Angiotensin II induces apoptosis in rat glomerular epithelial cells

Ding, Guohua; Reddy, Krishna; Kapasi, Aditi A.; Franki, Nicholas; Gibbons, Nora; Kasinath, Balakuntalam S.; Singhal, Pravin C.

doi:10.1152/ajprenal.00240.2001

Cited by 161 publications

(146 citation statements)

References 48 publications

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“…Plenty of studies have suggested apoptosis as the mainly mechanism contributing to podocyte loss. However, it should be noted that although there were numerous data demonstrating podocyte apoptosis in vitro studies 9, 10, the definite evidence for a primary role of apoptosis in either human or experimental DN is scant, and apoptotic cell death is rarely seen in diabetic glomeruli in situ 11, 12. There were also studies showing that apoptosis may only be a late consequence due to detachment or other podocyte dysfunction rather than a predominate initiator in podocyte loss 27.…”

Section: Discussionmentioning

confidence: 99%

MDM2 is implicated in high‐glucose‐induced podocyte mitotic catastrophe via Notch1 signalling

Tang

Lei

Wang

et al. 2017

J Cellular Molecular Medi

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Podocyte injury and depletion are essential events involved in the pathogenesis of diabetic nephropathy (DN). As a terminally differentiated cell, podocyte is restricted in ‘post‐mitosis’ state and unable to regenerate. Re‐entering mitotic phase will cause podocyte disastrous death which is defined as mitotic catastrophe (MC). Murine double minute 2 (MDM2), a cell cycle regulator, is widely expressed in renal resident cells including podocytes. Here, we explore whether MDM2 is involved in podocyte MC during hyperglycaemia. We found aberrant mitotic podocytes with multi‐nucleation in DN patients. In vitro, cultured podocytes treated by high glucose (HG) also showed an up‐regulation of mitotic markers and abnormal mitotic status, accompanied by elevated expression of MDM2. HG exposure forced podocytes to enter into S phase and bypass G2/M checkpoint with enhanced expression of Ki67, cyclin B1, Aurora B and p‐H3. Genetic deletion of MDM2 partly reversed HG‐induced mitotic phase re‐entering of podocytes. Moreover, HG‐induced podocyte injury was alleviated by MDM2 knocking down but not by nutlin‐3a, an inhibitor of MDM2‐p53 interaction. Interestingly, knocking down MDM2 or MDM2 overexpression showed inhibition or activation of Notch1 signalling, respectively. In addition, genetic silencing of Notch1 prevented HG‐mediated podocyte MC. In conclusion, high glucose up‐regulates MDM2 expression and leads to podocyte MC. Notch1 signalling is an essential downstream pathway of MDM2 in mediating HG‐induced MC in podocytes.

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Section: Discussionmentioning

confidence: 99%

MDM2 is implicated in high‐glucose‐induced podocyte mitotic catastrophe via Notch1 signalling

Tang

Lei

Wang

et al. 2017

J Cellular Molecular Medi

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“…Singhal and colleagues (121) showed that angiotensin II (AngII) induces apoptosis in cultured rat podocytes. This effect was dose-and time-dependent.…”

Section: Apoptosismentioning

confidence: 99%

Podocyte Biology and Response to Injury

Mündel¹,

Shankland²

2002

Journal of the American Society of Nephrology

595

541

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The visceral glomerular epithelial cell, also called podocyte, is a terminally differentiated cell that lines the outer aspect of the glomerular basement membrane (GBM). It therefore forms the final barrier to protein loss, which explains why podocyte injury is typically associated with marked proteinuria. Indeed, all forms of nephrotic syndrome are characterized by abnormalities in the podocyte. In this review, we will provide an update of the known functions of recent podocyte-specific proteins and focus on the slit diaphragm (SD) and the mechanisms underlying foot process (FP) flattening and how the podocyte responds to injury. Molecular Anatomy of the Podocyte FP CytoskeletonPodocyte FP are not static, but rather contain a contractile system similar to that seen in pericytes. This contractile apparatus is composed of actin, myosin-II, ␣-actinin-4, talin, and vinculin (1). The actin filament bundles form arches between adjacent FP of the same podocyte (2). Figure 1 is a schema of our current understanding of the molecular composition of the cytoskeleton in podocyte FP. Importantly, the actin filaments are connected to the underlying GBM at focal contacts via an ␣3␤1 integrin complex (3,4). The bends of the actin filament arches appear to be connected directly to the microtubules of the major processes (own unpublished results). FP are anchored to the GBM via ␣3␤1 integrin (5) and dystroglycans (6,7). Neighboring FP are connected by a cell-cell junction, the glomerular SD, which represents the main size selective filter barrier in the kidney (8 -10). The SD is thought to be a modified adherens junction (11) that is composed of a growing number of proteins, including nephrin (12-14), P-cadherin, CD2AP (15-18), , FAT (20), podocin (16,21), and possibly Neph1 (see reference 22 and below). In addition to the contractile proteins described above, we have reported the association of synaptopodin with the actin filaments in FP (23). Synaptopodin is the first member of a novel class of prolinerich proteins (24) and, like ␣-actinin-4, interacts with the tight junction protein MAGI-1 (25) that is also expressed in podocytes (26). Four Major Causes of FP EffacementThe basolateral portion of the foot processes represents the center of podocyte function and is defined by three membrane domains: the apical membrane domain, the SD protein complex, and the basal membrane domain or sole plate (27). The submembranous regions of all compartments are connected to the FP actin cytoskeleton, e.g., on the apical membrane domain, podocalyxin associates with the actin cytoskeleton through interactions with ezrin and the actin cytoskeleton via Na ϩ /H ϩ -exchanger regulatory factor 2 (NHERF2), a scaffold protein containing two PDZ (PSD-95/Dlg/ZO-1) domains and an ERM-binding region (28,29). The FP actin cytoskeleton is highly dynamic and ultimately determines the structural maintenance of the filtration slits as demonstrated in the acute PS/heparin model by several groups (30 -32). Interference with one of the three domains eventually ...

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“…In cultured mesangial cells, Ang II [35][36][37] and aldosterone 38,39 provoke synthesis of extracellular matrix (ECM) proteins that accumulate in glomerulosclerosis. In podocytes, Ang II has been shown to induce apoptosis, 40,41 cytoskeletal rearrangement 42 and nephrin loss 43 in podocytes, alterations that have been linked to albuminuria. 44 Aldosterone can also damage podocytes by inducing apoptosis and reducing nephrin gene expression.…”

Section: Intrarenal Raasmentioning

confidence: 99%

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

Feldman

2010

Hypertens Res

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The renin-angiotensin-aldosterone system (RAAS) has a central function in the regulation of blood pressure. Aliskiren, the first direct renin inhibitor to be approved for the treatment of hypertension, blocks the RAAS at its point of activation. As renin inhibition acts at the top of the RAAS cascade, this mechanism has been proposed to offer advantages over existing modes of RAAS blockade. The RAAS is also considered to be a major factor in the pathogenesis of many renal diseases, especially diabetic nephropathy (DN), the main cause of end-stage renal disease. Existing therapies to block the RAAS slow the progression of DN, but they do not halt the disease. Therefore, more effective modes of interventions are needed. Studies to determine the efficacy of aliskiren in human renal disease are in progress. This review summarizes in vivo studies in which the efficacy of aliskiren was tested in experimental models of renal disease, and presents in vitro studies that provide insights into the possible mechanisms by which aliskiren confers renoprotection in animals. These works are discussed in the framework of the intrarenal RAAS and suggest that aliskiren may act by unique renoprotective mechanisms. Keywords: aliskiren; kidney; mechanism; nephropathy; renin INTRODUCTIONThe renin-angiotensin-aldosterone system (RAAS) is an ancient pathway 1 that has evolved into a central mechanism by which mammalian blood pressure (BP) and fluid homeostasis are regulated. Research in this field started with the discovery in 1898 by Tigerstedt and Berman 2 that a renal extract when injected into rabbits induced a rapid increase in systemic BP. Subsequent work over many years established the RAAS as a pivotal contributor to cardiorenal diseases. Hence, inhibitors of the middle and distal portions of the RAAS pathway, angiotensin-converting enzyme (ACE) inhibitors (ACEI) and AT 1 receptor blockers, respectively, have become mainstay therapies for treating hypertension. In 2007, aliskiren, the first direct renin inhibitor (DRI), was approved for the treatment of hypertension. This heralded the therapeutic control of BP by inhibiting the RAAS at its first and rate-limiting step. However, RAAS blockade is also effective for treating renal disease 3-6 and the efficacy of aliskiren for this purpose is currently being investigated. Accordingly, the subject of this review is to summarize the preclinical evidence for renoprotection by aliskiren, and to discuss recently published information on the possible mechanism(s) for these benefits. As it is well recognized that there is a tissue as well as circulating RAAS, 7 the preclinical actions of aliskiren will be discussed in the context of the intrarenal RAAS and the potential for its inhibition by aliskiren.

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Angiotensin II induces apoptosis in rat glomerular epithelial cells

Cited by 161 publications

References 48 publications

MDM2 is implicated in high‐glucose‐induced podocyte mitotic catastrophe via Notch1 signalling

MDM2 is implicated in high‐glucose‐induced podocyte mitotic catastrophe via Notch1 signalling

Podocyte Biology and Response to Injury

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

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