Functional endothelin 1 receptors on human glomerular podocytes and mesangial cells

Rebibou, JM; He, Cijiang; Delarue, F; Péraldi, Marie-Noëlle; Adida, Colette; Rondeau, Éric; Sraër, Jean-Daniel

doi:10.1093/oxfordjournals.ndt.a092130

Cited by 50 publications

(36 citation statements)

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“…The presence of AT-1-subtype receptors for Ang II is illustrated by studies in podocyte cultures where Ang II depolarised podocytes [40]. Additionally, functional ET-1 receptors had been also found on podocytes [41].…”

Section: Discussionmentioning

confidence: 97%

ACE-inhibitors but not endothelin receptor blockers prevent podocyte loss in early diabetic nephropathy

et al. 2003

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Aims/hypothesis. It was the aim of our study to investigate the influence of a selective ET-A receptor antagonist LU 135252 alone and in combination with the ACE-inhibitor, trandolapril on podocyte number and morphology in streptozotocin diabetic rats. Methods. Male Sprague-Dawley rats were injected with 65 mg streptozotocin i.v. and subsequently developed diabetes. Animals were left untreated or received daily either trandolapril (0.3 mg/kg body weight), LU 135252 (50 mg/kg body weight) or a combination of both. After 6 months the experiment was terminated. Glomerular geometry and cellularity were assessed by stereological techniques. Protein expression of TGF-β, ET-1, PDGF-AB, fibronectin, desmin and α-smooth muscle cell actin was investigated by immunohistochemistry.Results. The mean number of podocytes per glomerulus was lower (86±17 vs. 138±25; p<0.05) and mean podocyte volume was higher in untreated diabetic animals than in non-diabetic controls. Only ACE-i alone and in combination, but not ET A -RB alone prevented loss of podocytes and podocyte hypertrophy. In diabetic rats, increased numbers of PCNA positive and p27 kip1 positive cells (mainly podocytes) were reduced by all treatments, but only ACE-i decreased numbers of desmin positive podocytes and tubulointerstitial expression of TGF-β. Albuminuria was increased in untreated diabetes and was prevented only by ACE-i and combination treatment. Conclusion/interpretation. Podocyte hypertrophy and degeneration is an early event in diabetic nephropathy leading to a loss of podocytes. Treatment with an ACE-i, but not with an ET A -RB, prevented the development of albuminuria as well as damage and loss of podocytes. The well known anti-proteinuric effect of ACE-i is presumably due at least in part to conservation of podocyte structure. Increased plasma endothelin-1 (ET-1) concentrations and urine excretion of ET-1 have been documented in patients with diabetes and proteinuria [1]. It has been shown that experimental diabetes mellitus increases renal ET-1 gene transcription [2]. To assess the relevance of the ET-system in the pathogenesis of renal structural changes in the model of the STZ-induced diabetic rat we compared the effect of an ET A -receptor specific antagonist with the well known beneficial effect of an ACE-i, especially on podocyte cell number and morphology. [Diabetologia (2003) 46:856-868]

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Section: Discussionmentioning

confidence: 97%

ACE-inhibitors but not endothelin receptor blockers prevent podocyte loss in early diabetic nephropathy

et al. 2003

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“…Several other agonists have been reported to modulate [Ca 2ϩ ] i in podocytes (19,35,121,159,176,313,348,349,363,422,(441)(442)(443). Table 1 summarizes the respective hormones and their receptors, which have been detected in podocytes in vitro and in vivo.…”

Section: Ca 2؉ Signalingmentioning

confidence: 99%

Cell Biology of the Glomerular Podocyte

Pavenstädt

Kriz

Kretzler

2003

Physiological Reviews

1,308

1,278

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Glomerular podocytes are highly specialized cells with a complex cytoarchitecture. Their most prominent features are interdigitated foot processes with filtration slits in between. These are bridged by the slit diaphragm, which plays a major role in establishing the selective permeability of the glomerular filtration barrier. Injury to podocytes leads to proteinuria, a hallmark of most glomerular diseases. New technical approaches have led to a considerable increase in our understanding of podocyte biology including protein inventory, composition and arrangement of the cytoskeleton, receptor equipment, and signaling pathways involved in the control of ultrafiltration. Moreover, disturbances of podocyte architecture resulting in the retraction of foot processes and proteinuria appear to be a common theme in the progression of acquired glomerular disease. In hereditary nephrotic syndromes identified over the last 2 years, all mutated gene products were localized in podocytes. This review integrates our recent physiological and molecular understanding of the role of podocytes during the maintenance and failure of the glomerular filtration barrier.

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“…We also determined the effects of darusentan treatment for glomerular gene expression in vivo of matrix metalloproteinase-9 (MMP-9), which is involved in glomerular matrix turnover. 5 MMP-9 gene expression was determined in laser-dissected glomeruli of the study animals and was found to be reduced by 65% after darusentan treatment (from 6.0 [2.8] to 2.1[1.6] units; nϭ10 per group; Pϭ0.0015; Figure 5a) Because stability and function of podocytes were improved after darusentan treatment in vivo and regulation of calcium signaling by endothelin 15 suggests that podocytes are functional targets of ET-1, we set out experiments to investigate the role of endogenous and exogenous endothelin in an in vitro podocyte injury model. Endothelin receptor expression of both endothelin receptor subtypes was present in human podocytes (Ortmann and Barton, unpublished observation, 2004), and MMP-9 gene expression and cytoskeletal disruption were chosen as a read-outs of podocyte injury as described previously.…”

Section: Ortmann Et Al Pedocytes and Reversal Of Renal Aging 977mentioning

confidence: 99%

“…12 As we have shown previously, ET-1 expression increases in the aging kidney in the absence of other risk factors. 13,14 Because podocytes are targets of ET-1, 15 we sought to investigate the effects of treatment with an orally active ET A receptor antagonist on renal structure and function in aged rats with established glomerulosclerosis and podocyte injury.…”

mentioning

confidence: 99%

Role of Podocytes for Reversal of Glomerulosclerosis and Proteinuria in the Aging Kidney After Endothelin Inhibition

et al. 2004

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Abstract-The cause of focal-segmental glomerulosclerosis as a consequence of physiological aging, which is believed to be inexorable, is unknown. This study investigated whether inhibition of endothelin-1, a growth-promoting peptide contributing to renal injury in hypertension and diabetes, affects established glomerulosclerosis and proteinuria in the aged kidney. We also determined the role of endothelin receptors for podocyte injury in vivo and in vitro. Aged Wistar rats, a model of spontaneous age-dependent glomerulosclerosis, were treated with the orally active endothelin subtype A (ET A ) receptor antagonist darusentan, and evaluation of renal histology, renal function studies, and expression analyses were performed. In vitro experiments using puromycin aminonucleoside to induce podocyte injury investigated the role of ET A receptor signaling for apoptosis, cytoskeletal injury, and DNA synthesis. In aged Wistar rats, established glomerulosclerosis and proteinuria were reduced by Ͼ50% after 4 weeks of darusentan treatment, whereas blood pressure, glomerular filtration rate, or tubulo-interstitial renal injury remained unaffected. Improvement of structural injury in glomeruli and podocytes was accompanied by a reduction of the expression of matrix metalloproteinase-9 and p21 Cip1/WAF1 . In vitro experiments blocking ET A receptors using specific antagonists or RNA interference prevented apoptosis and structural damage to podocytes induced by puromycin aminonucleoside. In conclusion, these results support the hypothesis that endogenous endothelin contributes to glomerulosclerosis and proteinuria in the aging kidney. The results further suggest that age-dependent glomerulosclerosis is not merely a "degenerative" but a reversible process locally confined to the glomerulus involving recovery of podocytes from previous injury. Key Words: arterial presure Ⅲ nephrosclerosis Ⅲ DNA Ⅲ kidney failure Ⅲ renal artery Ⅲ expression Ⅲ kidney Ⅲ renal disease A ging represents an important factor determining onset and course of disease and has become a significant issue in view of the anticipated increase of the aging population. Aging in humans and rodents progressively impairs renal function 1,2 and structure, the latter of which is characterized by damage of podocytes and mesangial matrix, as well as capillary hypertrophy and obliteration resulting in glomerulosclerosis. 2 The exact mechanisms underlying agedependent renal injury are unknown. In otherwise healthy individuals Ն65 years of age, even in the absence of known risk factors such as hypertension or diabetes, glomerulosclerosis is frequently present. 3 Currently, Ϸ1.4% of the US total population is affected, and the incidence is expected to increase to Ͼ2% within the next 15 years. 3 Glomerulosclerosis and proteinuria involve injury of podocytes, also known as glomerular epithelial cells that maintain an intact filtration barrier and control glomerular basement membrane turnover under normal conditions. 4 -7 In addition to cell-specific changes during aging, cell c...

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Functional endothelin 1 receptors on human glomerular podocytes and mesangial cells

Cited by 50 publications

References 0 publications

ACE-inhibitors but not endothelin receptor blockers prevent podocyte loss in early diabetic nephropathy

ACE-inhibitors but not endothelin receptor blockers prevent podocyte loss in early diabetic nephropathy

Cell Biology of the Glomerular Podocyte

Role of Podocytes for Reversal of Glomerulosclerosis and Proteinuria in the Aging Kidney After Endothelin Inhibition

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