Obstructive uropathies are a leading cause of renal injury, chronic renal insufficiency, and renal failure.1–3
While current surgical approaches are frequently able to alleviate urinary tract obstructions, the possibility for irreversible renal injury remains even following treatment.2, 3
Therefore, the clinical management of obstructive uropathies would benefit from the development of therapeutic approaches that promote renal recovery following injury.
While the development of renal injuries is well understood,2, 3
renal recovery following injury is less clearly understood. Despite lacking a true regenerative ability,4
the mature kidney has an innate ability to restore renal structure and function following injury. However, this reparative ability is diminished following severe renal injury.5, 6
Understanding the processes that promote renal recovery and their molecular regulation may enable the development of therapeutic approaches to stimulate the innate repair mechanisms of the kidney during the treatment of obstruction-induced injuries.
At the molecular level, the activation of the TGF-β pathway plays a central role in the pathogenesis of renal injury by promoting apoptosis, epithelial-mesenchymal transformation, matrix protein synthesis, and other pro-fibrotic events that lead to the disruption of renal structure and function.7
Accordingly, neutralization of TGF-β inhibits the progression of obstruction-induced renal injury.8–10
Another member of the TGF-β superfamily, BMP-7, has the distinguishing property of inhibiting TGF-β-dependent biological functions.11
Both TGF-β and BMP-7 signal through receptor complexes that phosphorylate Smad transcription factors.11–13
TGF-β and BMP-7 have different functions, in part, because they promote the activating phosphorylation of distinct Smad proteins. TGF-β activates Smad2/3 whereas BMP-7 activates Smad1/5/8. These phosphorylated Smad proteins then bind the Smad4 protein and regulate the transcription of target genes in a pathway-specific manner.11–13
While the signaling pathways downstream of TGF-β and BMP-7 have been well defined, the mechanisms by which BMP-7 counters TGF-β in the kidney have not yet been clearly defined.
Importantly, treatment with exogenous BMP-7 inhibits the development of renal injuries.14–16
In this manuscript, we explore the possibility that BMP-7 may inhibit the pathogenesis of renal injury, in part, by promoting the repair of the kidney. While several studies have demonstrated that exogenous BMP-7 reverses the progression of chronic renal injury, 17, 18
chronic injury models have not been able to effectively differentiate between the effects of BMP-7 on the development of renal injury and on the repair of renal injuries since, in these models, the injurious stimuli is continuously present.
In beginning to determine the role of the BMP-7 pathway in renal recovery following injury, several important questions remain to be answered: (1) Is the BMP-7 pathway regulated during renal recovery? (2) By what mechanisms does BMP-7 counter TGF-β in the injured kidney and are these counter-regulatory mechanisms subject to regulation during renal recovery? and (3) Is pharmacologic manipulation of the BMP-7 pathway an effective therapeutic approach to stimulate the innate repair mechanisms of the kidney during the treatment of renal injuries? Here, we begin to address these questions in order to better understand the molecular mechanisms that contribute to renal recovery following obstruction-induced injury.