FoxO1-Mediated Inhibition of STAT1 Alleviates Tubulointerstitial Fibrosis and Tubule Apoptosis in Diabetic Kidney Disease

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.

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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.

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FoxO1-mediated inhibition of STAT1 alleviates tubulointerstitial fibrosis and tubule apoptosis in diabetic kidney disease

EBioMedicine ◽

10.1016/j.ebiom.2019.09.002 ◽

2019 ◽

Vol 48 ◽

pp. 491-504 ◽

Cited By ~ 4

Author(s):

Fengjuan Huang ◽

Qingzhu Wang ◽

Feng Guo ◽

Yanyan Zhao ◽

Linlin Ji ◽

...

Keyword(s):

Kidney Disease ◽

Diabetic Kidney Disease ◽

Tubulointerstitial Fibrosis ◽

Diabetic Kidney

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Globally elevating the AGE clearance receptor, OST48, does not protect against the development of diabetic kidney disease, despite improving insulin secretion

Scientific Reports ◽

10.1038/s41598-019-50221-0 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Aowen Zhuang ◽

Felicia Y. T. Yap ◽

Domenica McCarthy ◽

Chris Leung ◽

Karly C. Sourris ◽

...

Keyword(s):

Insulin Secretion ◽

Kidney Disease ◽

Diabetic Kidney Disease ◽

Structural Parameters ◽

Tubulointerstitial Fibrosis ◽

Diabetic Mice ◽

Gene Encoding ◽

Diabetic Kidney ◽

Over Expression ◽

Glycation End Products

Abstract The accumulation of advanced glycation end products (AGEs) have been implicated in the development and progression of diabetic kidney disease (DKD). There has been interest in investigating the potential of AGE clearance receptors, such as oligosaccharyltransferase-48 kDa subunit (OST48) to prevent the detrimental effects of excess AGE accumulation seen in the diabetic kidney. Here the objective of the study was to increase the expression of OST48 to examine if this slowed the development of DKD by facilitating the clearance of AGEs. Groups of 8-week-old heterozygous knock-in male mice (n = 9–12/group) over-expressing the gene encoding for OST48, dolichyl-diphosphooligosaccharide-protein glycosyltransferase (DDOST+/−) and litter mate controls were randomised to either (i) no diabetes or (ii) diabetes induced via multiple low-dose streptozotocin and followed for 24 weeks. By the study end, global over expression of OST48 increased glomerular OST48. This facilitated greater renal excretion of AGEs but did not affect circulating or renal AGE concentrations. Diabetes resulted in kidney damage including lower glomerular filtration rate, albuminuria, glomerulosclerosis and tubulointerstitial fibrosis. In diabetic mice, tubulointerstitial fibrosis was further exacerbated by global increases in OST48. There was significantly insulin effectiveness, increased acute insulin secretion, fasting insulin concentrations and AUCinsulin observed during glucose tolerance testing in diabetic mice with global elevations in OST48 when compared to diabetic wild-type littermates. Overall, this study suggested that despite facilitating urinary-renal AGE clearance, there were no benefits observed on kidney functional and structural parameters in diabetes afforded by globally increasing OST48 expression. However, the improvements in insulin secretion seen in diabetic mice with global over-expression of OST48 and their dissociation from effects on kidney function warrant future investigation.

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Globally elevating the AGE clearance receptor, OST48, does not protect against the development of diabetic kidney disease, despite improving insulin secretion

10.1101/710558 ◽

2019 ◽

Author(s):

Aowen Zhuang ◽

Felicia YT Yap ◽

Domenica McCarthy ◽

Sherman S. Leung ◽

Sally A. Penfold ◽

...

Keyword(s):

Insulin Secretion ◽

Kidney Disease ◽

Diabetic Kidney Disease ◽

Structural Parameters ◽

Tubulointerstitial Fibrosis ◽

Diabetic Mice ◽

Gene Encoding ◽

Diabetic Kidney ◽

Over Expression ◽

Glycation End Products

AbstractThe accumulation of advanced glycation end products (AGEs) have been implicated in the development and progression of diabetic kidney disease (DKD). There has been interest in investigating the potential of AGE clearance receptors, such as oligosaccharyltransferase-48kDa subunit (OST48) to prevent the detrimental effects of excess AGE accumulation seen in the diabetic kidney. Here the objective of the study was to increase the expression of OST48 to examine if this slowed the development of DKD by facilitating the clearance of AGEs. Groups of 8-week-old heterozygous knock-in male mice (n=9-12/group) over-expressing the gene encoding for OST48, dolichyl-diphosphooligosaccharide-protein glycosyltransferase (DDOST+/-) and litter mate controls were randomised to either (i) no diabetes or (ii) diabetes induced via multiple low-dose streptozotocin and followed for 24 weeks. By the study end, global over expression of OST48 increased glomerular OST48. This facilitated greater renal excretion of AGEs but did not affect circulating or renal AGE concentrations. Diabetes resulted in kidney damage including lower glomerular filtration rate, albuminuria, glomerulosclerosis and tubulointerstitial fibrosis. In diabetic mice, tubulointerstitial fibrosis was further exacerbated by global increases in OST48. There was significantly insulin effectiveness, increased acute insulin secretion, fasting insulin concentrations and AUCinsulin observed during glucose tolerance testing in diabetic mice with global elevations in OST48 when compared to diabetic wild-type littermates. Overall, this study suggested that despite facilitating urinaryrenal AGE clearance, there were no benefits observed on kidney functional and structural parameters in diabetes afforded by globally increasing OST48 expression. However, the improvements in insulin secretion seen in diabetic mice with global over-expression of OST48 and their dissociation from effects on kidney function warrant future investigation.

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