Glomerular cell number in normal subjects and in type 1 diabetic patients

Steffes, Michael W.; Schmidt, D. W.; McCrery, Rebecca; Basgen, John M.

doi:10.1046/j.1523-1755.2001.00725.x

Cited by 363 publications

(273 citation statements)

References 27 publications

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“…In contrast to the decrease in podocyte number, mesangial and glomerular endothelial cell number remained normal. More recently, Steffes et al (110) showed a similar paradigm in patients with type I diabetic nephropathy. Taken together, these important studies showed that a decrease in podocyte number is a significant predictor of disease progression in diabetic nephropathy.…”

Section: Podocyte Number Contributes To Glomerulosclerosismentioning

confidence: 84%

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The bends of the actin filament arches appear to be connected directly to the microtubules of the major processes (own unpublished results).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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Section: Podocyte Number Contributes To Glomerulosclerosismentioning

confidence: 84%

Podocyte Biology and Response to Injury

Mündel¹,

Shankland²

2002

Journal of the American Society of Nephrology

595

541

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“…The podocyte changes per se may enhance proteinuria and contribute to later damage. Foot process broadening and effacement and a reduction in podocyte number are recognised in diabetes [39][40][41][42].…”

Section: Discussionmentioning

confidence: 99%

The effect of intrauterine environment and low glomerular number on the histological changes in diabetic glomerulosclerosis

et al. 2005

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Aims/hypothesis: We tested the hypothesis that diabetic glomerulosclerosis would develop more rapidly in animals with fewer glomeruli. Methods: We studied the female offspring of Wistar rats that had been fed a low-protein diet (LPD) containing 6% protein or a normal-protein diet (NPD) containing 18% protein during pregnancy. Streptozotocin diabetes was induced at 12 weeks and animals were killed at 40 weeks. Results: Non-diabetic LPD offspring were of lower birthweight than the NPD offspring (5.19± 0.64 vs 6.45±0.67 g, p<0.001) and had fewer glomeruli (27,402±3,137 vs 34,203±6,471, p<0.05). Glomerular volume correlated inversely with glomerular number (r=−0.64, p=0.035), but total glomerular filtration surface area was reduced in the LPD animals (4,770±541 vs 5,779±1,302 mm 2 , p=0.05). Other renal structural and functional parameters were similar. In LPD and NPD diabetic animals, glomerular volume and basement membrane width were significantly increased compared to their respective controls. Podocyte density was lowest in the LPD diabetic animals (not significant), and the area covered by each podocyte was greater in the LPD diabetic group (2.40±0.693 ×10 −3 mm 2 ) than in the LPD control group (1.68±0.374 ×10 −3 mm 2 , p<0.001) and in the NPD diabetic animals (1.71±0.291 ×10 −3 mm 2 , p<0.05). There was no difference in any other structural or functional parameter between the LPD and NPD diabetic animals. Conclusions/ interpretation: A decrease in glomerular number was not deleterious to renal structure and function over 40 weeks in this animal model. Further work in models with progressive renal impairment and hypertension is necessary to clarify the impact of glomerular number on the development of renal disease.

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“…[1][2][3] Studies in humans and DN animal models reveal podocyte injury, detachment, apoptosis and loss. [4][5][6][7][8] Although some stimuli induce necrosis of podocytes in culture, 9 there is more in vivo evidence for a role of apoptosis in podocyte loss in DN. [10][11][12] More specifically, podocyte apoptosis coincided with the onset of albuminuria and preceded podocytopenia in different mouse models of diabetes.…”

mentioning

confidence: 99%

HSP27/HSPB1 as an adaptive podocyte antiapoptotic protein activated by high glucose and angiotensin II

Sanchez-Niño

Sanz

Sánchez-López

et al. 2012

Laboratory Investigation

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Apoptosis is a driving force of diabetic end-organ damage, including diabetic nephropathy (DN). However, the mechanisms that modulate diabetes-induced cell death are not fully understood. Heat shock protein 27 (HSP27/HSPB1) is a cell stress protein that regulates apoptosis in extrarenal cells and is expressed by podocytes exposed to toxins causing nephrotic syndrome. We investigated the regulation of HSPB1 expression and its function in podocytes exposed to factors contributing to DN, such as high glucose and angiotensin (Ang) II. HSPB1 expression was assessed in renal biopsies from patients with DN, minimal change disease or focal segmental glomerulosclerosis (FSGS), in a rat model of diabetes induced by streptozotocin (STZ) and in Ang II-infused rats. The regulation of HSPB1 was studied in cultured human podocytes and the function of HSPB1 expressed in response to pathophysiologically relevant stimuli was explored by short interfering RNA knockdown. Total kidney HSPB1 mRNA and protein expression was increased in rats with STZ-induced diabetes and in rats infused with Ang II. Upregulation of HSPB1 protein was confirmed in isolated diabetic glomeruli. Immunohistochemistry showed increased glomerular expression of HSPB1 in both models and localized glomerular HSPB1 to podocytes. HSPB1 protein was increased in glomerular podocytes from patients with DN or FSGS. In cultured human podocytes HSPB1 mRNA and protein expression was upregulated by high glucose concentrations and Ang II. High glucose, but not Ang II, promoted podocyte apoptosis. HSPB1 short interfering RNA (siRNA) targeting increased apoptosis in a high-glucose milieu and sensitized to Ang II or TGFb1-induced apoptosis by promoting caspase activation. In conclusion, both high glucose and Ang II contribute to HSPB1 upregulation. HSPB1 upregulation allows podocytes to better withstand an adverse high-glucose or Ang II-rich environment, such as can be found in DN.

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Glomerular cell number in normal subjects and in type 1 diabetic patients

Cited by 363 publications

References 27 publications

Podocyte Biology and Response to Injury

Podocyte Biology and Response to Injury

The effect of intrauterine environment and low glomerular number on the histological changes in diabetic glomerulosclerosis

HSP27/HSPB1 as an adaptive podocyte antiapoptotic protein activated by high glucose and angiotensin II

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