Podocyte Depletion Causes Glomerulosclerosis

Wharram, Bryan L.; Goyal, Meera; Wiggins, Jocelyn; Sanden, Silja K.; Hussain, Sultana Monira; Filipiak, Wanda E.; Saunders, Thomas L.; Dysko, Robert C.; Kohno, Kenji; Holzman, Lawrence B.; Wiggins, Roger C.

doi:10.1681/asn.2005010055

Cited by 675 publications

(634 citation statements)

References 47 publications

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“…Podocyte loss results in a localized "bare" or denuded GBM and podocytopenia in glomeruli, which cause glomerulosclerosis, proteinuria, and renal dysfunction (24). There was a significantly positive correlation between UPCs and 24-h UP, which illustrates that podocyte detachment plays an important role in the occurrence and development of proteinuria.…”

Section: Discussionmentioning

confidence: 91%

1,25-Dihydroxyvitamin D3 Ameliorates Podocytopenia in Rats with Adriamycin-induced Nephropathy

Min-shu

Zhou

et al. 2010

Intern. Med.

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Objective To investigate the role of α3β1 integrin and α/β-dystroglycan in protective effects of 1,25(OH)2D3 on podocytes in rats with adriamycin-induced nephropathy. Methods Sprague-Dawley rats were randomly divided into three groups: control group (NC), nephropathy group (NE), and nephropathy+1,25(OH)2D3 group (ND). Rats in NE and ND group were injected intravenously with adriamycin (0.1 mg/10 g body weight) to induce nephropathy, and those in ND group were then subcutaneously treated with 1,25(OH)2D3 for 8 weeks. Urinary protein level, number of urine podocytes, foot process width and glomerulosclerotic index were determined. Nephrin and podocin mRNA and protein expressions were determined by RT-PCR and western blot, respectively. Podocyte density and expressions of α3β1 integrin and α/β-dystroglycan (DG) were analyzed by immunohistochemistry and western blot, respectively. Results The increase in proteinuria, podocyturia and width of foot process in NE group were ameliorated after treatment with 1,25(OH)2D3 for 8 weeks. The glomerulosclerotic index was significantly decreased in ND group when compared with NE group. The podocyte density in ND group (10.3 ± 1.64 cells/glomerulus) was significantly higher than that in NE group (8.43 ± 1.75 cells/glomerulus) (p=0.008). 1,25(OH)2D3 treatment could significantly up-regulate the mRNA and protein expressions of nephrin and podocin, and the protein expressions of α3β1 integrin and α/β-DG. Conclusion The expressions of nephrin, podocin, α3β1 integrin and α/β-DG were decreased in rats with nephropathy. However, 1,25(OH)2D3 treatment could significantly up-regulate the expressions of nephrin, podocin, α3β1 integrin and α/β-DG proteins which might suppress podocyte detachment and podocytopenia.

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Section: Discussionmentioning

confidence: 91%

1,25-Dihydroxyvitamin D3 Ameliorates Podocytopenia in Rats with Adriamycin-induced Nephropathy

Min-shu

Zhou

et al. 2010

Intern. Med.

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“…First, the models are based on a nontoxic physiologic stress and/or injury. A similar spectrum of glomerular injury can be achieved in, for instance, the adriamycin model 35,36 or models in which podocytes are specifically injured/depleted (Diphtheria toxin 2,37 and LMB2/NEP25 models 38 ) by injection of the different doses of the specific toxins. Using toxin-induced models, one cannot rule out that signaling necessary for a proper regeneration is also affected in the surviving podocytes.…”

Section: Discussionmentioning

confidence: 93%

The Regenerative Potential of Parietal Epithelial Cells in Adult Mice

Berger¹,

Schulte²,

Kuppe³

et al. 2014

Journal of the American Society of Nephrology

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Previously, we showed that some podocytes in juvenile mice are recruited from cells lining Bowman's capsule, suggesting that parietal epithelial cells (PECs) are a progenitor cell population for podocytes. To investigate whether PECs also replenish podocytes in adult mice, PECs were genetically labeled in an irreversible fashion in 5-week-old mice. No significant increase in labeled podocytes was observed, even after 18 months. To accelerate a potential regenerative mechanism, progressive glomerular hypertrophy was induced by progressive partial nephrectomies. Again, no significant podocyte replenishment was observed. Rather, labeled PECs exclusively invaded segments of the tuft affected by glomerulosclerosis, consistent with our previous findings. We next reassessed PEC recruitment in juvenile mice using a different reporter mouse and confirmed significant recruitment of labeled PECs onto the glomerular tuft. Moreover, some labeled cells on Bowman's capsule expressed podocyte markers, and cells on Bowman's capsule were also directly labeled in juvenile podocyte-specific Pod-rtTA transgenic mice. In 6-week-old mice, however, cells on Bowman's capsule no longer expressed podocyte-specific markers. Similarly, in human kidneys, some cells on Bowman's capsule expressed the podocyte marker synaptopodin from 2 weeks to 2 years of age but not at 7 years of age. In summary, podocyte regeneration from PECs could not be detected in aging mice or models of glomerular hypertrophy. We propose that a small fraction of committed podocytes reside on Bowman's capsule close to the vascular stalk and are recruited onto the glomerular tuft during infancy to adolescence in mice and humans.

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“…52 Podocyte injury results in proteinuric renal disease. 53 Contrary to MCD, both DN and FSGS are progressive glomerular diseases characterized by progressive loss of podocytes in which podocyte apoptosis has been observed. 13,14 Podocyte HSP27 expression was found in DN or FSGS, but not in normal kidney or MCD.…”

Section: Discussionmentioning

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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Podocyte Depletion Causes Glomerulosclerosis

Cited by 675 publications

References 47 publications

1,25-Dihydroxyvitamin D3 Ameliorates Podocytopenia in Rats with Adriamycin-induced Nephropathy

1,25-Dihydroxyvitamin D3 Ameliorates Podocytopenia in Rats with Adriamycin-induced Nephropathy

The Regenerative Potential of Parietal Epithelial Cells in Adult Mice

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

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