TY - JOUR
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
PY - 2009/4
Y1 - 2009/4
N2 - 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.
AB - 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.
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U2 - 10.2353/ajpath.2009.080605
DO - 10.2353/ajpath.2009.080605
M3 - Article
C2 - 19246639
AN - SCOPUS:65349142464
SN - 0002-9440
VL - 174
SP - 1221
EP - 1229
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 4
ER -