Renal extracellular matrix accumulation in acute puromycin aminonucleoside nephrosis in rats

C. L. Jones, S. Buch, M. Post, L. McCulloch, E. Liu, A. A. Eddy

Research output: Contribution to journalArticle

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Abstract

Progressive renal fibrosis is considered to be the final common pathway leading to chronic renal insufficiency. In this study, the authors examined some of the cellular and molecular mechanisms regulating the renal accumulation of extracellular matrix (ECM) proteins using rats with puromycin aminonucleoside (PAN) nephrosis as an acute model system. Puromycin aminonucleoside rats developed reversible nephrotic syndrome accompanied by an interstitial infiltrate of monocytes. The number of interstitial fibroblasts expressing ST4 antigen did not increase. During the first 4 days, steady-state mRNA levels for all genes examined remained at or below control levels. At 1 week, nephrotic syndrome and interstitial inflammation were established, and a period of renal cell proliferation occurred, identified by increased histone mRNA levels and localized by tritiated thymine autoradiography to tubular epithelial cells and occasional interstitial cells. Transforming growth factor-beta (TGF-β) steady-state mRNA levels were increased eightfold, but returned to control levels by 3 weeks. At week 1, there was a 10- to 20-fold increase in kidney steady-state mRNA levels for genes encoding interstitial matrix proteins collagen I and fibronectin and basement membrane collagen IV. By in situ hybridization, α1(I) procollagen mRNA was localized to interstitial cells. Immunofluorescence microscopy demonstrated focal accumulation of ECM proteins in the tubulointerstitial compartment at 2 and 3 weeks, but by 6 weeks, kidney immunohistology was normal again. Steady-state mRNA levels for the matrix degrading metalloproteinase stromelysin remained at control values, whereas the levels for interstitial collagenase were normal at week 1 and increased twofold to threefold at 2 and 3 weeks. Steady-state mRNA levels for the tissue inhibitor of metalloproteinases (TIMP) increased fivefold at 1 week and returned to baseline values over the next 2 weeks. The results of this study suggest that tubulointerstitial ECM accumulation occurs in rats with acute PAN nephrosis because of the activation of genes encoding several matrix proteins and inhibition of matrix degradation mediated by TIMP. These events are reversed during the phase of recovery from nephrotic syndrome. Increased mRNA levels for TGF-β, possibly originating from inflammatory interstitial monocytes, are likely to be one of the mediators of the molecular events observed.

Original languageEnglish (US)
Pages (from-to)1381-1396
Number of pages16
JournalAmerican Journal of Pathology
Volume141
Issue number6
StatePublished - Dec 1 1992

Fingerprint

Puromycin Aminonucleoside
Nephrosis
Extracellular Matrix
Kidney
Messenger RNA
Nephrotic Syndrome
Tissue Inhibitor of Metalloproteinases
Extracellular Matrix Proteins
Transforming Growth Factor beta
Monocytes
Collagen
Procollagen
Matrix Metalloproteinase 3
Matrix Metalloproteinase 1
Thymine
Autoradiography
Matrix Metalloproteinases
Chronic Renal Insufficiency
Fibronectins
Fluorescence Microscopy

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Jones, C. L., Buch, S., Post, M., McCulloch, L., Liu, E., & Eddy, A. A. (1992). Renal extracellular matrix accumulation in acute puromycin aminonucleoside nephrosis in rats. American Journal of Pathology, 141(6), 1381-1396.

Renal extracellular matrix accumulation in acute puromycin aminonucleoside nephrosis in rats. / Jones, C. L.; Buch, S.; Post, M.; McCulloch, L.; Liu, E.; Eddy, A. A.

In: American Journal of Pathology, Vol. 141, No. 6, 01.12.1992, p. 1381-1396.

Research output: Contribution to journalArticle

Jones, CL, Buch, S, Post, M, McCulloch, L, Liu, E & Eddy, AA 1992, 'Renal extracellular matrix accumulation in acute puromycin aminonucleoside nephrosis in rats', American Journal of Pathology, vol. 141, no. 6, pp. 1381-1396.
Jones, C. L. ; Buch, S. ; Post, M. ; McCulloch, L. ; Liu, E. ; Eddy, A. A. / Renal extracellular matrix accumulation in acute puromycin aminonucleoside nephrosis in rats. In: American Journal of Pathology. 1992 ; Vol. 141, No. 6. pp. 1381-1396.
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