade of TGFA attenuated kidney disease progression in both nondiabetic 129S6 nephron reduction and Type 2 diabetic uniNx db/db models, whereas overexpression of TGFA in uniNx db/db model accelerated renal disease. Therapeutic activity of the TGFA antibody was enhanced with renin angiotensin system inhibition with further improvement in renal parameters. These findings suggest a pathologic contribution of TGFA in DKD and support the possibility that therapeutic administration of neutralizing antibodies could provide a novel treatment for the disease.

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
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