Extent and Persistence of Streptozotocin-Induced DNA Damage and Cell Proliferation in Rat Kidney as Determined by in Vivo Alkaline Elution and BrdUrd Labeling Assays

Kraynak, Andrew R.; Storer, Richard D.; Jensen, R; Kloss, Michelle W.; Soper, Keith A.; Clair, James St.; DeLuca, John G.; Nichols, Warren W.; Eydelloth, R. S.

doi:10.1006/taap.1995.1234

Cited by 61 publications

(46 citation statements)

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“…Our data suggest that some of the detrimental effects of hyperglycemia/hypoinsulinemia together with STZ per se were recovered after ϳ2-5 wk. Similarly, in rat kidneys, STZ-induced DNA damage seemed to be recovered in ϳ3 wk (27). The results shown are not explained by the different survival rates of animals in different groups, because only one mouse died in both the 3-wk and 5-wk groups.…”

Section: Discussionmentioning

confidence: 48%

Altered REDD1, myostatin, and Akt/mTOR/FoxO/MAPK signaling in streptozotocin-induced diabetic muscle atrophy

Hulmi

Silvennoinen

Lehti

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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Hulmi JJ, Silvennoinen M, Lehti M, Kivelä R, Kainulainen H. Altered redd1, myostatin, and Akt/mTOR/FoxO/MAPK signaling in streptozotocin-induced diabetic muscle atrophy. Am J Physiol Endocrinol Metab 302: E307-E315, 2012. First published November 8, 2011 doi:10.1152/ajpendo.00398.2011.-Type 1 diabetes, if poorly controlled, leads to skeletal muscle atrophy, decreasing the quality of life. We aimed to search highly responsive genes in diabetic muscle atrophy in a common diabetes model and to further characterize associated signaling pathways. Mice were killed 1, 3, or 5 wk after streptozotocin or control. Gene expression of calf muscles was analyzed using microarray and protein signaling with Western blotting. We identified translational repressor protein REDD1 (regulated in development and DNA damage responses) that increased seven-to eightfold and was associated with muscle atrophy in diabetes. The diabetes-induced increase in REDD1 was confirmed at the protein level. This result was accompanied by the increased gene expression of DNA damage/repair pathways and decreased expression in ATP production pathways. Concomitantly, increased phosphorylation of AMPK and dephosphorylation of the Akt/mTOR/S6K1/FoxO pathway of proteins were observed together with increased protein ubiquitination. These changes were especially evident during the first 3 wk, along with the strong decrease in muscle mass. Diabetes also induced an increase in myostatin protein and decreased MAPK signaling. These, together with decreased serum insulin and increased serum glucose, remained altered throughout the 5-wk period. In conclusion, diabetic myopathy induced by streptozotocin led to alteration of multiple signaling pathways. Of those, increased REDD1 and myostatin together with decreased Akt/mTOR/FoxO signaling are associated with diabetic muscle atrophy. The increased REDD1 and decreased Akt/mTOR/FoxO signaling followed a similar time course and thus may be explained, in part, by increased expression of genes in DNA damage/repair and possibly also decrease in ATP-production pathways.

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Section: Discussionmentioning

confidence: 48%

Altered REDD1, myostatin, and Akt/mTOR/FoxO/MAPK signaling in streptozotocin-induced diabetic muscle atrophy

Hulmi

Silvennoinen

Lehti

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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“…However, STZ toxic effects are generally seen in shorter term studies. 27 Nonetheless, ␤-actin levels were not decreased by STZ. Furthermore, these animals might also be expected to have upregulated (RAAS) activity.…”

Section: Discussionmentioning

confidence: 95%

Reduced Expression of Insulin Receptors in the Kidneys of Insulin-Resistant Rats

Tiwari¹,

Halagappa²,

Riazi³

et al. 2007

Journal of the American Society of Nephrology

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Insulin resistance is accompanied by hyperinsulinemia and activation of the renin-angiotensin system, both of which are associated with hypertension. Because the kidney plays a major role in the regulation of blood pressure, we studied the regulation of insulin receptor expression in the kidney during states of insulin resistance. Using two rat models of insulin resistance, Western blot analysis demonstrated a significant reduction in the expression of insulin receptor subunits in the kidney compared to lean control rats. Treatment of insulin resistance in Zucker rats with the insulin-sensitizing drug rosiglitazone partially restored renal insulin receptor levels. Conversely, treatment with the angiotensin II type 1 receptor (AT1) antagonist candesartan increased renal insulin receptor expression compared to untreated rats. Streptozotocin-induced hyperglycemia, which results from hypoinsulinemia, reduced expression of renal insulin receptors. Hyperinsulinemia induced by insulin infusion, however, did not produce a similar effect. In conclusion, insulin receptors are downregulated in the kidneys of insulin resistant rats, possibly mediated by hyperglycemia and angiotensin II.

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“…However, its toxicity to ␤-cells has been frequently reported to be accompanied by aspecific detrimental effects to other tissues, particularly in high dose treatment regimens (5,8,10,11,33). This phenomenon is well known and limits the use of the STZ-induced diabetic rodent model in DN research (1-3).…”

Section: Discussionmentioning

confidence: 99%

“…However, besides ␤-cells, other tissues such as the kidney are also susceptible to STZ toxicity (5,6), making it difficult to distinguish between DN-related events and direct effects of STZ in these organs. In this regard, single high doses of STZ have a nonspecific cytotoxic effect that causes acute kidney damage in rodents (7)(8)(9). In addition, STZ induces direct damage to the liver, causing lipid peroxidation, mitochondrial swelling, and peroxisome proliferation, which occur before the onset of hyperglycemia (10).…”

Section: Streptozotocin (Stz)mentioning

confidence: 99%

Phlorizin Pretreatment Reduces Acute Renal Toxicity in a Mouse Model for Diabetic Nephropathy

Brouwers

Pruniau

Cauwelier

et al. 2013

Journal of Biological Chemistry

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Background:The diabetogenic agent streptozotocin (STZ) induces direct kidney injury, which is a setback in diabetic nephropathy (DN) research. Results: The Sglt inhibitor phlorizin reduces STZ uptake and hence toxicity in the kidneys. Conclusion: In the kidney, STZ toxicity is mediated by Sglts. Significance: Using the proposed STZ regimen, researchers can now induce DN without direct damage to proximal tubuli.

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Extent and Persistence of Streptozotocin-Induced DNA Damage and Cell Proliferation in Rat Kidney as Determined by in Vivo Alkaline Elution and BrdUrd Labeling Assays

Cited by 61 publications

References 0 publications

Altered REDD1, myostatin, and Akt/mTOR/FoxO/MAPK signaling in streptozotocin-induced diabetic muscle atrophy

Altered REDD1, myostatin, and Akt/mTOR/FoxO/MAPK signaling in streptozotocin-induced diabetic muscle atrophy

Reduced Expression of Insulin Receptors in the Kidneys of Insulin-Resistant Rats

Phlorizin Pretreatment Reduces Acute Renal Toxicity in a Mouse Model for Diabetic Nephropathy

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