Progressive renal fibrosis in routine polycystic kidney disease: An immunohistochemical observation

Hirokazu Okada, Shinichi Ban, Shizuko Nagao, Hisahide Takahashi, Hiromichi Suzuki, Eric G. Neilson

Research output: Contribution to journalArticle

129 Citations (Scopus)

Abstract

Background. The appearance of interstitial fibrosis in polycystic kidneys is emblematic of progressive disease. Matrix forming this scar tissue is derived from local renal cells in response to cystogenesis. We investigated the phenotype of collagen producing cells in the cystic kidneys of DBA/2-pcy mice to better characterize the spectrum of interstitial cells associated with renal fibrogenesis. Methods. The extent of interstitial fibrosis and the number of fibroblasts in cystic kidneys were first quantitated over time using computer-assisted image analysis. Subsequently, antisera to four cell protein markers were studied by coexpression immunohistochemistry during progression of fibrosis using confocal microscopy. The antisera included fibroblast-specific protein 1 (FSP1) for fibroblast phenotype, α-smooth muscle actin (α-SMA) for contractile phenotype, vimentin (VIM) for mesenchymal phenotype, and heat shock protein 47 (HSP47) for interstitial collagen-producing phenotype. Results. Interstitial fibrosis in cystic kidneys gradually increased throughout the 30-week observation period of our study. With progression of cystogenesis, most of the tubules in pcy mice either dilate4d or disappeared with time. FSP1+ fibroblasts were distributed sparsely throughout the renal interstitium of young pcy and wild-type mice. Their number increased in the widening fibrotic septa by 18 weeks of age and persisted through 30 weeks of the study interval. Some epithelia among remnant tubules trapped within fibrotic septa around adjacent cysts also acquired the phenotype of FSP1+, HSP47+ collagen-producing fibroblasts, suggesting a possible role for epithelial-mesenchy-real transformation (EMT) in this process. Most FSP1+ fibroblasts were α-SMA-, but HSP47+, suggesting they were producing collagen proteins for the extracellular matrix, α-SMA+, FSP1-, HSP47+ or HSP47- cells were also observed, and the latter tended to distribute independently in a linear pattern, reminiscent of vasculature adjacent to forming cysts. VIM+ expression was not observed in α-SMA+ cells. Conclusions. Many nonoverlapping as well as fewer overlapping populations of FSP1+ and α-SMA+ cells shared in the collagen expression associated with progressive fibrogenesis in pcy mice undergoing cystogenesis. Some FSP1+ fibroblasts are likely derived from tubular epithelium undergoing EMT, while αSMA+, VIM- cells probably represent vascular smooth muscle cells or pericytes surviving vessel attenuation during the chaos of fibrogenesis. Importantly, not all interstitial cells producing collagens are α-SMA+.

Original languageEnglish
Article number4491725
Pages (from-to)587-597
Number of pages11
JournalKidney International
Volume58
Issue number2
DOIs
Publication statusPublished - 01-01-2000

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Polycystic Kidney Diseases
HSP47 Heat-Shock Proteins
Fibrosis
Observation
Kidney
Collagen
Fibroblasts
Cystic Kidney Diseases
Phenotype
Vimentin
Cysts
Immune Sera
Epithelium
Pericytes
Computer-Assisted Image Processing
Extracellular Matrix Proteins
S100 Calcium-Binding Protein A4
Vascular Smooth Muscle
Confocal Microscopy
Smooth Muscle Myocytes

All Science Journal Classification (ASJC) codes

  • Nephrology

Cite this

Okada, Hirokazu ; Ban, Shinichi ; Nagao, Shizuko ; Takahashi, Hisahide ; Suzuki, Hiromichi ; Neilson, Eric G. / Progressive renal fibrosis in routine polycystic kidney disease : An immunohistochemical observation. In: Kidney International. 2000 ; Vol. 58, No. 2. pp. 587-597.
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abstract = "Background. The appearance of interstitial fibrosis in polycystic kidneys is emblematic of progressive disease. Matrix forming this scar tissue is derived from local renal cells in response to cystogenesis. We investigated the phenotype of collagen producing cells in the cystic kidneys of DBA/2-pcy mice to better characterize the spectrum of interstitial cells associated with renal fibrogenesis. Methods. The extent of interstitial fibrosis and the number of fibroblasts in cystic kidneys were first quantitated over time using computer-assisted image analysis. Subsequently, antisera to four cell protein markers were studied by coexpression immunohistochemistry during progression of fibrosis using confocal microscopy. The antisera included fibroblast-specific protein 1 (FSP1) for fibroblast phenotype, α-smooth muscle actin (α-SMA) for contractile phenotype, vimentin (VIM) for mesenchymal phenotype, and heat shock protein 47 (HSP47) for interstitial collagen-producing phenotype. Results. Interstitial fibrosis in cystic kidneys gradually increased throughout the 30-week observation period of our study. With progression of cystogenesis, most of the tubules in pcy mice either dilate4d or disappeared with time. FSP1+ fibroblasts were distributed sparsely throughout the renal interstitium of young pcy and wild-type mice. Their number increased in the widening fibrotic septa by 18 weeks of age and persisted through 30 weeks of the study interval. Some epithelia among remnant tubules trapped within fibrotic septa around adjacent cysts also acquired the phenotype of FSP1+, HSP47+ collagen-producing fibroblasts, suggesting a possible role for epithelial-mesenchy-real transformation (EMT) in this process. Most FSP1+ fibroblasts were α-SMA-, but HSP47+, suggesting they were producing collagen proteins for the extracellular matrix, α-SMA+, FSP1-, HSP47+ or HSP47- cells were also observed, and the latter tended to distribute independently in a linear pattern, reminiscent of vasculature adjacent to forming cysts. VIM+ expression was not observed in α-SMA+ cells. Conclusions. Many nonoverlapping as well as fewer overlapping populations of FSP1+ and α-SMA+ cells shared in the collagen expression associated with progressive fibrogenesis in pcy mice undergoing cystogenesis. Some FSP1+ fibroblasts are likely derived from tubular epithelium undergoing EMT, while αSMA+, VIM- cells probably represent vascular smooth muscle cells or pericytes surviving vessel attenuation during the chaos of fibrogenesis. Importantly, not all interstitial cells producing collagens are α-SMA+.",
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Progressive renal fibrosis in routine polycystic kidney disease : An immunohistochemical observation. / Okada, Hirokazu; Ban, Shinichi; Nagao, Shizuko; Takahashi, Hisahide; Suzuki, Hiromichi; Neilson, Eric G.

In: Kidney International, Vol. 58, No. 2, 4491725, 01.01.2000, p. 587-597.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Progressive renal fibrosis in routine polycystic kidney disease

T2 - An immunohistochemical observation

AU - Okada, Hirokazu

AU - Ban, Shinichi

AU - Nagao, Shizuko

AU - Takahashi, Hisahide

AU - Suzuki, Hiromichi

AU - Neilson, Eric G.

PY - 2000/1/1

Y1 - 2000/1/1

N2 - Background. The appearance of interstitial fibrosis in polycystic kidneys is emblematic of progressive disease. Matrix forming this scar tissue is derived from local renal cells in response to cystogenesis. We investigated the phenotype of collagen producing cells in the cystic kidneys of DBA/2-pcy mice to better characterize the spectrum of interstitial cells associated with renal fibrogenesis. Methods. The extent of interstitial fibrosis and the number of fibroblasts in cystic kidneys were first quantitated over time using computer-assisted image analysis. Subsequently, antisera to four cell protein markers were studied by coexpression immunohistochemistry during progression of fibrosis using confocal microscopy. The antisera included fibroblast-specific protein 1 (FSP1) for fibroblast phenotype, α-smooth muscle actin (α-SMA) for contractile phenotype, vimentin (VIM) for mesenchymal phenotype, and heat shock protein 47 (HSP47) for interstitial collagen-producing phenotype. Results. Interstitial fibrosis in cystic kidneys gradually increased throughout the 30-week observation period of our study. With progression of cystogenesis, most of the tubules in pcy mice either dilate4d or disappeared with time. FSP1+ fibroblasts were distributed sparsely throughout the renal interstitium of young pcy and wild-type mice. Their number increased in the widening fibrotic septa by 18 weeks of age and persisted through 30 weeks of the study interval. Some epithelia among remnant tubules trapped within fibrotic septa around adjacent cysts also acquired the phenotype of FSP1+, HSP47+ collagen-producing fibroblasts, suggesting a possible role for epithelial-mesenchy-real transformation (EMT) in this process. Most FSP1+ fibroblasts were α-SMA-, but HSP47+, suggesting they were producing collagen proteins for the extracellular matrix, α-SMA+, FSP1-, HSP47+ or HSP47- cells were also observed, and the latter tended to distribute independently in a linear pattern, reminiscent of vasculature adjacent to forming cysts. VIM+ expression was not observed in α-SMA+ cells. Conclusions. Many nonoverlapping as well as fewer overlapping populations of FSP1+ and α-SMA+ cells shared in the collagen expression associated with progressive fibrogenesis in pcy mice undergoing cystogenesis. Some FSP1+ fibroblasts are likely derived from tubular epithelium undergoing EMT, while αSMA+, VIM- cells probably represent vascular smooth muscle cells or pericytes surviving vessel attenuation during the chaos of fibrogenesis. Importantly, not all interstitial cells producing collagens are α-SMA+.

AB - Background. The appearance of interstitial fibrosis in polycystic kidneys is emblematic of progressive disease. Matrix forming this scar tissue is derived from local renal cells in response to cystogenesis. We investigated the phenotype of collagen producing cells in the cystic kidneys of DBA/2-pcy mice to better characterize the spectrum of interstitial cells associated with renal fibrogenesis. Methods. The extent of interstitial fibrosis and the number of fibroblasts in cystic kidneys were first quantitated over time using computer-assisted image analysis. Subsequently, antisera to four cell protein markers were studied by coexpression immunohistochemistry during progression of fibrosis using confocal microscopy. The antisera included fibroblast-specific protein 1 (FSP1) for fibroblast phenotype, α-smooth muscle actin (α-SMA) for contractile phenotype, vimentin (VIM) for mesenchymal phenotype, and heat shock protein 47 (HSP47) for interstitial collagen-producing phenotype. Results. Interstitial fibrosis in cystic kidneys gradually increased throughout the 30-week observation period of our study. With progression of cystogenesis, most of the tubules in pcy mice either dilate4d or disappeared with time. FSP1+ fibroblasts were distributed sparsely throughout the renal interstitium of young pcy and wild-type mice. Their number increased in the widening fibrotic septa by 18 weeks of age and persisted through 30 weeks of the study interval. Some epithelia among remnant tubules trapped within fibrotic septa around adjacent cysts also acquired the phenotype of FSP1+, HSP47+ collagen-producing fibroblasts, suggesting a possible role for epithelial-mesenchy-real transformation (EMT) in this process. Most FSP1+ fibroblasts were α-SMA-, but HSP47+, suggesting they were producing collagen proteins for the extracellular matrix, α-SMA+, FSP1-, HSP47+ or HSP47- cells were also observed, and the latter tended to distribute independently in a linear pattern, reminiscent of vasculature adjacent to forming cysts. VIM+ expression was not observed in α-SMA+ cells. Conclusions. Many nonoverlapping as well as fewer overlapping populations of FSP1+ and α-SMA+ cells shared in the collagen expression associated with progressive fibrogenesis in pcy mice undergoing cystogenesis. Some FSP1+ fibroblasts are likely derived from tubular epithelium undergoing EMT, while αSMA+, VIM- cells probably represent vascular smooth muscle cells or pericytes surviving vessel attenuation during the chaos of fibrogenesis. Importantly, not all interstitial cells producing collagens are α-SMA+.

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