Podocyte depletion and glomerulosclerosis have a direct relationship in the PAN-treated rat

Kim, Yeong Hoon; Goyal, Meera; Kurnit, David M.; Wharram, Bryan L.; Wiggins, Jocelyn; Holzman, Lawrence B.; Kershaw, David B.; Wiggins, Roger C.

doi:10.1046/j.1523-1755.2001.060003957.x

Cited by 356 publications

(307 citation statements)

References 33 publications

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“…Recent observations in humans describe a striking relationship between podocyte depletion and progression to end-stage renal disease in types 1 and 2 diabetic glomerulosclerosis and in IgA nephropathy (20 -24). These reports are based in turn on an extensive body of literature in experimental animals that provides a strong experimental underpinning for this conclusion (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). These experimental studies are well supported by a long-standing clinical literature describing a correlation between glomerulosclerosis and podocyte injury (1).…”

Section: Discussionmentioning

confidence: 83%

“…We previously used a method for estimating podocyte number that examined only midglomerular profiles and that did not correct podocyte nuclear counts for double counting and where we assumed the section thickness to be 3 m (19). By means of this approach, we defined a value for glomerular area per podocyte of 1500 to 1600 m 2 to be the approximate threshold above which glomerulosclerosis would be expected to occur.…”

Section: Discussionmentioning

confidence: 99%

“…This is the method used for calculating podocyte number per glomerulus in a previous publication (19) and gives a value that is significantly larger than the value of 204 podocytes per glomerular tuft obtained by adding up the mean number of WT-1-positive nuclei in every section (column E). There is therefore a discrepancy between the number of counted WT-1-positive cells and the derived value.…”

Section: Serial Section Experimentsmentioning

confidence: 97%

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Evaluation of a Thick and Thin Section Method for Estimation of Podocyte Number, Glomerular Volume, and Glomerular Volume Per Podocyte in Rat Kidney with Wilms’ Tumor-1 Protein Used as a Podocyte Nuclear Marker

Sanden¹,

Wiggins²,

Goyal³

et al. 2003

Journal of the American Society of Nephrology

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Abstract. Podocyte loss and glomerular hypertrophy are associated with development of glomerulosclerosis, suggesting that there may be a maximal area for each podocyte in terms of its capacity to support and maintain the glomerular filter. This study hypothesized that exceeding this maximal threshold will result in mesangial expansion and glomerulosclerosis. It may therefore be useful to measure podocyte number, glomerular volume, and glomerular volume per podocyte in clinical biopsysamples. An approach that uses thick and thin histologic sections cut from paraffin-embedded tissue to measure Wilms' tumor-1 protein-positive podocyte nuclear number and glomerular tuft area was studied. A rat model of aging has been used to track changes in glomerular podocyte number, glomerular volume per podocyte, and glomerular volume. Implications for clinical use of these variables are discussed.There is increasing evidence from human biopsy material and experimental models that podocyte injury and reduction in the number of podocytes in a glomerular tuft may be an important factor determining the propensity for glomerulosclerosis . If this is true, then it may be useful to routinely quantitate the number of podocytes in renal biopsy material and in experimental models to predict susceptibility to development of glomerulosclerosis and efficacy of treatment. Measurement of podocyte number has proved quite difficult because of the complexity of both podocyte and glomerular structure (18 -26).Although podocyte number appears to be a key variable, it is likely that podocyte number in relation to the glomerular basement membrane (GBM) area to be served by the podocyte may be more important. The relationship between GBM area and the podocyte can be approximated by relating glomerular tuft volume to podocyte number, and has been previously expressed as the "density" of podocytes or the glomerular volume per podocyte (GV/P) (21-28). There are extensive data to support the relationship between large glomerular tuft size and glomerulosclerosis (reviewed in [29]), an observation that could well be related to a relative deficiency of podocytes.We have attempted to develop a method that might be applicable for regular clinical use in renal biopsy material and experimental models of glomerular disease. We then used the method to examine changes in glomerular volume, podocyte number, and GV/P in the renal cortex of Brown Norway rats during normal maturation and aging. Materials and Methods Experimental Animal ModelRats at a range of ages were obtained from the Aging Rodent Colony maintained by the National Institute for Aging. For these experiments, we used Brown Norway rats killed at 2 mo (adolescent), 5 to 7 mo (young adult), 15 to 17 mo (midage), and 32 mo (old). Rats were anesthetized by injection of xylazine and ketamine before perfusion of kidneys with phosphate-buffered saline for 2 min, followed by 2% PLP paraformaldehyde, lysine, and periodate in PBS for 8 min at a perfusion pressure of 125 mmHg. After perfusion, kidneys were quickl...

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Serial Section Experimentsmentioning

confidence: 97%

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Evaluation of a Thick and Thin Section Method for Estimation of Podocyte Number, Glomerular Volume, and Glomerular Volume Per Podocyte in Rat Kidney with Wilms’ Tumor-1 Protein Used as a Podocyte Nuclear Marker

Sanden¹,

Wiggins²,

Goyal³

et al. 2003

Journal of the American Society of Nephrology

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“…Increasing evidence suggests that the podocyte is the culprit in the great majority of glomerular diseases because loss of podocytes beyond a certain threshold induces glomerulosclerosis [1-4]. For example, podocyte numbers are reduced in proportion to the severity of injury and the magnitude of proteinuria is related to the extent of reduced podocyte number.…”

Section: Introductionmentioning

confidence: 99%

Podocyte Mitosis – A Catastrophe

Lasagni

Lazzeri²,

Shankland

et al. 2012

CMM

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Podocyte loss plays a key role in the progression of glomerular disorders towards glomerulosclerosis and chronic kidney disease. Podocytes form unique cytoplasmic extensions, foot processes, which attach to the outer surface of the glomerular basement membrane and interdigitate with neighboring podocytes to form the slit diaphragm. Maintaining these sophisticated structural elements requires an intricate actin cytoskeleton. Genetic, mechanic, and immunologic or toxic forms of podocyte injury can cause podocyte loss, which causes glomerular filtration barrier dysfunction, leading to proteinuria. Cell migration and cell division are two processes that require a rearrangement of the actin cytoskeleton; this rearrangement would disrupt the podocyte foot processes, therefore, podocytes have a limited capacity to divide or migrate. Indeed, all cells need to rearrange their actin cytoskeleton to assemble a correct mitotic spindle and to complete mitosis. Podocytes, even when being forced to bypass cell cycle checkpoints to initiate DNA synthesis and chromosome segregation, cannot complete cytokinesis efficiently and thus usually generate aneuploid podocytes. Such aneuploid podocytes rapidly detach and die, a process referred to as mitotic catastrophe. Thus, detached or dead podocytes cannot be adequately replaced by the proliferation of adjacent podocytes. However, even glomerular disorders with severe podocyte injury can undergo regression and remission, suggesting alternative mechanisms to compensate for podocyte loss, such as podocyte hypertrophy or podocyte regeneration from resident renal progenitor cells. Together, mitosis of the terminally differentiated podocyte rather accelerates podocyte loss and therefore glomerulosclerosis. Finding ways to enhance podocyte regeneration from other sources remains a challenge goal to improve the treatment of chronic kidney disease in the future.

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“…Increasing experimental and clinical evidence has demonstrated that the podocyte number is a critical determinant in the development of glomerulosclerosis (1), and podocytopenia may lead to massive proteinuria and ultimate renal scarring (2). The causes of podocytopenia include apoptosis, detachment, and inability or lack of podocytes to proliferate (3).…”

Section: Introductionmentioning

confidence: 99%

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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Podocyte depletion and glomerulosclerosis have a direct relationship in the PAN-treated rat

Cited by 356 publications

References 33 publications

Evaluation of a Thick and Thin Section Method for Estimation of Podocyte Number, Glomerular Volume, and Glomerular Volume Per Podocyte in Rat Kidney with Wilms’ Tumor-1 Protein Used as a Podocyte Nuclear Marker

Evaluation of a Thick and Thin Section Method for Estimation of Podocyte Number, Glomerular Volume, and Glomerular Volume Per Podocyte in Rat Kidney with Wilms’ Tumor-1 Protein Used as a Podocyte Nuclear Marker

Podocyte Mitosis – A Catastrophe

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

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