Mechanisms underlying transition from acute glomerular injury to late glomerular sclerosis in a rat model of nephrotic syndrome.

Anderson, Sharon; Diamond, Jonathan R.; Karnovsky, Morris J.; Brenner, Barry M.

doi:10.1172/jci113789

Cited by 118 publications

(60 citation statements)

References 44 publications

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“…Results are from two independent experiments, each in duplicate. (22,45). We observed, as expected, that injured podocytes were ineffective in mediating GEN angiogenesis, proliferation, and migration.…”

Section: Discussionsupporting

confidence: 83%

Angiotensin Type 1 Receptor Blocker Restores Podocyte Potential to Promote Glomerular Endothelial Cell Growth

Liang¹,

Li²,

Naito³

et al. 2006

Journal of the American Society of Nephrology

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Both podocytes and glomerular endothelial cells (GEN) are postulated to play important roles in the progression and potential regression of glomerulosclerosis. Inhibition of angiotensin is crucial in treatment of chronic kidney disease, presumably via effects on BP and extracellular matrix. This study aimed to investigate how angiotensin inhibition altered the interactions between podocytes and GEN. The effects of supernatants from primary cultured mouse podocytes, before or after sublethal injury by puromycin aminonucleoside, in the presence or absence of angiotensin type 1 receptor blocker (ARB), on GEN sprouting and growth were assessed. Supernatant from normal podocytes significantly increased GEN sprouting, whereas puromycin aminonucleoside-injured podocyte supernatant decreased these GEN responses. These effects were linked to decreased vascular endothelial growth factor A (VEGF-A) and angiopoietin-1 (Ang-1) protein from injured podocytes. This downregulation of VEGF-A and Ang-1 protein was reversed when injured podocytes were treated with ARB. Inhibition of VEGF-A or Ang-1 prevented this restored response by ARB. Activation of intracellular kinases (p38, extracellular signalregulated kinase, and AKT) was suppressed in GEN that were treated with medium from injured podocytes but restored by medium from ARB-treated injured podocytes. Therefore, injured podocytes are ineffective in promoting GEN sprouting, and this effect is reversed by ARB treatment of the injured podocyte. These data support the idea that ARB effects on podocytes may mediate capillary remodeling in vivo.

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Section: Discussionsupporting

confidence: 83%

Angiotensin Type 1 Receptor Blocker Restores Podocyte Potential to Promote Glomerular Endothelial Cell Growth

Liang¹,

Li²,

Naito³

et al. 2006

Journal of the American Society of Nephrology

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“…By week 18, approximately 10-15% of the glomeruli show well-defined segmental sclerosis. The course is accelerated with uni-nephrectomy and multiple intraperitoneal injections (10 mg/kg body weight for the first dose, followed by additional doses of 40 mg/kg body weight at every 4 week), with well-defined glomerulosclerosis developed by week 8 [17,18] (Table 1).…”

Section: Puromycin Aminonucleosidementioning

confidence: 99%

Recent advances of animal model of focal segmental glomerulosclerosis

Yang

Dettmar

Kronbichler³

et al. 2018

Clin Exp Nephrol

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In the last decade, great advances have been made in understanding the genetic basis for focal segmental glomerulosclerosis (FSGS). Animal models using specific gene disruption of the slit diaphragm and cytoskeleton of the foot process mirror the etiology of the human disease. Many animal models have been developed to understand the complex pathophysiology of FSGS. Therefore, we need to know the usefulness and exact methodology of creating animal models. Here, we review classic animal models and newly developed genetic animal models. Classic animal models of FSGS involve direct podocyte injury and indirect podocyte injury due to adaptive responses. However, the phenotype depends on the animal background. Renal ablation and direct podocyte toxin (PAN, adriamycin) models are leading animal models for FSGS, which have some limitations depending on mice background. A second group of animal models were developed using combinations of genetic mutation and toxin, such as NEP25, diphtheria toxin, and Thy1.1 models, which specifically injure podocytes. A third group of animal models involves genetic engineering techniques targeting podocyte expression molecules, such as podocin, CD2-associated protein, and TRPC6 channels. More detailed information about podocytopathy and FSGS can be expected in the coming decade. Different animal models should be used to study FSGS depending on the specific aim and sometimes should be used in combination.

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“…The average number of glomeruli among the 12 control biopsies was also 19 (range [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30]. A dedicated computer system (Southern Micro Instruments, Inc., Atlanta, GA), consisting of a video camera, screen, microscope, and digitizing tablet, was used to perform measurements ( 1,2).…”

Section: Patient Populationmentioning

confidence: 99%

Structural basis for reduced glomerular filtration capacity in nephrotic humans.

Drumond¹,

Kristal²,

Myers³

et al. 1994

J. Clin. Invest.

111

108

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IntroductionPrevious studies have established that in a variety of human glomerulopathies the reduced glomerular filtration rate (GFR) is due to a marked lowering of the ultrafiltration coefficient (Kf Studies of a variety of human glomerulopathies have demonstrated that the overall ultrafiltration coefficient (Kf)1 for the two kidneys is reduced relative to that in healthy controls (1-5). Although the inability to measure the glomerular transcapillary hydraulic pressure difference (AP) in humans precludes precise calculations of Kf, the reductions in Kf computed for nephrotic individuals are typically so large that there is little doubt that glomerular ultrafiltration capacity is severely compromised in such disorders. Because Kf as determined in these human studies is the product of the hydraulic permeability of the glomerular capillary wall (k) and the total capillary surface area available for filtration in the two kidneys, the observed reductions in Kf might be due to decreased k, decreased surface area per glomerulus, a decreased number of functioning glomeruli, or some combination of these factors. Measurements have been reported for some of the key quantities in humans which should influence Kf, including surface area per glomerulus (1, 2, 4, 6), basement membrane thickness (1-4, 6, 7), and filtration slit frequency, which is the number of filtration slits per unit length of peripheral capillary wall (1-4). Reductions in filtration slit frequency reflect broadening and "effacement" of the epithelial foot processes, a uniform finding in virtually all humans with the nephrotic syndrome, regardless of its etiology. The most consistent inference from morphometric analysis of glomeruli of nephrotic individuals has been a strong correlation between decreases in estimated Kf and reductions in filtration slit frequency ( 8-11 ). Efforts to ascertain whether changes in filtration slit frequency or other factors can account for the observed alterations in Kf have been hampered by an inadequate understanding of the relationship between the various structural quantities and k. These relationships have been clarified recently by a mathematical model of the glomerular capillary wall, which is based on detailed analyses of viscous flow across the various structural components (12, 13). The structures include the endothelial fenestrae, glomerular basement membrane, and filtration slits. Using as inputs certain morphometric data from rats and the hydraulic permeability measured for isolated rat glomerular basement membrane, this "ultrastructural model" was able to predict a value for k that is in good agreement with micropuncture measurements in normal rats (13). It was also able to explain changes in k in an experimental rat model of glomerular injury, suggesting that it might be useful in interpreting data in human glomerular diseases.

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Mechanisms underlying transition from acute glomerular injury to late glomerular sclerosis in a rat model of nephrotic syndrome.

Cited by 118 publications

References 44 publications

Angiotensin Type 1 Receptor Blocker Restores Podocyte Potential to Promote Glomerular Endothelial Cell Growth

Angiotensin Type 1 Receptor Blocker Restores Podocyte Potential to Promote Glomerular Endothelial Cell Growth

Recent advances of animal model of focal segmental glomerulosclerosis

Structural basis for reduced glomerular filtration capacity in nephrotic humans.

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