Endogenous BMP-7 is a critical molecular determinant of the reversibility
of obstruction-induced renal injuries
Scott R. Manson,1Robert A. Niederhoff,1Keith A. Hruska,2and Paul F. Austin1
1Department of Surgery, Division of Pediatric Urology, and2Departments of Medicine and Pediatrics, Division of Pediatric
Nephrology, Washington University, St. Louis Children’s Hospital, St. Louis, Missouri
Submitted 31 January 2011; accepted in final form 25 August 2011
Manson SR, Niederhoff RA, Hruska KA, Austin PF. Endog-
enous BMP-7 is a critical molecular determinant of the reversibil-
ity of obstruction-induced renal injuries. Am J Physiol Renal
Physiol 301: F1293–F1302, 2011. First published August 31, 2011;
doi:10.1152/ajprenal.00071.2011.—Although obstructive uropa-
thies are frequently correctable through surgery, the potential for
permanent renal injury remains even following the successful correc-
tion of obstructions. Little is known about the intrinsic mechanisms
that determine the reversibility of renal injuries. We and others found
that exogenous bone morphogenic protein 7 (BMP-7) inhibits the
pathogenesis of renal injury. Here, we examine the role of endogenous
BMP-7 in the outcome of renal recovery following the correction of
obstructive uropathies using a reversible murine model of ureteral
obstruction. The role of BMP-7 was determined by examining the
regulation of BMP-7 during renal recovery and by treating with either
BMP-7-neutralizing antibodies or exogenous BMP-7. While BMP-7
is upregulated following the correction of obstructions that lead to
reversible renal injury, the upregulation of BMP-7 is diminished
following the correction of prolonged obstructions that lead to irre-
versible renal injury. The activation of the BMP-7 pathway is required
for several processes that contribute to renal recovery including the
suppression of transforming growth factor-?-dependent profibrotic
pathways, the restoration of renal architecture, and the resolution of
fibrotic changes in the kidney. Importantly, the therapeutic restoration
of BMP-7 enhances renal recovery following the correction of pro-
longed obstructions that typically lead to irreversible renal injury.
Together, these findings show that, while BMP-7 plays a critical role
in the repair of obstruction-induced renal injuries, the potential for
renal recovery from prolonged obstruction is diminished, in part, due
to the dysregulation of BMP-7. Accordingly, renal recovery from
obstructive uropathies may be optimized through timely intervention
and adjuvant approaches to restore BMP-7 activity.
kidney; ureteral obstruction; fibrosis; bone morphogenic protein 7;
THE CLINICAL MANAGEMENT of obstructive uropathies represents a
significant challenge to the nephrologist/urologist. Although
current surgical approaches are frequently able to correct
obstructive uropathies, the potential for permanent renal injury
remains even following surgical intervention as evidenced by
the fact that obstructive uropathies remain a leading cause of
renal injury, chronic renal insufficiency, and renal failure (3, 4,
18). Thus, important goals in the development of improved
treatment strategies for obstructive uropathies are to identify
the molecular mechanisms that determine the outcome of renal
recovery following surgical intervention and to develop adju-
vant therapeutic approaches to optimize renal recovery in the
patient by targeting those critical molecular mechanisms.
Obstructive uropathies result in the loss of renal structure
and function through a well-described series of pathological
events characterized by apoptosis, inflammation, and fibrosis
(3, 4). Importantly, the kidney has the potential to restore renal
structure and function following moderate levels of renal injury
(5, 13). The repair of renal injuries is mediated in part by a
cycle of dedifferentiation, proliferation, and redifferentiation of
intrinsic renal cells that promotes the regeneration of renal
architecture (10, 12), the recruitment of extrarenal cells that
stimulate repair through paracrine mechanisms (9), and by the
activation of proteolytic pathways that resolve fibrotic changes
in the kidney (13). Nonetheless, in severe renal injuries, the
ability of the kidney to recover from renal injury is frequently
diminished (3, 4). Little is known about the repair-promoting
mechanisms that are impaired during renal recovery in irre-
versible renal injuries.
At the molecular level, the activation of the transforming
growth factor (TGF)-? pathway plays a central role in the
pathogenesis of renal injury by promoting apoptosis, epithelial-
mesenchymal transformation, an increase in matrix protein
synthesis, and other profibrotic events that lead to the disrup-
tion of renal structure and function (2). Accordingly, neutral-
ization of TGF-? inhibits the development of obstruction-
induced renal injury (6, 11, 15). The importance of the TGF-?
pathway in the pathogenesis of renal injury suggests that the
downregulation of the TGF-? pathway is likely an important
event during renal recovery from injury, although this possi-
bility has not yet been thoroughly examined.
Another member of the TGF-? protein superfamily, bone
morphogenic protein 7 (BMP-7), has been demonstrated to
inhibit TGF-?-dependent biological functions (16). Impor-
tantly, treatment with exogenous BMP-7 inhibits the develop-
ment of obstruction-induced renal injury (8, 17, 19). Interest-
ingly, it has been demonstrated that BMP-7 levels are de-
creased during the development of renal injury, suggesting that
the loss of BMP-7 is a critical molecular event during the
pathogenesis of renal injuries (1, 22–24, 26).
Furthermore, our previous studies demonstrated that treat-
ment with exogenous BMP-7 during renal recovery promotes
the repair of obstruction-induced renal injuries (14). These
findings are supported by the findings of Zeisberg et al. (27, 28)
that demonstrated that treatment with exogenous BMP-7 re-
verses the progression of chronic renal injury. While these
studies demonstrate that the renal protective effects of BMP-7
extend beyond simply preventing the development of renal
injury, it remains to be determined what role endogenous
BMP-7 plays in renal recovery following obstruction-induced
In beginning to determine the role of the intrinsic BMP-7
pathway in renal recovery following injury, several important
Address for reprint requests and other correspondence: P. F. Austin, Wash-
ington Univ., 4990 Children’s Place, Suite 1120, Campus Box 8242, St. Louis,
MO 63110 (e-mail: email@example.com).
Am J Physiol Renal Physiol 301: F1293–F1302, 2011.
First published August 31, 2011; doi:10.1152/ajprenal.00071.2011.
1931-857X/11 Copyright © 2011 the American Physiological Societyhttp://www.ajprenal.orgF1293
Fig. 1. Recovery of the kidney following obstruction-induced renal injury. Mice (n ? 3 mice/sample) underwent either sham operation, 2 or 7 days (D) of
obstruction, or 2 or 7 days of obstruction followed by reversal, and 10 days of recovery (REC). Kidneys were analyzed by Masson’s trichrome staining (?200;
left) and type IV collagen immunofluorescence (?200; right; A), interstitial volume quantification (B), tubular volume quantification (C), and kidney collagen
content quantification (D). *P ? 0.05; **P ? 0.01; n.s. denotes P ? 0.05. UUO, unilateral ureteral obstruction.
ENDOGENOUS BMP-7 AND THE REVERSIBILITY OF RENAL INJURIES
AJP-Renal Physiol • VOL 301 • DECEMBER 2011 • www.ajprenal.org
As we work toward realizing the full potential of the utility
of the BMP-7 pathway in the evaluation and treatment of
obstructive uropathies and other conditions that lead to renal
injury, an important future direction will be to elucidate the
molecular mechanisms that regulate BMP-7 levels/activity
during the pathogenesis of renal injury. These and other studies
aimed toward a better understanding of renal recovery follow-
ing injury may allow the innate repair mechanisms of the
kidney to be evaluated during the diagnosis of renal injuries
and manipulated during the treatment of renal injuries.
This research was supported through funding from the Midwest Stone
Institute provided to P. F. Austin.
No conflicts of interest, financial or otherwise, are declared by the author(s).
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ENDOGENOUS BMP-7 AND THE REVERSIBILITY OF RENAL INJURIES
AJP-Renal Physiol • VOL 301 • DECEMBER 2011 • www.ajprenal.org