Open AccesseNOS Deficiency Predisposes Podocytes to Injury in Diabetes
Author(s) -
Darren A. Yuen,
Bailey E. Stead,
Yanling Zhang,
Kathryn White,
M. Golam Kabir,
Kerri Thai,
Suzanne L. Advani,
Kim A. Connelly,
Tomoko Takano,
Lei Zhu,
Alison Cox,
Darren J. Kelly,
Ian W. Gibson,
Takamune Takahashi,
Raymond C. Harris,
Andrew Advani
Publication year - 2012
Publication title -
journal of the american society of nephrology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.451
H-Index - 279
eISSN - 1533-3450
pISSN - 1046-6673
DOI - 10.1681/asn.2011121170
Subject(s) - enos , medicine , endocrinology , diabetic nephropathy , diabetes mellitus , podocyte , albuminuria , endothelial dysfunction , losartan , glomerular hyperfiltration , nitric oxide , proteinuria , angiotensin ii , nitric oxide synthase , kidney , receptor
Endothelial nitric oxide synthase (eNOS) deficiency may contribute to the pathogenesis of diabetic nephropathy in both experimental models and humans, but the underlying mechanism is not fully understood. Here, we studied two common sequelae of endothelial dysfunction in diabetes: glomerular capillary growth and effects on neighboring podocytes. Streptozotocin-induced diabetes increased glomerular capillary volume in both C57BL/6 and eNOS(-/-) mice. Inhibiting the vascular endothelial growth factor receptor attenuated albuminuria in diabetic C57BL/6 mice but not in diabetic eNOS(-/-) mice, even though it inhibited glomerular capillary enlargement in both. In eNOS(-/-) mice, an acute podocytopathy and heavy albuminuria occurred as early as 2 weeks after inducing diabetes, but treatment with either captopril or losartan prevented these effects. In vitro, serum derived from diabetic eNOS(-/-) mice augmented actin filament rearrangement in cultured podocytes. Furthermore, conditioned medium derived from eNOS(-/-) glomerular endothelial cells exposed to both high glucose and angiotensin II activated podocyte RhoA. Taken together, these results suggest that the combined effects of eNOS deficiency and hyperglycemia contribute to podocyte injury, highlighting the importance of communication between endothelial cells and podocytes in diabetes. Identifying mediators of this communication may lead to the future development of therapies targeting endothelial dysfunction in albuminuric individuals with diabetes.