Targeted expression of a dominant-negative EGF-R in the kidney reduces tubulo-interstitial lesions after renal injury
Fabiola Terzi, … , Pascale Briand, Gérard Friedlander
Fabiola Terzi, … , Pascale Briand, Gérard Friedlander
Published January 15, 2000
Citation Information: J Clin Invest. 2000;106(2):225-234. https://doi.org/10.1172/JCI8315.
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Article

Targeted expression of a dominant-negative EGF-R in the kidney reduces tubulo-interstitial lesions after renal injury

Abstract

The role of EGF in the evolution of renal lesions after injury is still controversial. To determine whether the EGF expression is beneficial or detrimental, we generated transgenic mice expressing a COOH-terminal–truncated EGF-R under the control of the kidney-specific type 1 γ-glutamyl transpeptidase promoter. As expected, the transgene was expressed exclusively at the basolateral membrane of proximal tubular cells. Under basal conditions, transgenic mice showed normal renal morphology and function. Infusion of EGF to transgenic animals revealed that the mutant receptor behaved in a dominant-negative manner and prevented EGF-signaled EGF-R autophosphorylation. We next evaluated the impact of transgene expression on the development of renal lesions in two models of renal injury. After 75% reduction of renal mass, tubular dilations were less severe in transgenic mice than in wild-type animals. After prolonged renal ischemia, tubular atrophy and interstitial fibrosis were reduced in transgenic mice as compared with wild-type mice. The beneficial effect of the transgene included a reduction of tubular cell proliferation, interstitial collagen accumulation, and mononuclear cell infiltration. In conclusion, functional inactivation of the EGF-R in renal proximal tubular cells reduced tubulo-interstitial lesions after renal injury. These data suggest that blocking the EGF pathway may be a therapeutic strategy to reduce the progression of chronic renal failure.

Authors

Fabiola Terzi, Martine Burtin, Mehrak Hekmati, Pierre Federici, Giselle Grimber, Pascale Briand, Gérard Friedlander

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Figure 1

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Transgene expression and function in transgenic mice. (a) Northern blot ...
Transgene expression and function in transgenic mice. (a) Northern blot analysis. The transgene was detected exclusively in the kidney using the human β-globin poly(A) probe. (b) Immunohistochemical analysis with a specific anti-human EGF-R antibody. The transgene was localized in basolateral membranes of proximal transgenic tubules (EGF-R-M, middle panel), but not in those of wild-type membranes (WT, left panel). Specific staining was detected in the cortex (C) but not in the medulla (M) of transgenic mice (right panel). (c) Western blot analysis of mouse (m-EGF-R) and human (h-EGF-R) EGF receptors in proximal tubular cells from WT and EGF-R-M mice. Similar amounts of endogenous EGF-R were detected by a specific anti–EGF-R intracellular domain antibody in EGF-R-M and WT mice (m-EGF-R), whereas a 110-kDa protein, corresponding to the truncated receptor, was evidenced in transgenic but not in wild-type mice, by a specific anti-human EGF-R antibody (h-EGF-R). A431 cells overexpressing the human endogenous EGF-R (h-EGF-R, 170 kDa) was used as positive control.