A stereological study of the renal glomerular vasculature in the <i>db</i>/<i>db</i> mouse model of diabetic nephropathy

Guo, Min; Ricardo, Sharon D.; Deane, James A.; Shi, Ming; Cullen‐McEwen, Luise A.; Bertram, John F.

doi:10.1111/j.1469-7580.2005.00492.x

Cited by 80 publications

(80 citation statements)

References 39 publications

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“…Increased glomerular capillary volume (one, but not the sole, cause of glomerular hypertrophy in diabetes) occurs as a consequence of an increase in the number, length, and surface area of glomerular capillaries and is mediated by an increase in both cell size and cell number. 5,36 The lack of effect of eNOS deficiency on this trophic response highlights that glomerular capillary growth in diabetes, although responsive to anti-VEGF therapy, is not strictly analogous to angiogenesis that occurs in other vascular beds, during development or in other disease states. That at least some VEGF-mediated processes may occur independently of downstream eNOS is readily illustrated by the observations that although eNOS 2/2 mice are viable and fertile, VEGF deletion results in embryonic lethality.…”

Section: Discussionmentioning

confidence: 99%

eNOS Deficiency Predisposes Podocytes to Injury in Diabetes

Yuen

Stead

Zhang

et al. 2012

Journal of the American Society of Nephrology

129

130

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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 2/2 mice. Inhibiting the vascular endothelial growth factor receptor attenuated albuminuria in diabetic C57BL/6 mice but not in diabetic eNOS 2/2 mice, even though it inhibited glomerular capillary enlargement in both. In eNOS 2/2 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 2/2 mice augmented actin filament rearrangement in cultured podocytes. Furthermore, conditioned medium derived from eNOS 2/2 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.

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Section: Discussionmentioning

confidence: 99%

eNOS Deficiency Predisposes Podocytes to Injury in Diabetes

Yuen

Stead

Zhang

et al. 2012

Journal of the American Society of Nephrology

129

130

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“…31,[47][48][49] In the renal circulation, there is increased renal angiogenesis in early stages of diabetes in both clinical and experimental studies. [50][51][52][53][54] These early vascular changes were attributed to increased VEGF expression and mild inflammation. 51,55 At later stages of diabetes, vascular regression occurs, where chronic inflammation leads to increases in vascular permeability, thickening of the glomerular basement membrane, endothelial cell apoptosis, and loss of peritubular capillaries.…”

Section: Diabetes and Neovascularizationmentioning

confidence: 99%

Cerebral Neovascularization in Diabetes: Implications for Stroke Recovery and beyond

Ergul

Abdelsaid

Fouda

et al. 2014

J Cereb Blood Flow Metab

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Neovascularization is an innate physiologic response by which tissues respond to various stimuli through collateral remodeling (arteriogenesis) and new vessel formation from existing vessels (angiogenesis) or from endothelial progenitor cells (vasculogenesis). Diabetes has a major impact on the neovascularization process but the response varies between different organ systems. While excessive angiogenesis complicates diabetic retinopathy, impaired neovascularization contributes to coronary and peripheral complications of diabetes. How diabetes influences cerebral neovascularization remained unresolved until recently. Diabetes is also a major risk factor for stroke and poor recovery after stroke. In this review, we discuss the impact of diabetes, stroke, and diabetic stroke on cerebral neovascularization, explore potential mechanisms involved in diabetes-mediated neovascularization as well as the effects of the diabetic milieu on poststroke neovascularization and recovery, and finally discuss the clinical implications of these effects.

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“…Glomerular size increases with normal body growth as well before and during multiple renal pathologies, including both diabetic nephropathy [13][14][15][16][17] and FSGS. [18][19][20][21][22][23][24] It has been suggested that an increase in glomerular size (also known as glomerular hypertrophy) is usually a compensatory mechanism that serves to match physiologic demands and sustain renal function.…”

mentioning

confidence: 99%

Podocyte Number in Children and Adults

Puelles

Douglas-Denton

Cullen‐McEwen

et al. 2015

Journal of the American Society of Nephrology

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Increases in glomerular size occur with normal body growth and in many pathologic conditions. In this study, we determined associations between glomerular size and numbers of glomerular resident cells, with a particular focus on podocytes. Kidneys from 16 male Caucasian-Americans without overt renal disease, including 4 children (#3 years old) to define baseline values of early life and 12 adults ($18 years old), were collected at autopsy in Jackson, Mississippi. We used a combination of immunohistochemistry, confocal microscopy, and design-based stereology to estimate individual glomerular volume (IGV) and numbers of podocytes, nonepithelial cells (NECs; tuft cells other than podocytes), and parietal epithelial cells (PECs). Podocyte density was calculated. Data are reported as medians and interquartile ranges (IQRs). Glomeruli from children were small and contained 452 podocytes (IQR=335-502), 389 NECs (IQR=265-498), and 146 PECs (IQR=111-206). Adult glomeruli contained significantly more cells than glomeruli from children, including 558 podocytes (IQR=431-746; P,0.01), 1383 NECs (IQR=998-2042; P,0.001), and 367 PECs (IQR=309-673; P,0.001). However, large adult glomeruli showed markedly lower podocyte density (183 podocytes per 10 6 mm 3 ) than small glomeruli from adults and children (932 podocytes per 10 6 mm 3 ; P,0.001). In conclusion, large adult glomeruli contained more podocytes than small glomeruli from children and adults, raising questions about the origin of these podocytes. The increased number of podocytes in large glomeruli does not match the increase in glomerular size observed in adults, resulting in relative podocyte depletion. This may render hypertrophic glomeruli susceptible to pathology.

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A stereological study of the renal glomerular vasculature in the db/db mouse model of diabetic nephropathy

Cited by 80 publications

References 39 publications

eNOS Deficiency Predisposes Podocytes to Injury in Diabetes

eNOS Deficiency Predisposes Podocytes to Injury in Diabetes

Cerebral Neovascularization in Diabetes: Implications for Stroke Recovery and beyond

Podocyte Number in Children and Adults

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