TGF-β Receptor Deletion in the Renal Collecting System... : Journal of the American Society of Nephrology (original) (raw)

Basic Research

TGF-β Receptor Deletion in the Renal Collecting System Exacerbates Fibrosis

Gewin, Leslie*; Bulus, Nada*; Mernaugh, Glenda*; Moeckel, Gilbert†; Harris, Raymond C.*,‡,§; Moses, Harold L.‖; Pozzi, Ambra*,§,‖; Zent, Roy*,§,‖,¶

Division of Nephrology, Departments of *Medicine,

†Pathology,

‡Molecular Physiology and Biophysics,

‖Cancer Biology, and

¶Cell and Developmental Biology, Vanderbilt Medical Center, Nashville, Tennessee; and

§Department of Medicine, Veterans Affairs Hospital, Nashville, Tennessee

Correspondence: Dr. Roy Zent, Room C3210 MCN, Vanderbilt University Medical Center, Nashville, TN, 37232. Phone: 615-322-4632; Fax: 615-343-7156; E-mail: [email protected]

Received February 5, 2010

Accepted April 11, 2010

Abstract

TGF-β plays a key role in upregulating matrix production in injury-induced renal fibrosis, but how TGF-β signaling in distinct compartments of the kidney, such as specific segments of the nephron, affects the response to injury is unknown. In this study, we determined the role of TGF-β signaling both in development of the renal collecting system and in response to injury by selectively deleting the TGF-β type II receptor in mice at the initiation of ureteric bud development. These mice developed normally but demonstrated a paradoxic increase in fibrosis associated with enhanced levels of active TGF-β after unilateral ureteral obstruction. Consistent with this observation, TGF-β type II receptor deletion in cultured collecting duct cells resulted in excessive integrin αvβ6-dependent TGF-β activation that increased collagen synthesis in co-cultured renal interstitial fibroblasts. These results suggest that inhibiting TGF-β receptor–mediated function in collecting ducts may exacerbate renal fibrosis by enhancing paracrine TGF-β signaling between epithelial and interstitial cells.