Progressive renal fibrosis in murine polycystic kidney disease: an immunohistochemical observation

Kidney Int. 2000 Aug;58(2):587-97. doi: 10.1046/j.1523-1755.2000.00205.x.


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, alpha-smooth muscle actin (alpha-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 dilated 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-mesenchymal transformation (EMT) in this process. Most FSP1+ fibroblasts were alpha-SMA-, but HSP47+, suggesting they were producing collagen proteins for the extracellular matrix. alpha-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 alpha-SMA+ cells.

Conclusions: Many nonoverlapping as well as fewer overlapping populations of FSP1+ and alpha-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 alphaSMA+, 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 alpha-SMA+.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Actins / analysis*
  • Animals
  • Biomarkers
  • Cadherins / analysis
  • Calcium-Binding Proteins / analysis*
  • Fibroblasts / chemistry
  • Fibroblasts / pathology
  • Fibrosis
  • Fluorescent Antibody Technique
  • HSP47 Heat-Shock Proteins
  • Heat-Shock Proteins / analysis*
  • Keratins / analysis
  • Kidney / chemistry*
  • Kidney / pathology
  • Male
  • Mice
  • Mice, Inbred DBA
  • Polycystic Kidney Diseases / pathology*
  • S100 Calcium-Binding Protein A4
  • S100 Proteins


  • Actins
  • Biomarkers
  • Cadherins
  • Calcium-Binding Proteins
  • HSP47 Heat-Shock Proteins
  • Heat-Shock Proteins
  • S100 Calcium-Binding Protein A4
  • S100 Proteins
  • S100a4 protein, mouse
  • Serpinh1 protein, mouse
  • Keratins