scholarly journals The Attenuation of Diabetic Nephropathy by Annexin A1 via Regulation of Lipid Metabolism through AMPK/PPARα/CPT1b Pathway

2021 ◽  
Author(s):  
Liang Wu ◽  
Changjie Liu ◽  
Dong-Yuan Chang ◽  
Rui Zhan ◽  
Mingming Zhao ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Lipid Metabolism ◽  
Lipid Accumulation ◽  
Annexin A1 ◽  
Diabetic Mice ◽  
Tubulointerstitial Lesions ◽  
Matrix Expansion ◽  
Elevated Expression ◽  
Abnormal Metabolism ◽  
Proximal Tubular Epithelial Cells

Inflammation and abnormal metabolism play important roles in the pathogenesis of diabetic nephropathy (DN). Annexin A1 (ANXA1) contributes to inflammation resolution and improves metabolism. Here, we assess the effects of ANXA1 in diabetic mice and proximal tubular epithelial cells (PTECs) treated with high glucose plus palmitate acid (HGPA), and explore the association of ANXA1 with lipid accumulation in DN patients. It is found that ANXA1 deletion aggravates renal injuries, including albuminuria, mesangial matrix expansion and tubulointerstitial lesions in HFD/STZ-induced diabetic mice. ANXA1 deficiency promotes intra-renal lipid accumulation and drives mitochondrial alterations in kidneys. In addition, Ac2-26, an ANXA1 mimetic peptide, has a therapeutic effect against lipid toxicity in diabetic mice. In HGPA-treated human PTECs, <i>ANXA1</i> silencing causes FPR2/ALX-driven deleterious effects, which suppress phosphorylated Thr<sup>172</sup>AMPK, resulting in decreased PPARα and CPT1b expression and increased HGPA-induced lipid accumulation, apoptosis and elevated expression of pro-inflammatory and pro-fibrotic genes. Last but not least, the extent of lipid accumulation correlates with renal function, and the level of tubulointerstitial ANXA1 expression correlates with ectopic lipid deposition in kidneys of DN patients. These data demonstrate that ANXA1 regulates lipid metabolism of PTECs to ameliorate disease progression, hence it holds great potential as a therapeutic target for DN.

scholarly journals The Attenuation of Diabetic Nephropathy by Annexin A1 via Regulation of Lipid Metabolism through AMPK/PPARα/CPT1b Pathway

2021 ◽  
Author(s):  
Liang Wu ◽  
Changjie Liu ◽  
Dong-Yuan Chang ◽  
Rui Zhan ◽  
Mingming Zhao ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Lipid Metabolism ◽  
Lipid Accumulation ◽  
Annexin A1 ◽  
Diabetic Mice ◽  
Tubulointerstitial Lesions ◽  
Matrix Expansion ◽  
Elevated Expression ◽  
Abnormal Metabolism ◽  
Proximal Tubular Epithelial Cells

Inflammation and abnormal metabolism play important roles in the pathogenesis of diabetic nephropathy (DN). Annexin A1 (ANXA1) contributes to inflammation resolution and improves metabolism. Here, we assess the effects of ANXA1 in diabetic mice and proximal tubular epithelial cells (PTECs) treated with high glucose plus palmitate acid (HGPA), and explore the association of ANXA1 with lipid accumulation in DN patients. It is found that ANXA1 deletion aggravates renal injuries, including albuminuria, mesangial matrix expansion and tubulointerstitial lesions in HFD/STZ-induced diabetic mice. ANXA1 deficiency promotes intra-renal lipid accumulation and drives mitochondrial alterations in kidneys. In addition, Ac2-26, an ANXA1 mimetic peptide, has a therapeutic effect against lipid toxicity in diabetic mice. In HGPA-treated human PTECs, <i>ANXA1</i> silencing causes FPR2/ALX-driven deleterious effects, which suppress phosphorylated Thr<sup>172</sup>AMPK, resulting in decreased PPARα and CPT1b expression and increased HGPA-induced lipid accumulation, apoptosis and elevated expression of pro-inflammatory and pro-fibrotic genes. Last but not least, the extent of lipid accumulation correlates with renal function, and the level of tubulointerstitial ANXA1 expression correlates with ectopic lipid deposition in kidneys of DN patients. These data demonstrate that ANXA1 regulates lipid metabolism of PTECs to ameliorate disease progression, hence it holds great potential as a therapeutic target for DN.

scholarly journals The Attenuation of Diabetic Nephropathy by Annexin A1 via Regulation of Lipid Metabolism through AMPK/PPARα/CPT1b Pathway

2021 ◽  
Author(s):  
Liang Wu ◽  
Changjie Liu ◽  
Dong-Yuan Chang ◽  
Rui Zhan ◽  
Mingming Zhao ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Lipid Metabolism ◽  
Lipid Accumulation ◽  
Annexin A1 ◽  
Diabetic Mice ◽  
Tubulointerstitial Lesions ◽  
Matrix Expansion ◽  
Elevated Expression ◽  
Abnormal Metabolism ◽  
Proximal Tubular Epithelial Cells

Inflammation and abnormal metabolism play important roles in the pathogenesis of diabetic nephropathy (DN). Annexin A1 (ANXA1) contributes to inflammation resolution and improves metabolism. Here, we assess the effects of ANXA1 in diabetic mice and proximal tubular epithelial cells (PTECs) treated with high glucose plus palmitate acid (HGPA), and explore the association of ANXA1 with lipid accumulation in DN patients. It is found that ANXA1 deletion aggravates renal injuries, including albuminuria, mesangial matrix expansion and tubulointerstitial lesions in HFD/STZ-induced diabetic mice. ANXA1 deficiency promotes intra-renal lipid accumulation and drives mitochondrial alterations in kidneys. In addition, Ac2-26, an ANXA1 mimetic peptide, has a therapeutic effect against lipid toxicity in diabetic mice. In HGPA-treated human PTECs, <i>ANXA1</i> silencing causes FPR2/ALX-driven deleterious effects, which suppress phosphorylated Thr<sup>172</sup>AMPK, resulting in decreased PPARα and CPT1b expression and increased HGPA-induced lipid accumulation, apoptosis and elevated expression of pro-inflammatory and pro-fibrotic genes. Last but not least, the extent of lipid accumulation correlates with renal function, and the level of tubulointerstitial ANXA1 expression correlates with ectopic lipid deposition in kidneys of DN patients. These data demonstrate that ANXA1 regulates lipid metabolism of PTECs to ameliorate disease progression, hence it holds great potential as a therapeutic target for DN.

Characterization of diabetic nephropathy in a transgenic model of hypoinsulinemic diabetes

2006 ◽  
Vol 291 (6) ◽  
pp. F1315-F1322 ◽  
Author(s):  
Yukiko Kanetsuna ◽  
Keita Hirano ◽  
Michio Nagata ◽  
Maureen A. Gannon ◽  
Keiko Takahashi ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Diabetic Mice ◽  
Renal Hypertrophy ◽  
Type Iv ◽  
Mesangial Area ◽  
Matrix Expansion ◽  
Renal Changes ◽  
Complex Deposition ◽  
Genetic And Environmental Factors ◽  
Matrix Accumulation

Genetic mouse models provide a unique opportunity to investigate gene function in the natural course of the disease. Although diabetic nephropathy (DN) in models of type II diabetes has been well characterized, diabetic renal disease in hypoinsulinemic diabetic mice is still incompletely understood. Here, we characterized renal changes in the pdx1PB-HNF6 transgenic mouse that exhibits β-cell dysfunction and nonobese hypoinsulinemic diabetes. Male transgenic mice developed hyperglycemia by the age of 7 wk and survived for over 1 yr without insulin treatment. Diabetes ensued earlier and progressed more severely in the HNF6 males than the females. The HNF6 males exhibited albuminuria as early as 10 wk of age, and the urinary albumin excretion increased with age, exceeding 150 μg/24 h at 11 mo of age. Diabetic males developed renal hypertrophy after 7 wk of age, whereas glomerular hyperfiltration was not observed in the mice. Hypertension and hyperlipidemia were not observed in the diabetic mice. Histological analysis of the HNF6 kidneys displayed diabetic glomerular changes, including glomerular enlargement, diffuse mesangial proliferation and matrix expansion, thickened glomerular basement membrane, and arteriolar hyalinosis. Mesangial matrix accumulation increased with age, resulting in nodular lesions by 44 wk of age. Immunohistochemistry showed accumulation of type IV collagen and TGF-β1 in the mesangial area. No significant immune complex deposition was observed in the HNF6 glomeruli. Thus the HNF6 mouse exhibits diabetic renal changes that parallel the early phase of human DN. The model should facilitate studies of genetic and environmental factors that may affect DN in hypoinsulinemic diabetes.

All-trans retinoic acid suppresses bone morphogenetic protein 4 in mouse diabetic nephropathy through a unique retinoic acid response element

2019 ◽  
Vol 316 (3) ◽  
pp. E418-E431 ◽  
Author(s):  
Masanori Tamaki ◽  
Tatsuya Tominaga ◽  
Yui Fujita ◽  
Yasuhiko Koezuka ◽  
Go Ichien ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Retinoic Acid ◽  
Regulatory Mechanism ◽  
Bone Morphogenetic Protein 4 ◽  
Diabetic Mice ◽  
Mesangial Matrix ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Morphogenetic Protein ◽  
Matrix Expansion

Diabetic nephropathy (DN) causes mesangial matrix expansion, which results in glomerulosclerosis and renal failure. Collagen IV (COL4) is a major component of the mesangial matrix that is positively regulated by bone morphogenetic protein 4 (BMP4)/suppressor of mothers against decapentaplegic (Smad1) signaling. Because previous studies showed that retinoids treatment had a beneficial effect on kidney disease, we investigated the therapeutic potential of retinoids in DN, focusing especially on the regulatory mechanism of BMP4. Diabetes was induced with streptozotocin in 12-wk-old male Crl:CD1(ICR) mice, and, 1 mo later, we initiated intraperitoneal injection of all-trans retinoic acid (ATRA) three times weekly. Glomerular matrix expansion, which was associated with increased BMP4, phosphorylated Smad1, and COL4 expression, worsened in diabetic mice at 24 wk of age. ATRA administration alleviated DN and downregulated BMP4, phosopho-Smad1, and COL4. In cultured mouse mesangial cells, treatment with ATRA or a retinoic acid receptor-α (RARα) agonist significantly decreased BMP4 and COL4 expression. Genomic analysis suggested two putative retinoic acid response elements (RAREs) for the mouse Bmp4 gene. Chromatin immunoprecipitation analysis and reporter assays indicated a putative RARE of the Bmp4 gene, located 11,488–11,501 bp upstream of exon 1A and bound to RARα and retinoid X receptor (RXR), which suppressed BMP4 expression after ATRA addition. ATRA suppressed BMP4 via binding of a RARα/RXR heterodimer to a unique RARE, alleviating glomerular matrix expansion in diabetic mice. These findings provide a novel regulatory mechanism for treatment of DN.

Interference with TGF-β signaling by Smad3-knockout in mice limits diabetic glomerulosclerosis without affecting albuminuria

2007 ◽  
Vol 293 (5) ◽  
pp. F1657-F1665 ◽  
Author(s):  
Amy Wang ◽  
Fuad N. Ziyadeh ◽  
Eun Young Lee ◽  
Petr E. Pyagay ◽  
Sun Hee Sung ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Critical Role ◽  
Renal Involvement ◽  
Diabetic Mice ◽  
Renal Hypertrophy ◽  
Diabetic Glomerulosclerosis ◽  
Matrix Expansion ◽  
In The Wild

Transforming growth factor (TGF)-β plays a critical role in diabetic nephropathy. To isolate the contribution of one of the signaling pathways of TGF-β, the Smad3 gene in the mouse was knocked out at exons 2 and 3, and the effect was studied in streptozotocin (STZ)-induced diabetes over a period of 6 wk. TGF-β activity was increased in the diabetic mice but was not able to signal via Smad3 in the knockout (KO) mice. As expected in the wild type, the kidneys of the STZ-diabetic mice showed both structural and functional defects that are characteristic of diabetic renal involvement. In the Smad3-KO mice, however, the defects that were improved were renal hypertrophy, mesangial matrix expansion, fibronectin overproduction, glomerular basement membrane thickening, plasma creatinine, and the blood urea nitrogen. The parameters not significantly altered by the Smad3-KO were albuminuria, reduction in podocyte slit pore density, and the increase in vascular endothelial growth factor abundance and activity. It seems that the absence of Smad3 modifies the natural course of murine diabetic nephropathy, providing renal functional protection and preventing structural lesions relating to kidney hypertrophy and matrix accumulation, even though albuminuria and changes in podocyte morphology persist. In conclusion, the effects of the Smad3-KO mirror the effects of anti-TGF-β therapy in diabetes, suggesting that the chief component of TGF-β signaling that is relevant to kidney disease is the Smad3 pathway.

scholarly journals Altered renal lipid metabolism and renal lipid accumulation in human diabetic nephropathy

2013 ◽  
Vol 55 (3) ◽  
pp. 561-572 ◽  
Author(s):  
Michal Herman-Edelstein ◽  
Pnina Scherzer ◽  
Ana Tobar ◽  
Moshe Levi ◽  
Uzi Gafter
Keyword(s):  
Diabetic Nephropathy ◽  
Lipid Metabolism ◽  
Lipid Accumulation

The attenuation of diabetic nephropathy by annexin A1 via regulation of lipid metabolism through AMPK/PPARα/CPT1b pathway

Diabetes ◽  
2021 ◽  
pp. db210050
Author(s):  
Liang Wu ◽  
Changjie Liu ◽  
Dong-Yuan Chang ◽  
Rui Zhan ◽  
Mingming Zhao ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Lipid Metabolism ◽  
Annexin A1

scholarly journals CCR2 antagonism improves insulin resistance, lipid metabolism, and diabetic nephropathy in type 2 diabetic mice

2010 ◽  
Vol 78 (9) ◽  
pp. 883-894 ◽  
Author(s):  
Young Sun Kang ◽  
Mi Hwa Lee ◽  
Hye Kyoung Song ◽  
Gang Jee Ko ◽  
Oh Sung Kwon ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Diabetic Nephropathy ◽  
Lipid Metabolism ◽  
Diabetic Mice ◽  
Type 2 Diabetic

1060-P: The Effect of FGF21/GLP-1 Fusion Protein on Glucose and Lipid Metabolism Using Diabetic Mice Models

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 1060-P
Author(s):  
LIXIN GUO ◽  
QI PAN ◽  
CHAO CHEN ◽  
SHUSHAN LIN ◽  
YU LI ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Fusion Protein ◽  
Diabetic Mice ◽  
Glucose And Lipid Metabolism
Sign in / Sign up

Export Citation Format

Share Document