Mouse Models of Diabetic Nephropathy

Brosius, Frank C.; Alpers, Charles E.; Böttinger, Erwin P.; Breyer, Matthew D.; Coffman, Thomas M.; Gurley, Susan B.; Harris, Raymond C.; Kakoki, Masao; Kretzler, Matthias; Leiter, Edward H.; Levi, Moshe; McIndoe, Richard A.; Sharma, Kumar; Smithies, Oliver; Suszták, Katalin; Takahashi, Nobuyuki; Takahashi, Takamune

doi:10.1681/asn.2009070721

Cited by 600 publications

(452 citation statements)

References 72 publications

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“…To determine whether the transcriptomic predictions resulted in functional alterations, we determined changes in metabolite levels in kidney cortex from 12-and 24-week-old diabetic and control mice, corresponding to early and established DKD, respectively (14,15). Kidney cortex was analyzed using targeted liquid chromatography-MS (LC/MS) and gas chromatography-MS (GC/MS) for ~65 metabolites representing central carbon metabolism, including acyl-CoAs, acylcarnitines, and amino acids, as well as metabolites in glycolysis, the pentose phosphate pathway, and the TCA cycle ( Figure 1C and Supplemental Table 2).…”

Section: Resultsmentioning

confidence: 99%

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Tissue-specific metabolic reprogramming drives nutrient flux in diabetic complications

Sas¹,

Kayampilly²,

Byun³

et al. 2016

JCI Insight

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Section: Resultsmentioning

confidence: 99%

“…Male BKS db/db mice (BKS.Cg-m +/+ Lepr db /J) and littermate controls (db/+) were used at 12 and 24 weeks of age, corresponding to very early and established, but still early, DKD, respectively (14,15). Prior to sacrifice and following a 2-hour fast, blood and urine were collected.…”

Section: Methodsmentioning

confidence: 99%

Tissue-specific metabolic reprogramming drives nutrient flux in diabetic complications

Sas¹,

Kayampilly²,

Byun³

et al. 2016

JCI Insight

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216

218

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“…We induced type 1 diabetes in uninephrectomized male mice with a low dose STZ injection (at 5 weeks of age) (33). Albuminuria was highly increased in diabetic NPHS2 Cre …”

Section: And D)mentioning

confidence: 99%

Wnt/β-Catenin Pathway in Podocytes Integrates Cell Adhesion, Differentiation, and Survival

Kato

Gruenwald

Suh

et al. 2011

Journal of Biological Chemistry

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193

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Diabetic kidney disease (DKD) is the single most common cause of albuminuria and end-stage kidney disease in the UnitedStates. We found increased expression of Wnt/␤-catenin (Ctnnb1) pathway transcripts and proteins in glomeruli and podocytes of patients and mouse models of DKD. Mice with podocyte-specific expression of stabilized Ctnnb1 exhibited basement membrane abnormalities, albuminuria, and increased susceptibility to glomerular injury. Mice with podocyte-specific deletion of Ctnnb1 or podocyte-specific expression of the canonical Wnt inhibitor Dickkopf-related protein 1 (Dkk1) also showed increased susceptibility to DKD. Podocytes with stabilized Ctnnb1 were less motile and less adhesive to different matrices. Deletion of Ctnnb1 in cultured podocytes increased the expression of podocyte differentiation markers and enhanced cell motility; however, these cells were more susceptible to apoptosis. These results indicate that Wnt/Ctnnb1 signaling in podocytes plays a critical role in integrating cell adhesion, motility, cell death, and differentiation. Balanced Ctnnb1 expression is critical for glomerular filtration barrier maintenance. Diabetic kidney disease (DKD)2 is one of the most devastating complications of diabetes and the single most common cause of albuminuria, chronic kidney disease, and end-stage renal disease (ESRD) in the Western world (1). DKD causes filtration unit dysfunction leading to the development of albuminuria, which is the most abundant protein component of the blood. The glomerular filtration barrier consists of three layers as follows: glomerular endothelial cells, the glomerular basement membrane (GBM), and the glomerular epithelial cell (or podocyte) layer (2-4). Decreased glomerular podocyte density is shown to be the strongest predictor for end-stage renal disease development in patients with diabetes (5). Hyperglycemia via the generation of reactive oxygen species induces podocyte apoptosis and loss, which has been well documented in many different mouse DKD models (6, 7). As podocytes are terminally differentiated cells, they are unable to proliferate; therefore, apoptosis or detachment can lead to podocyte deficiency, which in turn will lead to glomerulosclerosis development (8, 9). Early administration of drugs that prevent podocyte apoptosis has been shown to ameliorate DKD in rodent models; however, this may not be a clinically translatable strategy (6, 10). Another early lesion in diabetes is the thickening of the basement membrane. The role and mechanism of GBM thickening are not fully understood. It is speculated that GBM thickening could cause alterations in integrin expression, which could interfere with podocyte adhesiveness. Genetic deletion of podocyte-specific integrins, Itgb1 and Itga3, causes albuminuria and glomerulosclerosis; however, the contribution of podocyte adhesion to DKD development has not been demonstrated (11,12). Understanding the mechanism of podocyte differentiation, adhesion and cell death could be highly relevant for the development of targets f...

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“…We employed the db/db mouse for these studies, one of the most widely used models of type 2 diabetes mellitus (Sharma et al 2003;Tesch and Lim 2011). Although this model has shortcomings (Breyer et al 2005;Brosius et al 2009;Breyer 2012), these mice do recapitulate early renal consequences of systemic hyperglycemia, such as the development of glomerular hyperfiltration (elevated glomerular filtration rate (GFR) above the normal filtration rates), increased albuminuria and some histopathologic changes. Metabolomic comparisons of urinary metabolites show similarities between this mouse model and type 2 diabetic humans (Salek et al 2007).…”

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confidence: 99%

Hyperbaric oxygen therapy (HBOT) suppresses biomarkers of cell stress and kidney injury in diabetic mice

Verma

Chopra

Giardina

et al. 2015

Cell Stress and Chaperones

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The disease burden from diabetic kidney disease is large and growing. Effective therapies are lacking, despite an urgent need. Hyperbaric oxygen therapy (HBOT) activates Nrf2 and cellular antioxidant defenses; therefore, it may be generally useful for treating conditions that feature chronic oxidative tissue damage. Herein, we determined how periodic exposure to oxygen at elevated pressure affected type 2 diabetes mellitus-related changes in the kidneys of db/db mice. Two groups of db/db mice, designated 2.4 ATA and 1.5 ATA, were treated four times per week with 100 % oxygen at either 1.5 or 2.4 ATA (atmospheres absolute) followed by tests to assess kidney damage and function. The sham group of db/db mice and the Hets group of db/+ mice were handled but did not receive HBOT. Several markers of kidney damage were reduced significantly in the HBOT groups including urinary biomarkers neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C (CyC) along with significantly lower levels of caspase-3 activity in kidney tissue extracts. Other stress biomarkers also showed trends to improvement in the HBOT groups, including urinary albumin levels. Expressions of the stress response genes NRF2, HMOX1, MT1, and HSPA1A were reduced in the HBOT groups at the end of the experiment, consistent with reduced kidney damage in treated mice. Urinary albumin/creatinine ratio (ACR), a measure of albuminuria, was significantly reduced in the db/db mice receiving HBOT. All of the db/db mouse groups had qualitatively similar changes in renal histopathology. Glycogenated nuclei, not previously reported in db/db mice, were observed in these three experimental groups but not in the control group of nondiabetic mice. Overall, our findings are consistent with therapeutic HBOT alleviating stress and damage in the diabetic kidney through cytoprotective responses. These findings support an emerging paradigm in which tissue oxygenation and cellular defenses effectively limit damage from chronic oxidative stress more effectively than chemical antioxidants.

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Mouse Models of Diabetic Nephropathy

Cited by 600 publications

References 72 publications

Tissue-specific metabolic reprogramming drives nutrient flux in diabetic complications

Tissue-specific metabolic reprogramming drives nutrient flux in diabetic complications

Wnt/β-Catenin Pathway in Podocytes Integrates Cell Adhesion, Differentiation, and Survival

Hyperbaric oxygen therapy (HBOT) suppresses biomarkers of cell stress and kidney injury in diabetic mice

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