Can murine diabetic nephropathy be separated from superimposed acute renal failure?

Tay, Yuet‐Ching; Wang, Yiping; Kairaitis, Lukas; Rangan, Gopala K.; Zhang, Chun; Harris, David C.H.

doi:10.1111/j.1523-1755.2005.00405.x

Cited by 87 publications

(98 citation statements)

References 18 publications

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“…STZ is a DNA-alkylating reagent, and single large doses produce tubular necrosis, but repeated lower doses and the resulting hyperglycemia produce glomerular changes more typical of, but not identical to, diabetic nephropathy (29). The observations here do not rigorously rule out the possibility that the improvements in the glomeruli were secondary to the lower blood glucose levels in the treated diabetic mice.…”

Section: Discussionmentioning

confidence: 47%

“…The mice do not spontaneously develop diabetes but lack functional B and T cells and have lymphopenia and hypogammaglobulinemia together with a normal hematopoietic microenviron-ment (28). Multiple low doses of STZ were administered to the mice (Scheme 1) under conditions that tend to minimize nephrotoxicity from the drug (29). In initial experiments, we administered 35 mg͞kg STZ daily for 5 days following the protocol of Hess et al (9), but the mice either died or had to be killed after 3-5 weeks because of severe weight loss and cachexia.…”

Section: Resultsmentioning

confidence: 99%

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Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/ scid mice

Lee

Seo

Reger

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

670

556

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We tested the hypothesis that multipotent stromal cells from human bone marrow (hMSCs) can provide a potential therapy for human diabetes mellitus. Severe but nonlethal hyperglycemia was produced in NOD͞scid mice with daily low doses of streptozotocin on days 1-4, and hMSCs were delivered via intracardiac infusion on days 10 and 17. The hMSCs lowered blood glucose levels in the diabetic mice on day 32 relative to untreated controls (18.34 mM ؎ 1.12 SE vs. 27.78 mM ؎ 2.45 SE, P ‫؍‬ 0.0019). ELISAs demonstrated that blood levels of mouse insulin were higher in the hMSC-treated as compared with untreated diabetic mice, but human insulin was not detected. PCR assays detected human Alu sequences in DNA in pancreas and kidney on day 17 or 32 but not in other tissues, except heart, into which the cells were infused. In the hMSC-treated diabetic mice, there was an increase in pancreatic islets and ␤ cells producing mouse insulin. Rare islets contained human cells that colabeled for human insulin or PDX-1. Most of the ␤ cells in the islets were mouse cells that expressed mouse insulin. In kidneys of hMSC-treated diabetic mice, human cells were found in the glomeruli. There was a decrease in mesangial thickening and a decrease in macrophage infiltration. A few of the human cells appeared to differentiate into glomerular endothelial cells. Therefore, the results raised the possibility that hMSCs may be useful in enhancing insulin secretion and perhaps improving the renal lesions that develop in patients with diabetes mellitus.insulin ͉ pancreas ͉ streptozotocin ͉ transplantation P revious publications presented conflicting observations as to whether cells from bone marrow can provide a potential therapy for diabetes mellitus. One strategy (1-4) was to differentiate plastic adherent marrow cells in culture into insulin-secreting cells. A second strategy was to transplant diabetic mice with genetically labeled marrow and to search for labeled insulinproducing cells in the recipient mice. One study using a CRELoxP-GFP system found that 1.7-3% of the cells in islets of the recipient mice were marrow-derived and that GFP-labeled donor cells isolated from the islets expressed insulin, glucose transporter 2, and transcription factors typically found in ␤ cells (5). Three subsequent reports in which mice were transplanted with GFPexpressing bone marrow did not find evidence of marrow cells becoming insulin-producing cells in the pancreas of recipient mice (6-8), but in the reports it was difficult to exclude the possibility that the GFP gene was inactivated or that GFP-labeled cells were destroyed as they engrafted into islets. A third strategy was to determine whether systemically administered marrow cells enhanced regeneration of pancreatic insulin-producing cells in diabetic models. Hess et al. (9) reported that in NOD͞scid mice in which diabetes was induced with streptozotocin (STZ), partial marrow ablation followed by transplantation of either GFP-labeled whole-marrow or GFP-labeled c-kit ϩ cells from murine marrowenhanced r...

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Section: Discussionmentioning

confidence: 47%

Section: Resultsmentioning

confidence: 99%

Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/ scid mice

Lee

Seo

Reger

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

670

556

View full text Add to dashboard Cite

show abstract

“…Therefore, we postulate that the HO-2 deletion is responsible for the impairment in renal functional and histologic alterations that were observed and amplified as a result of STZ-induced diabetes in HO-2 (Ϫ/Ϫ) mice. Recently, Tay et al (18) also reported STZ-induced renal toxicity with acute tubular necrosis in the murine model of diabetic nephropathy. Consonant with our findings in the wild type, renal functional impairment without evidence of histologic damage was noted even at very low doses of STZ (75 mg/kg) by these authors.…”

Section: Discussionmentioning

confidence: 99%

“…On the basis of our data, it is clear that HO-2 deficiency per se contributes to renal dysfunction. It is known that STZ alone may be an instigator of the renal tissue injury manifested by an increase in plasma creatinine and tubular injury and expression of Ig antigen (18,45).…”

Section: Discussionmentioning

confidence: 99%

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Heme Oxygenase-2 Deficiency Contributes to Diabetes-Mediated Increase in Superoxide Anion and Renal Dysfunction

Goodman¹,

Chander²,

Rezzani³

et al. 2006

Journal of the American Society of Nephrology

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Heme oxygenase-1 (HO-1) and -2 play an important role in cytoprotection and are physiologic regulators of heme-dependent protein synthesis in renal tissues. The impact of HO-2 deletion comparing hyperglycemic HO-2 (؉/؉) mice and HO-2 knockout (؊/؊) mice was examined. Hyperglycemia was induced by streptozotocin (STZ) injection, and its effect on renal HO-1/HO-2 protein, HO activity, and creatinine levels were assessed. The effect of HO induction using systemic administration of the HO inducers heme or cobalt protoporphyrin and the effect of HO inhibition using systemic administration of the HO inhibitor tin mesoporphyrin also were assessed in STZ-treated mice. In STZ-treated HO-2 (؊/؊) mice, there was marked renal functional impairment as reflected by an increase in plasma creatinine, associated with acute tubular damage and microvascular pathology as compared with HO-2 (؉/؉). In these animals, HO activity was decreased with a concomitant increase in superoxide anion. Upregulation of HO-1 in HO-2 (؊/؊) mice by weekly administration of cobalt protoporphyrin prevented the increase in plasma creatinine levels and tubulointerstitial and microvascular pathology. Inhibition of HO activity by administration of tin mesoporphyrin accentuated superoxide production and increased creatinine levels in hyperglycemic HO-2 (؊/؊) mice. In conclusion, HO-2 deficiency enhanced STZ-induced renal dysfunction and morphologic injury and HO-1 upregulation in HO-2 (؊/؊) mouse rescue and prevented the morphologic damage. These observations indicate that HO activity is essential in preserving renal function and morphology in STZ-induced diabetic mice probably via mitigation of concomitant oxidative stress.

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Mouse Models for Studying Diabetic Nephropathy

Chow

Allen

2015

CP Mouse Biology

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Diabetic nephropathy (DN) is a term used to describe kidney damage cause by diabetes. With DN as one of the leading causes of end-stage renal disease worldwide, there is a strong need for appropriate animal models to study DN pathogenesis and develop therapeutic strategies. To date, most experiments are carried out in mouse models as opposed to other species for several reasons including lower cost, ease of handling, and easy manipulation of the mouse genome to generate transgenic and knockout animals. This unit provides detailed insights and technical knowledge in setting up one of the most widely used models of DN, the streptozotocin (STZ)-induced model. This model has been extensively exploited to study the mechanism of diabetic renal injury. The advantages and limitations of the STZ model and the availability of other genetic models of DN are also discussed.

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Can murine diabetic nephropathy be separated from superimposed acute renal failure?

Cited by 87 publications

References 18 publications

Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/ scid mice

Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/ scid mice

Heme Oxygenase-2 Deficiency Contributes to Diabetes-Mediated Increase in Superoxide Anion and Renal Dysfunction

Mouse Models for Studying Diabetic Nephropathy

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