Lowering blood pressure blocks mesangiolysis and mesangial nodules, but not tubulointerstitial injury, In Diabetic eNOS knockout mice

Tomoki Kosugi, Marcelo Heinig, Takahiro Nakayama, Thomas Connor, Yukio Yuzawa, Qiuhong Li, William W. Hauswirth, Maria B. Grant, Byron P. Croker, Martha Campbell-Thompson, Li Zhang, Mark A. Atkinson, Mark S. Segal, Takahiko Nakagawa

Research output: Contribution to journalArticle

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Abstract

Recently, we and others reported that diabetic endothelial nitric oxide synthase knockout (eNOSKO) mice develop advanced glomerular lesions that include mesangiolysis and nodular lesions. Interestingly, insulin treatment lowered blood pressure and prevented renal lesions, raising the question as to whether these beneficial effects of insulin were due to its ability to lower either high glucose levels or high blood pressure. We, therefore, examined the effect of lowering blood pressure using hydralazine in this diabetic eNOSKO mouse model. Hydralazine treatment significantly blocked the development of me- sangiolysis and microaneurysms, whereas tubulointerstitial injury was not prevented in these mice. Additionally, hydralazine did not reduce expression levels of either tubulointerstitial thrombospondin-1 or transforming growth factor-β despite controlling blood pressure. On the other hand, the critical role of high glucose levels on the development of tubuloin- terstitial injury was suggested by the observation that serum glucose levels were correlated with tubuloin- terstitial injury, as well as with the expression levels of both transforming growth factor-β and throm bospondin-1. Importantly, controlling blood glucose with insulin completely blocked tubulointerstitial injury in diabetic eNOSKO mice. These data suggest that glomerular injury is dependent on systemic blood pressure, whereas hyperglycemia may have a more important role in tubulointerstitial injury, possibly due to the stimulation of the thrombospondin-1-transforming growth factor-β pathway in diabetic eNOSKO mice. This study could provide insights into the pathogenesis of advanced diabetic nephropathy in the presence of endothelial dysfunction.

Original languageEnglish
Pages (from-to)1221-1229
Number of pages9
JournalAmerican Journal of Pathology
Volume174
Issue number4
DOIs
Publication statusPublished - 01-01-2009
Externally publishedYes

Fingerprint

Knockout Mice
Nitric Oxide Synthase Type III
Blood Pressure
Hydralazine
Wounds and Injuries
Transforming Growth Factors
Thrombospondin 1
Insulin
Glucose
Diabetic Nephropathies
Hyperglycemia
Blood Glucose
Hypertension
Kidney
Serum

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

Cite this

Kosugi, Tomoki ; Heinig, Marcelo ; Nakayama, Takahiro ; Connor, Thomas ; Yuzawa, Yukio ; Li, Qiuhong ; Hauswirth, William W. ; Grant, Maria B. ; Croker, Byron P. ; Campbell-Thompson, Martha ; Zhang, Li ; Atkinson, Mark A. ; Segal, Mark S. ; Nakagawa, Takahiko. / Lowering blood pressure blocks mesangiolysis and mesangial nodules, but not tubulointerstitial injury, In Diabetic eNOS knockout mice. In: American Journal of Pathology. 2009 ; Vol. 174, No. 4. pp. 1221-1229.
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abstract = "Recently, we and others reported that diabetic endothelial nitric oxide synthase knockout (eNOSKO) mice develop advanced glomerular lesions that include mesangiolysis and nodular lesions. Interestingly, insulin treatment lowered blood pressure and prevented renal lesions, raising the question as to whether these beneficial effects of insulin were due to its ability to lower either high glucose levels or high blood pressure. We, therefore, examined the effect of lowering blood pressure using hydralazine in this diabetic eNOSKO mouse model. Hydralazine treatment significantly blocked the development of me- sangiolysis and microaneurysms, whereas tubulointerstitial injury was not prevented in these mice. Additionally, hydralazine did not reduce expression levels of either tubulointerstitial thrombospondin-1 or transforming growth factor-β despite controlling blood pressure. On the other hand, the critical role of high glucose levels on the development of tubuloin- terstitial injury was suggested by the observation that serum glucose levels were correlated with tubuloin- terstitial injury, as well as with the expression levels of both transforming growth factor-β and throm bospondin-1. Importantly, controlling blood glucose with insulin completely blocked tubulointerstitial injury in diabetic eNOSKO mice. These data suggest that glomerular injury is dependent on systemic blood pressure, whereas hyperglycemia may have a more important role in tubulointerstitial injury, possibly due to the stimulation of the thrombospondin-1-transforming growth factor-β pathway in diabetic eNOSKO mice. This study could provide insights into the pathogenesis of advanced diabetic nephropathy in the presence of endothelial dysfunction.",
author = "Tomoki Kosugi and Marcelo Heinig and Takahiro Nakayama and Thomas Connor and Yukio Yuzawa and Qiuhong Li and Hauswirth, {William W.} and Grant, {Maria B.} and Croker, {Byron P.} and Martha Campbell-Thompson and Li Zhang and Atkinson, {Mark A.} and Segal, {Mark S.} and Takahiko Nakagawa",
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Kosugi, T, Heinig, M, Nakayama, T, Connor, T, Yuzawa, Y, Li, Q, Hauswirth, WW, Grant, MB, Croker, BP, Campbell-Thompson, M, Zhang, L, Atkinson, MA, Segal, MS & Nakagawa, T 2009, 'Lowering blood pressure blocks mesangiolysis and mesangial nodules, but not tubulointerstitial injury, In Diabetic eNOS knockout mice', American Journal of Pathology, vol. 174, no. 4, pp. 1221-1229. https://doi.org/10.2353/ajpath.2009.080605

Lowering blood pressure blocks mesangiolysis and mesangial nodules, but not tubulointerstitial injury, In Diabetic eNOS knockout mice. / Kosugi, Tomoki; Heinig, Marcelo; Nakayama, Takahiro; Connor, Thomas; Yuzawa, Yukio; Li, Qiuhong; Hauswirth, William W.; Grant, Maria B.; Croker, Byron P.; Campbell-Thompson, Martha; Zhang, Li; Atkinson, Mark A.; Segal, Mark S.; Nakagawa, Takahiko.

In: American Journal of Pathology, Vol. 174, No. 4, 01.01.2009, p. 1221-1229.

Research output: Contribution to journalArticle

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T1 - Lowering blood pressure blocks mesangiolysis and mesangial nodules, but not tubulointerstitial injury, In Diabetic eNOS knockout mice

AU - Kosugi, Tomoki

AU - Heinig, Marcelo

AU - Nakayama, Takahiro

AU - Connor, Thomas

AU - Yuzawa, Yukio

AU - Li, Qiuhong

AU - Hauswirth, William W.

AU - Grant, Maria B.

AU - Croker, Byron P.

AU - Campbell-Thompson, Martha

AU - Zhang, Li

AU - Atkinson, Mark A.

AU - Segal, Mark S.

AU - Nakagawa, Takahiko

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