Cell Biology – Immunology – Pathology
Kidney International (2000) 58, 587–597; doi:10.1046/j.1523-1755.2000.00205.x
Progressive renal fibrosis in murine polycystic kidney disease: An immunohistochemical observation
Editor's Note: Jared Grantham served as Guest Editor during the review of this article.
Hirokazu Okada, Shinichi Ban, Shizuko Nagao, Hisahide Takahashi, Hiromichi Suzuki and Eric G Neilson
Department of Nephrology, and Second Department of Pathology, Saitama Medical College, Irumagun, and Laboratory Animal Center, Fujita Health University, Toyoake, Japan; and Division of Nephrology and Hypertension, Departments of Medicine and Cell Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
Correspondence: Eric G. Neilson, M.D., Department of Medicine, D-3100 MCN, Vanderbilt University Medical Center, Nashville, Tennessee 37232-2358, USA. E-mail: Eric.Neilson@mcmail.vanderbilt.edu
Received 12 August 1999; Revised 27 January 2000; Accepted 18 February 2000.
Abstract
Progressive renal fibrosis in murine polycystic kidney disease: An immunohistochemical observation.
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, 
-smooth muscle actin (-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 -SMA-, but HSP47+, suggesting they were producing collagen proteins for the extracellular matrix. -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 -SMA+ cells.
Conclusions
Many nonoverlapping as well as fewer overlapping populations of FSP1+ and -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 SMA+, 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 -SMA+.
Keywords:
fibroblast, myofibroblast, -smooth muscle actin, heat shock protein 47
