Caveolin-1 deficiency protects against mesangial matrix expansion in a mouse model of type 1 diabetic nephropathy

Diabetologia ◽  
2013 ◽  
Vol 56 (9) ◽  
pp. 2068-2077 ◽  
Author(s):  
T. H. Guan ◽  
G. Chen ◽  
B. Gao ◽  
M. R. Janssen ◽  
L. Uttarwar ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Mouse Model ◽  
Mesangial Matrix ◽  
Caveolin 1 ◽  
Matrix Expansion

Diabetic kidney disease in thedb/dbmouse

2003 ◽  
Vol 284 (6) ◽  
pp. F1138-F1144 ◽  
Author(s):  
Kumar Sharma ◽  
Peter McCue ◽  
Stephen R. Dunn
Keyword(s):  
Diabetic Nephropathy ◽  
Kidney Disease ◽  
Mouse Model ◽  
Renal Disease ◽  
Mouse Models ◽  
Diabetic Kidney Disease ◽  
Diabetic Kidney ◽  
Matrix Expansion ◽  
Stage Renal Disease ◽  
End Stage

Diabetic nephropathy is increasing in incidence and is now the number one cause of end-stage renal disease in the industrialized world. To gain insight into the genetic susceptibility and pathophysiology of diabetic nephropathy, an appropriate mouse model of diabetic nephropathy would be critical. A large number of mouse models of diabetes have been identified and their kidney disease characterized to various degrees. Perhaps the best characterized and most intensively investigated model is the db/ db mouse. Because this model appears to exhibit the most consistent and robust increase in albuminuria and mesangial matrix expansion, it has been used as a model of progressive diabetic renal disease. In this review, we present the findings from various studies on the renal pathology of the db/ db mouse model of diabetes in the context of human diabetic nephropathy. Furthermore, we discuss shortfalls of assessing functional renal disease in mouse models of diabetic kidney disease.

scholarly journals Expression of Smad1 is directly associated with mesangial matrix expansion in rat diabetic nephropathy

2006 ◽  
Vol 86 (4) ◽  
pp. 357-368 ◽  
Author(s):  
Takeshi Matsubara ◽  
Hideharu Abe ◽  
Hidenori Arai ◽  
Kojiro Nagai ◽  
Akira Mima ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Mesangial Matrix ◽  
Matrix Expansion

scholarly journals Urinary Smad1 Is a Novel Marker to Predict Later Onset of Mesangial Matrix Expansion in Diabetic Nephropathy

Diabetes ◽  
2008 ◽  
Vol 57 (6) ◽  
pp. 1712-1722 ◽  
Author(s):  
A. Mima ◽  
H. Arai ◽  
T. Matsubara ◽  
H. Abe ◽  
K. Nagai ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Mesangial Matrix ◽  
Matrix Expansion

scholarly journals Mesangial matrix expansion in a novel mouse model of diabetic kidney disease associated with the metabolic syndrome

2020 ◽  
Vol 10 (2) ◽  
pp. e17-e17
Author(s):  
Elisabet Van Loon ◽  
Joseph Pierre Aboumsallem ◽  
Evelyne Lerut ◽  
Marija Bogojevic ◽  
Aleksandar Denic ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Kidney Disease ◽  
Mouse Model ◽  
Diabetic Kidney Disease ◽  
Mesangial Matrix ◽  
Diabetic Kidney ◽  
The Metabolic Syndrome ◽  
Matrix Expansion

Increased class A scavenger receptor and glomerular lipid precede mesangial matrix expansion in the bGH mouse model

2010 ◽  
Vol 20 (4) ◽  
pp. 326-332 ◽  
Author(s):  
Sonia Q. Doi ◽  
Geetha C. Chilakamarri ◽  
Maria C. Mendonca ◽  
Magali Araujo ◽  
Nga Nguyen ◽  
...  
Keyword(s):  
Mouse Model ◽  
Scavenger Receptor ◽  
Mesangial Matrix ◽  
Class A ◽  
Matrix Expansion ◽  
Class A Scavenger Receptor

scholarly journals Senescence marker protein‐30/gluconolactonase deficiency exacerbates diabetic nephropathy through tubular injury in a mouse model of type 1 diabetes

2014 ◽  
Vol 6 (1) ◽  
pp. 35-43 ◽  
Author(s):  
Hiroshi Okada ◽  
Takafumi Senmaru ◽  
Michiaki Fukui ◽  
Yoshitaka Kondo ◽  
Akihito Ishigami ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Diabetic Nephropathy ◽  
Mouse Model ◽  
Marker Protein ◽  
Tubular Injury

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.

scholarly journals Accumulation of worn-out GBM material substantially contributes to mesangial matrix expansion in diabetic nephropathy

2017 ◽  
Vol 312 (6) ◽  
pp. F1101-F1111 ◽  
Author(s):  
Wilhelm Kriz ◽  
Jana Löwen ◽  
Giuseppina Federico ◽  
Jacob van den Born ◽  
Elisabeth Gröne ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Diabetic Nephropathy ◽  
In Situ Hybridization ◽  
Mesangial Cells ◽  
Collagen Iv ◽  
Mesangial Matrix ◽  
Electron Microscopic ◽  
Matrix Expansion ◽  
Production Mechanisms

Thickening of the glomerular basement membrane (GBM) and expansion of the mesangial matrix are hallmarks of diabetic nephropathy (DN), generally considered to emerge from different sites of overproduction: GBM components from podocytes and mesangial matrix from mesangial cells. Reevaluation of 918 biopsies with DN revealed strong evidence that these mechanisms are connected to each other, wherein excess GBM components fail to undergo degradation and are deposited in the mesangium. These data do not exclude that mesangial cells also synthesize components that contribute to the accumulation of matrix in the mesangium. Light, electron microscopic, immunofluorescence, and in situ hybridization studies clearly show that the thickening of the GBM is due not only to overproduction of components of the mature GBM (α3 and α5 chains of collagen IV and agrin) by podocytes but also to resumed increased synthesis of the α1 chain of collagen IV and of perlecan by endothelial cells usually seen during embryonic development. We hypothesize that these abnormal production mechanisms are caused by different processes: overproduction of mature GBM-components by the diabetic milieu and regression of endothelial cells to an embryonic production mode by decreased availability of mediators from podocytes.

scholarly journals Effects of cholesterol-tagged small interfering RNAs targeting 12/15-lipoxygenase on parameters of diabetic nephropathy in a mouse model of type 1 diabetes

2008 ◽  
Vol 295 (2) ◽  
pp. F605-F617 ◽  
Author(s):  
Hang Yuan ◽  
Linda Lanting ◽  
Zhong-Gao Xu ◽  
Shu-Lian Li ◽  
Piotr Swiderski ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Diabetic Nephropathy ◽  
Growth Factor ◽  
Mouse Model ◽  
Tissue Growth ◽  
Type I ◽  
Small Interfering Rnas ◽  
Matrix Deposition

We previously showed that the 12/15-lipoxygenase (12/15-LO) pathway of arachidonate acid metabolism is involved in multiple events related to diabetic nephropathy (DN), including glomerular hypertrophy and extracellular matrix deposition (Kang SW, Adler SG, Nast CC, LaPage J, Gu JL, Nadler JL, Natarajan R. Kidney Int 59: 1354–1362, 2001; Kang SW, Natarajan R, Shahed A, Nast CC, LaPage J, Mundel P, Kashtan C, Adler SG. J Am Soc Nephrol 14: 3178–3187, 2003; Kim YS, Lanting L, Adler SG, Natarajan R. Kindney Int 64: 1702–1714, 2003; Reddy MA, Adler SG, Kim YS, Lanting L, Rossi JJ, Kang SW, Nadler JL, Shahed A, Natarajan R. Am J Physiol Renal Physiol 283: F985–F994, 2002). In this study, we investigated whether in vivo delivery of small interfering RNAs (siRNAs) targeting 12/15-LO can ameliorate renal injury and DN in a streptozotocin-injected mouse model of type 1 diabetes. To achieve greater in vivo access and siRNA expression in the kidney, we used double-stranded 12/15-LO siRNA oligonucleotides conjugated with cholesterol. Diabetic DBA/2J mice were injected subcutaneously with either cholesterol-tagged 12/15-LO siRNA, mismatched control siRNA, or vehicle alone, twice weekly for 7 wk. Relative to controls, mice that received 12/15-LO siRNA showed significant reduction in albuminuria, kidney-to-body weight ratios, glomerular mesangial matrix expansion, renal structural damage, and monocyte/macrophage infiltration. These effects were associated with lower renal cortical or glomerular levels of profibrotic markers transforming growth factor-β, connective tissue growth factor, type I and type IV collagens, plasminogen activator inhibitor 1, and fibronectin. The diabetes-induced increase in glomerular cyclin-dependent kinase inhibitors that are associated with hypertrophy was also prevented by siRNA administration. Our results show for the first time that systemic delivery of cholesterol-tagged siRNAs targeting 12/15-LO has renoprotective effects under diabetic conditions and therefore could be a novel therapeutic approach for DN.

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