Angiotensin converting enzyme inhibition prevents development of collapsing focal segmental glomerulosclerosis in Thy-1.1 transgenic mice

Smeets, Bart; Steenbergen, Mark L. M.; Dijkman, Henry; Verrijp, Kiek; Loeke, Nathalie A. J. M. te; Aten, Jan; Steenbergen, Eric J.; Wetzels, Jack F.M.

doi:10.1093/ndt/gfl495

Cited by 12 publications

(8 citation statements)

References 19 publications

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“…The findings of X-gal positive proliferating cells in the present study provide direct evidence for the contribution of PECs in the formation of the CG lesions in the Thy-1.1 mouse model and are in line with the previously reported marker studies performed in the Thy-1.1 transgenic mouse model. 25,26 In a parallel study on human biopsies, 29 we also found that proliferative lesions in patients with CrGN and CG predominantly contained PECs. These hyperplastic cells were identified by their expression of the renal progenitor markers CD133 and CD24, similar to the cells on Bowman's capsule.…”

Section: Discussionmentioning

confidence: 57%

“…The histopathology resembled that of the heterozygous Thy-1.1 transgenic mice described in previous studies. 25,26 Increased X-gal staining in Bowman's space was noted in most of the affected glomeruli. X-gal positive cells populated cellular lesions covering glomerular tuft segments (Figure 7, C and D).…”

Section: Phenotype Of Proliferating Cells In Crescentic Glomerulonephmentioning

confidence: 99%

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Tracing the Origin of Glomerular Extracapillary Lesions from Parietal Epithelial Cells

Smeets¹,

Uhlig²,

Fuss³

et al. 2009

Journal of the American Society of Nephrology

218

237

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Cellular lesions form in Bowman's space in both crescentic glomerulonephritis and collapsing glomerulopathy. The pathomechanism and origin of the proliferating cells in these lesions are unknown. In this study, we examined proliferating cells by lineage tracing of either podocytes or parietal epithelial cells (PECs) in the nephrotoxic nephritis model of inflammatory crescentic glomerulonephritis. In addition, we traced the fate of genetically labeled PECs in the Thy-1.1 transgenic mouse model of collapsing glomerulopathy. In both models, cellular bridges composed of PECs were observed between Bowman's capsule and the glomerular tuft. Genetically labeled PECs also populated larger, more advanced cellular lesions. In these lesions, we detected de novo expression of CD44 in activated PECs. In contrast, we rarely identified genetically labeled podocytes within the cellular lesions of crescentic glomerulonephritis. In conclusion, PECs constitute the majority of cells that compose early extracapillary proliferative lesions in both crescentic glomerulonephritis and collapsing glomerulopathy, suggesting similar pathomechanisms in both diseases.

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Section: Discussionmentioning

confidence: 57%

Section: Phenotype Of Proliferating Cells In Crescentic Glomerulonephmentioning

confidence: 99%

Tracing the Origin of Glomerular Extracapillary Lesions from Parietal Epithelial Cells

Smeets¹,

Uhlig²,

Fuss³

et al. 2009

Journal of the American Society of Nephrology

218

237

View full text Add to dashboard Cite

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“…In this study, we found that AlCl 3 affects the Bowman's capsule by thinning its basement membrane, which is the first step in the filtration of blood to form urine. Al also changed the aspect of the glomerulus filtration membrane that acts as a selective barrier and reduced and reduced the Bowman's space into which the glomerular plasma filtrate collects as it leaves the capillaries through the filtration membrane, until it disappears These changes are features of many kidney diseases, like Alport syndrome, which is a glomerular basement membrane (GBM) disease caused by mutations in type IV collagen genes characterized by irregular thickening and thinning of GBM [21], or Focal and segmental glomerulosclerosis (FSGS) known by the formation of adhesions between the glomerular tuft and Bowman's capsule as a consequence of Bowman's space reduction [22]. In addition to renal corpuscle, AlCl 3 also affects the renal tubule histology by changing the aspect of their lining epithelia.…”

Section: Discussionmentioning

confidence: 99%

Fenugreek seeds reduce aluminum toxicityassociated with renal failure in rats

et al. 2013

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Despite the reports on safety concerns regarding the relationship between aluminum salts and neurological and bone disease, many countries continue to use aluminum as phosphate binders among patients with renal failure. In search for a diet supplement that could reduce aluminum toxicity related to renal failure, we carried out this prospective animal study in which the fenugreek seeds were assessed for their effects on rats nephrotoxicity induced by aluminum chloride (AlCl3). Oral AlCl3 administration during 5 months (500 mg/kg bw i.g for one month then 1600 ppm via drinking water) led to plasma biochemical changes, an inhibition of alkaline phosphatase (ALP), a decrease of total antioxidant status (TAS), and an induction of lipid peroxidation (LPO) in the blood and brain, in addition to kidney atrophy and morphological alterations at the level of Bowman's capsule, the glomerulus and different sorts of tubules, reminiscent of some known kidney disease. The treatment with the whole fenugreek seed powder (FSP) (5% in the diet) during the last 2 months showed its effectiveness in restoring normal plasma values of urea, creatinine, ALP and glucose, as well as re-increasing the TAS, inhibiting LPO and alleviating histopathological changes in the injured kidneys. This study highlights the induced nephrotoxicicity, as well as the related toxicity in the brain and bone, by chronic oral ingestion of the aluminum salts. However, the maintenance of a diet supplemented with fenugreek seeds could offer protection for the kidney, bone and brain, at the same time.

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“…Blockade of Ang II synthesis with Ang I converting enzyme (ACE) inhibitors or of Ang II action with AT1 receptor blocker (ARB) is a clinically established therapeutic measure for slowing the progression of chronic kidney diseases. ACE inhibitors and ARB have been shown to attenuate podocyte damage, proteinuria and development of glomerulosclerosis in a variety of animal models, including, among others,1–7 subtotal nephrectomy model8 and diabetic nephropathy models 9, 10…”

Section: Introductionmentioning

confidence: 99%

Angiotensin Receptor Blocker Protection Against Podocyte-Induced Sclerosis Is Podocyte Angiotensin II Type 1 Receptor-Independent

et al. 2010

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Abstract-In the present study, we tested the hypothesis that the renoprotective effect of an angiotensin receptor blocker depends on the angiotensin II type 1 (AT 1 ) receptor on podocytes. For this purpose, we generated podocyte-specific knockout mice for the AT 1 gene (Agtr1a) and crossed with NEP25, in which selective podocyte injury can be induced by immunotoxin, anti-Tac(Fv)-PE38. Four weeks after the addition of anti-Tac(Fv)-PE38, urinary albumin:creatinine ratio was not attenuated in Agtr1a knockout/NEP25 mice (nϭ18) compared with that in control NEP25 mice (nϭ13; 8.08Ϯ2.41 in knockout versus 4.84Ϯ0.73 in control). Both strains of mice showed similar degrees of sclerosis (0.66Ϯ0.17 versus 0.82Ϯ0.27 on a 0 to 4 scale) and downregulation of nephrin (5.78Ϯ0.45 versus 5.65Ϯ0.58 on a 0 to 8 scale). In contrast, AT 1 antagonist or an angiotensin I-converting enzyme inhibitor, but not hydralazine, remarkably attenuated proteinuria and sclerosis in NEP25 mice. Moreover, continuous angiotensin II infusion induced microalbuminuria similarly in both Agtr1a knockout and wild-type mice. Thus, angiotensin inhibition can protect podocytes and prevent the development of glomerulosclerosis independent of podocyte AT 1 . Possible mechanisms include inhibitory effects on AT 1 of other cells or through mechanisms independent of AT 1 . Our study further demonstrates that measures that directly affect only nonpodocyte cells can have beneficial effects even when sclerosis is triggered by podocyte-specific injury. (Hypertension. 2010;55:967-973.)Key Words: podocyte Ⅲ glomerulosclerosis Ⅲ chronic renal failure Ⅲ AT 1 antagonist Ⅲ knockout mice Ⅲ proteinuria P odocytes play an indispensable role as a filtration barrier for macromolecules in the glomerulus. Damage of podocytes is a key step triggering the progression of glomerulosclerosis. A large volume of evidence indicates that angiotensin (Ang) II acting on the Ang II type 1 receptor (AT 1 ) plays important roles in this process. Blockade of Ang II synthesis with Ang I-converting enzyme (ACE) inhibitors or of Ang II action with AT 1 receptor blocker (ARB) is a clinically established therapeutic measure for slowing the progression of chronic kidney diseases. ACE inhibitors and ARBs have been shown to attenuate podocyte damage, proteinuria, and development of glomerulosclerosis in a variety of animal models, including, among others, 1-7 the subtotal nephrectomy model 8 and diabetic nephropathy models. 9,10 Continuous infusion of Ang II in normal rats increased desmin expression 11 and suppressed nephrin and podocin mRNA. 6 Studies conducted thus far collectively indicate that Ang II is involved in triggering, enhancing, and expanding podocyte injury and in the progression of glomerular injury toward sclerosis through mechanisms beyond its effect on systemic blood pressure.Because podocyte injury along with proteinuria ubiquitously precedes progressive development of glomerulosclerosis, and because Ang II inhibition attenuates podocyte damage and progressive glomerulosclerosis, it...

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Angiotensin converting enzyme inhibition prevents development of collapsing focal segmental glomerulosclerosis in Thy-1.1 transgenic mice

Cited by 12 publications

References 19 publications

Tracing the Origin of Glomerular Extracapillary Lesions from Parietal Epithelial Cells

Tracing the Origin of Glomerular Extracapillary Lesions from Parietal Epithelial Cells

Fenugreek seeds reduce aluminum toxicityassociated with renal failure in rats

Angiotensin Receptor Blocker Protection Against Podocyte-Induced Sclerosis Is Podocyte Angiotensin II Type 1 Receptor-Independent

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