Glomerulosclerosis, tubulointerstitial fibrosis, and obstructive uropathy in PEPCK-TGF-β1 transgenic mice

Diabetic kidney disease (DKD) is still one of the unresolved major complications of diabetes mellitus, which leads ultimately to end-stage renal disease in both type 1 and type 2 diabetes patients. Available drugs that suppress the renin–angiotensin system have partially minimized the disease impact. Yet, there is an unmet need for new therapeutic interventions to protect the kidneys of diabetic patients. In DN, glomerular sclerosis and tubulointerstitial fibrosis are mediated through several pathways, of which JAK/STAT is a key one. The current study explored the potential renoprotective effect of the JAK1/JAK2 inhibitor ruxolitinib (at doses of 0.44, 2.2, and 4.4 mg·kg−1) compared to that of enalapril at a dose of 10 mg·kg−1, in a rat model of streptozotocin-induced diabetes mellitus over 8 weeks. The effect of ruxolitinib was assessed by determining urinary albumin/creatinine ratio, serum level of cystatin, and levels of TGF-β1, NF-κB, and TNF-α in renal tissue homogenates by biochemical assays, the glomerular sclerosis and tubulointerstitial fibrosis scores by histological analysis, and fibronectin, TGF-β1, and Vimentin levels by immunohistochemical staining with the respective antibodies. Our results revealed a significant early favorable effect of a two-week ruxolitinib treatment on the renal function, supported by a decline in the proinflammatory biomarkers of DKD. This pre-clinical study suggests that the renoprotective effect of ruxolitinib in the long term should be investigated in animals, as this drug may prove to be a potential option for the treatment of diabetic kidney disease.

Download Full-text

Disruption of anterior segment development by TGF-β1 overexpression in the eyes of transgenic mice

Developmental Dynamics ◽

10.1002/dvdy.10144 ◽

2002 ◽

Vol 225 (2) ◽

pp. 111-125 ◽

Cited By ~ 39

Author(s):

Cassandra Flügel-Koch ◽

Andreas Ohlmann ◽

Joram Piatigorsky ◽

Ernst R. Tamm

Keyword(s):

Transgenic Mice ◽

Anterior Segment ◽

Tgf Β1

Download Full-text

Impairment of TGF-β signaling in T cells increases susceptibility to experimental autoimmune hepatitis in mice

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00286.2002 ◽

2003 ◽

Vol 284 (3) ◽

pp. G525-G535 ◽

Cited By ~ 39

Author(s):

Christoph Schramm ◽

Martina Protschka ◽

Heinz H. Köhler ◽

Jürgen Podlech ◽

Matthias J. Reddehase ◽

...

Keyword(s):

T Cells ◽

Transgenic Mice ◽

Autoimmune Hepatitis ◽

Mononuclear Cells ◽

Dominant Negative ◽

Wild Type ◽

Histological Score ◽

Tgf Β1 ◽

Increased Susceptibility ◽

Experimental Autoimmune

In autoimmune hepatitis, strong TGF-β1 expression is found in the inflamed liver. TGF-β overexpression may be part of a regulatory immune response attempting to suppress autoreactive T cells. To test this hypothesis, we determined whether impairment of TGF-β signaling in T cells leads to increased susceptibility to experimental autoimmune hepatitis (EAH). Transgenic mice of strain FVB/N were generated expressing a dominant-negative TGF-β type II receptor in T cells under the control of the human CD2 promoter/locus control region. On induction of EAH, transgenic mice showed markedly increased portal and periportal leukocytic infiltrations with hepatocellular necroses compared with wild-type mice (median histological score = 1.8 ± 0.26 vs. 0.75 ± 0.09 in wild-type mice; P < 0.01). Increased IFN-γ production (118 vs. 45 ng/ml) and less IL-4 production (341 vs. 1,256 pg/ml) by mononuclear cells isolated from transgenic livers was seen. Impairment of TGF-β signaling in T cells therefore leads to increased susceptibility to EAH in mice. This suggests an important role for TGF-β in immune homeostasis in the liver and may teleologically explain TGF-β upregulation in response to T cell-mediated liver injury.

Download Full-text

Mesenchymal Stem Cells Ameliorate Interstitial Fibrosis in Adenine-induced Nephropathy Based on Renal Proteomics

10.21203/rs.3.rs-100450/v1 ◽

2020 ◽

Author(s):

Huajun Tang ◽

Peiyue Zhang ◽

Lianlin Zeng ◽

Yu Zhao ◽

Libo Xie ◽

...

Keyword(s):

Western Blot ◽

Therapeutic Target ◽

Bioinformatics Analysis ◽

Interstitial Fibrosis ◽

Kidney Diseases ◽

Histopathological Change ◽

Collagen Type I ◽

Tubulointerstitial Fibrosis ◽

Type I ◽

Tgf Β1

Abstract Background: Tubulointerstitial fibrosis (TIF) is one of the main pathological features of various progressive renal damages and chronic kidney diseases. Mesenchymal stromal cells (MSCs) have been verified with significant improvement in the therapy of fibrosis diseases, but the mechanism is still unclear. We attempted to explore the new mechanism and therapeutic target of MSCs against renal fibrosis based on renal proteomics.Methods: TIF model was induced by adenine gavage. Bone marrow derived MSCs was injected by tail vein after modeling. Fibrosis biomarkers or extracellular matrix proteins and histopathological change were assessed by Masson staining, Sirius red staining, immunohistochemistry, and western blot. Renal proteomics was analyzed using iTRAQ-based mass spectrometry.Results: MSCs treatment clearly decreased the expression of α-SMA, collagen type I, II, III, TGF-β1, p-Smad2/3, IL-6, IL-1β, and TNFα compared with model rats, while p38 MAPK increased. 6,213 proteins were identified, but only 40 proteins exhibited significant differences (30 upregulated, 10 downregulated) compared MSCs group with the model group. Bioinformatics analysis revealed that these proteins play important roles in the proliferation, inflammatory and immune responses, apoptosis, phagosome, etc. According to literatures and bioinformatics analysis, the most markedly downregulated protein, galectin3, was further assessed by quantitative PCR and western blot in renal tissues. Galectin3 levels were downregulated in adenine-induced renal tissues and TGF-β1 induced tubular epithelial cells and interstitial fibroblasts in consistent with iTRAQ after MSCs treatment.Conclusion: The founds suggest that galectin3 maybe involves in the antifibrotic mechanisms of MSCs therapy for tubulointerstitial fibrosis as well as a possible therapeutic target.

Download Full-text

Silymarin Regulates Tgf-β1/Smad3 Signaling Pathway and Improves Renal Tubular Interstitial Fibrosis Caused by Obstructive Nephropathy

Current Topics in Nutraceutical Research ◽

10.37290/ctnr2641-452x.19:508-513 ◽

2021 ◽

Vol 19 (4) ◽

pp. 508-513

Author(s):

Jinhao Wu ◽

Chao Huang ◽

Gang Kan ◽

Hanyu Xiao ◽

Xiaoping Zhang ◽

...

Keyword(s):

Signaling Pathway ◽

Interstitial Fibrosis ◽

Tubulointerstitial Fibrosis ◽

Obstructive Nephropathy ◽

Therapeutic Drugs ◽

Renal Tubulointerstitial Fibrosis ◽

Liver And Kidney ◽

Renal Tubular ◽

Antioxidant Effects ◽

Tgf Β1

Obstructive nephropathy often leads to renal tubulointerstitial fibrosis. Understanding of the pathogenesis of renal tubulointerstitial fibrosis caused by obstructive nephropathy is crucial to the development of effective therapeutic drugs to improve the prognosis of the patients. Silymarin, a polyphenolic flavonoid extracted from plants, has been shown to exhibit antiinflammatory and antioxidant effects ameliorating liver and kidney damage. However, the effect of silymarin on renal fibrosis in obstructive nephropathy remains to be explored. In this study, we found silymarin improved interstitial fibrosis and apoptosis induced by TGF-β1 and ameliorated oxidative damage. Our data further confirmed that silymarin regulates the TGF-β1/ Smad3 signaling pathway, and therefore improves renal tubular interstitial fibrosis caused by obstructive nephropathy.

Download Full-text

Effects of ZnT8 on epithelial-to-mesenchymal transition and tubulointerstitial fibrosis in diabetic kidney disease

Cell Death and Disease ◽

10.1038/s41419-020-2731-6 ◽

2020 ◽

Vol 11 (7) ◽

Cited By ~ 2

Author(s):

Xiuli Zhang ◽

Tingwen Guan ◽

Boxuan Yang ◽

Harvest F. Gu ◽

Zhihong Chi

Keyword(s):

Kidney Disease ◽

Pancreatic Beta Cells ◽

Diabetic Kidney Disease ◽

Epithelial To Mesenchymal Transition ◽

Gene Transfection ◽

Tubulointerstitial Fibrosis ◽

Inflammatory Factors ◽

Diabetic Kidney ◽

Mesenchymal Transition ◽

Tgf Β1

Abstract Zinc transporter 8 (ZnT8) transports zinc ions for crystallization and storage of insulin in pancreatic beta-cells and ZnT8 dysfunction is involved in pathogenesis of diabetes. The current study aimed to investigate whether ZnT8 has effects in pathophysiology of diabetic kidney disease (DKD) by using animal models for diabetes, including STZ-induced diabetic, db/db, ZnT8-KO, ZnT8-KO-STZ and ZnT8-KO-db/db mice. Results demonstrated that urine albumin to creatinine ratio and epithelial-to-mesenchymal transition (EMT) were increased in kidneys of ZnT8-KO-STZ and ZnT8-KO-db/db mice compared with C57BL/6 J and ZnT8-KO mice, while serum TGF-β1, IL-6, and TNF-α levels were elevated in parallel. In kidneys of mice intercrossed between ZnT8-KO and STZ-induced diabetic or db/db mice, these three inflammatory factors, ACR and EMT were also found to be increased compared with C57BL/6J, db/db and ZnT8-KO mice. Furthermore, ZnT8 up-regulation by hZnT8-EGFP reduced the levels of high glucose (HG)-induced EMT and inflammatory factors in normal rat kidney tubular epithelial cell (NRK-52E cells). Expression of phosphorylated Smad2/Smad3 was up-regulated after HG stimulation and further enhanced by ZnT8 siRNA but down-regulated after hZnT8-EGFP gene transfection. The current study thus provides the first evidence that ZnT8 protects against EMT-tubulointerstitial fibrosis though the restrain of TGF-β1/Smads signaling activation in DKD.

Download Full-text