Mouse model of immune complex–mediated kidney disease

Abstract Chronic Kidney Disease is a growing problem across the world and can lead to end-stage kidney disease and cardiovascular disease. Fibrosis is the underlying mechanism that leads to organ dysfunction, but as yet we have no therapeutics that can influence this process. Ras monomeric GTPases are master regulators that direct many of the cytokines known to drive fibrosis to downstream effector cascades. We have previously shown that K-Ras is a key isoform that drives fibrosis in the kidney. Here we demonstrate that K-Ras expression and activation are increased in rodent models of CKD. By knocking down expression of K-Ras using antisense oligonucleotides in a mouse model of chronic folic acid nephropathy we can reduce fibrosis by 50% and prevent the loss of renal function over 3 months. In addition, we have demonstrated in vitro and in vivo that reduction of K-Ras expression is associated with a reduction in Jag1 expression; we hypothesise this is the mechanism by which targeting K-Ras has therapeutic benefit. In conclusion, targeting K-Ras expression with antisense oligonucleotides in a mouse model of CKD prevents fibrosis and protects against renal dysfunction.

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The effects of type 1 IGF receptor inhibition in a mouse model of diabetic kidney disease

Growth Hormone & IGF Research ◽

10.1016/j.ghir.2011.07.007 ◽

2011 ◽

Vol 21 (5) ◽

pp. 285-291 ◽

Cited By ~ 1

Author(s):

Ariel Troib ◽

Daniel Landau ◽

Jack F. Youngren ◽

Leonid Kachko ◽

Ralph Rabkin ◽

...

Keyword(s):

Kidney Disease ◽

Mouse Model ◽

Diabetic Kidney Disease ◽

Diabetic Kidney ◽

Receptor Inhibition ◽

Igf Receptor

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Diabetic kidney disease in thedb/dbmouse

AJP Renal Physiology ◽

10.1152/ajprenal.00315.2002 ◽

2003 ◽

Vol 284 (6) ◽

pp. F1138-F1144 ◽

Cited By ~ 267

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.

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Nicotinamide Attenuates the Progression of Renal Failure in a Mouse Model of Adenine-Induced Chronic Kidney Disease

Toxins ◽

10.3390/toxins13010050 ◽

2021 ◽

Vol 13 (1) ◽

pp. 50

Author(s):

Satoshi Kumakura ◽

Emiko Sato ◽

Akiyo Sekimoto ◽

Yamato Hashizume ◽

Shu Yamakage ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Renal Failure ◽

Kidney Disease ◽

Mouse Model ◽

Metabolic Pathways ◽

Krebs Cycle ◽

Inflammatory Reactions ◽

Progression Of Kidney Disease ◽

Progression Of Renal Failure

Nicotinamide adenine dinucleotide (NAD+) supplies energy for deoxidation and anti-inflammatory reactions fostering the production of adenosine triphosphate (ATP). The kidney is an essential regulator of body fluids through the excretion of numerous metabolites. Chronic kidney disease (CKD) leads to the accumulation of uremic toxins, which induces chronic inflammation. In this study, the role of NAD+ in kidney disease was investigated through the supplementation of nicotinamide (Nam), a precursor of NAD+, to an adenine-induced CKD mouse model. Nam supplementation reduced kidney inflammation and fibrosis and, therefore, prevented the progression of kidney disease. Notably, Nam supplementation also attenuated the accumulation of glycolysis and Krebs cycle metabolites that occurs in renal failure. These effects were due to increased NAD+ supply, which accelerated NAD+-consuming metabolic pathways. Our study suggests that Nam administration may be a novel therapeutic approach for CKD prevention.

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Effect of Trehalose Supplementation on Autophagy and Cystogenesis in a Mouse Model of Polycystic Kidney Disease

Nutrients ◽

10.3390/nu11010042 ◽

2018 ◽

Vol 11 (1) ◽

pp. 42 ◽

Cited By ~ 9

Author(s):

Li-Fang Chou ◽

Ya-Lien Cheng ◽

Chun-Yih Hsieh ◽

Chan-Yu Lin ◽

Huang-Yu Yang ◽

...

Keyword(s):

Drinking Water ◽

Kidney Disease ◽

Mouse Model ◽

Polycystic Kidney Disease ◽

Renal Cyst ◽

Pure Water ◽

Immunohistochemical Analysis ◽

Positive Staining ◽

Wild Type ◽

Polycystic Kidney

Autophagy impairment has been demonstrated in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD) and could be a new target of treatment. Trehalose is a natural, nonreducing disaccharide that has been shown to enhance autophagy. Therefore, we investigated whether trehalose treatment reduces renal cyst formation in a Pkd1-hypomorphic mouse model. Pkd1 miRNA transgenic (Pkd1 miR Tg) mice and wild-type littermates were given drinking water supplemented with 2% trehalose from postnatal day 35 to postnatal day 91. The control groups received pure water or 2% sucrose for the control of hyperosmolarity. The effect on kidney weights, cystic indices, renal function, cell proliferation, and autophagic activities was determined. We found that Pkd1 miR Tg mice had a significantly lower renal mRNA expression of autophagy-related genes, including atg5, atg12, ulk1, beclin1, and p62, compared with wild-type control mice. Furthermore, immunohistochemical analysis showed that cystic lining cells had strong positive staining for the p62 protein, indicating impaired degradation of the protein by the autophagy-lysosome pathway. However, trehalose treatment did not improve reduced autophagy activities, nor did it reduce relative kidney weights, plasma blood urea nitrogen levels, or cystatin C levels in Pkd1 miR Tg mice. Histomorphological analysis revealed no significant differences in the renal cyst index, fibrosis score, or proliferative score among trehalose-, sucrose-, and water-treated groups. Our results demonstrate that adding trehalose to drinking water does not modulate autophagy activities and renal cystogenesis in Pkd1-deficient mice, suggesting that an oral supplement of trehalose may not affect the progression of ADPKD.

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