Fetal Programming of Adult Kidney Disease

Hershkovitz, Dov; Burbea, Zvi; Skorecki, Karl; Brenner, Barry M.

doi:10.2215/cjn.03291006

Cited by 52 publications

(42 citation statements)

References 102 publications

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“…Consistent with our results, knocking out MDM2 in mouse embryos and MDM2 knockdown by siRNA in podocytes of adult mice caused cell death (27,32). A previous study in MDM2-deficient mice also demonstrated that defects in kidney development at fetal stages enhance development of hypertensive and chronic kidney disease at the adult stage (40)(41)(42). It is conceivable that the kidney may undergo periods of regeneration during the natural history of diabetic nephropathy and regeneration and development of new tubular cells will be inhibited with MDM2 reduction.…”

Section: Discussionsupporting

confidence: 92%

Systems biology analysis reveals role of MDM2 in diabetic nephropathy

et al. 2016

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Section: Discussionsupporting

confidence: 92%

Systems biology analysis reveals role of MDM2 in diabetic nephropathy

et al. 2016

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“…Notably, our previous studies have shown that young adult FVB mice have significantly fewer glomeruli per kidney compared with B6 mice. 25 It has been postulated that congenital nephron deficit predisposes to arterial hypertension and progressive kidney injury 42 ; however, there were no significant differences in systemic arterial pressure between the two adult strains used in this study. 25 It remains possible that altered intraglomerular hemodynamics are present in FVB mice and these contribute to the altered ECM we report.…”

Section: Discussionmentioning

confidence: 56%

Genetic Background is a Key Determinant of Glomerular Extracellular Matrix Composition and Organization

Randles

Woolf

Huang

et al. 2015

Journal of the American Society of Nephrology

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Glomerular disease often features altered histologic patterns of extracellular matrix (ECM). Despite this, the potential complexities of the glomerular ECM in both health and disease are poorly understood. To explore whether genetic background and sex determine glomerular ECM composition, we investigated two mouse strains, FVB and B6, using RNA microarrays of isolated glomeruli combined with proteomic glomerular ECM analyses. These studies, undertaken in healthy young adult animals, revealed unique strain-and sexdependent glomerular ECM signatures, which correlated with variations in levels of albuminuria and known predisposition to progressive nephropathy. Among the variation, we observed changes in netrin 4, fibroblast growth factor 2, tenascin C, collagen 1, meprin 1-a, and meprin 1-b. Differences in protein abundance were validated by quantitative immunohistochemistry and Western blot analysis, and the collective differences were not explained by mutations in known ECM or glomerular disease genes. Within the distinct signatures, we discovered a core set of structural ECM proteins that form multiple protein-protein interactions and are conserved from mouse to man. Furthermore, we found striking ultrastructural changes in glomerular basement membranes in FVB mice. Pathway analysis of merged transcriptomic and proteomic datasets identified potential ECM regulatory pathways involving inhibition of matrix metalloproteases, liver X receptor/retinoid X receptor, nuclear factor erythroid 2-related factor 2, notch, and cyclin-dependent kinase 5. These pathways may therefore alter ECM and confer susceptibility to disease.

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“…Fetal programming by maternal malnutrition results in low birth weight and reduction in nephron number [1][2][3] increasing the risk for adult development of cardiovascular and renal diseases. 4,5 Vikse et al 6 showed that in humans the low birth weight increased in 70% the risk for end-stage kidney failure in adults.…”

Section: Introductionmentioning

confidence: 99%

Fetal kidney programming by severe food restriction: Effects on structure, hormonal receptor expression and urinary sodium excretion in rats

Vaccari

Mesquita

Gontijo

et al. 2013

J Renin Angiotensin Aldosterone Syst

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Introduction: The present study investigates, in 23-day-old and adult male rats, the effect of severe food restriction in utero on blood pressure (BP), and its association with nephron structure and function changes, angiotensin II (AT1R/ AT2R), glucocorticoid (GR) and mineralocorticoid (MR) receptor expression. Materials and methods:The daily food supply to pregnant rats was measured and one group (n=15) received normal quantity of food (NF) while the other received 50% of that (FR50%) (n=15). Kidneys were processed to AT1R, AT2R, MR, and GR immunolocalization and for western blotting analysis. The renal function was estimated by creatinine and lithium clearances in 12-week-old offspring. Results: By stereological analyses, FR50% offspring present a reduction of nephron numbers (35%) with unchanged renal volume. Expression of AT1R and AT2R was significantly decreased in FR50% while the expression of GR and MR increased in FR50%. We also verified a pronounced decrease in urinary sodium excretion accompanied by increased BP in 12-week-old FR50% offspring. Conclusion:The current data suggest that changes in renal function are conducive to excess sodium tubule reabsorption, and this might potentiate the programming of adult hypertension. It is plausible to arise in the current study an association between decreasing natriuresis, reciprocal changes in renal AngII and steroid receptors with the hypertension development found in FR50% compared with age-matched NF offspring.

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Fetal Programming of Adult Kidney Disease

Cited by 52 publications

References 102 publications

Systems biology analysis reveals role of MDM2 in diabetic nephropathy

Systems biology analysis reveals role of MDM2 in diabetic nephropathy

Genetic Background is a Key Determinant of Glomerular Extracellular Matrix Composition and Organization

Fetal kidney programming by severe food restriction: Effects on structure, hormonal receptor expression and urinary sodium excretion in rats

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