The BMP-7–Smad1/5/8 Pathway Promotes Kidney Repair After Obstruction Induced Renal Injury

Abstract

PURPOSE Urinary tract obstruction causes hydroureteronephrosis and requires surgical intervention to prevent the development of permanent renal injury. While many studies have focused on the development of renal injuries, here we examine the molecular mechanisms that promote renal recovery following the correction of obstruction. MATERIALS AND METHODS A reversible murine model of ureteral obstruction was used to examine the BMP-7 and TGF-β signaling pathways during renal recovery following obstruction-induced injury. Analysis was conducted using standard molecular techniques including RT-PCR, ELISA, immunoblotting, and co-immunoprecipitation. RESULTS We found that the upregulation of BMP-7 following the correction of obstruction inhibits TGF-β-dependent pro-fibrotic pathways that are central to the pathogenesis of renal injury. The inhibitory effects of BMP-7 are mediated, in part, by the activation of its downstream target proteins, Smad1, Smad5, and Smad8, which suppress the activity of TGF-β-dependent Smad proteins and, in turn, inhibit the expression of TGF-β-dependent genes. Finally, the activation of the BMP-7–Smad1/5/8 pathway during renal recovery promotes the restoration of renal architecture and resolution of fibrosis in the kidney following the correction of obstruction. CONCLUSIONS Together, these findings demonstrate that the BMP-7–Smad1/5/8 pathway promotes the repair of the kidney following obstruction-induced injury. Accordingly, the BMP-7 pathway represents an important therapeutic target to stimulate the innate repair mechanisms of the kidney during the treatment of obstruction-induced renal injuries.

Endogenous BMP-7 is a critical molecular determinant of the reversibility of obstruction-induced renal injuries

“…Furthermore, our previous studies demonstrated that treatment 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 reverses the progression of chronic renal injury.…”

“…2, P Ͻ 0.01; 2 days UUO vs. 2 days UUO/10 days REC, n ϭ 3). The upregulation of BMP-7 is observed within 3 days following the correction of obstruction, the time period where the majority of repair also occurs (14). In contrast, BMP-7 levels remain suppressed during renal recovery following prolonged obstruction, even at 10 days following the correction of obstruction ( Fig.…”

“…Based on the previously described findings (14,27,28), we hypothesized that the activity of the intrinsic BMP-7 pathway plays an important role in determining the outcome of renal recovery following obstruction. Accordingly, we examined the regulation of endogenous BMP-7.…”

Gremlin1 preferentially binds to bone morphogenetic protein-2 (BMP-2) and BMP-4 over BMP-7

“…We and others have shown that Grem1 levels increase during DN whereas levels of BMP-7 decrease [33,46]. Strategies that stimulate BMP-7 signalling have been shown to attenuate renal fibrosis [5,[12][13][14][15][16][17], and reductions in Grem1 levels have a similar beneficial effect in mouse models of DN [32,37]. In vivo reduction of Grem1 via siRNA targeting recovered BMP-7 levels, suggesting that elevated Grem1 may have a role in repressing BMP-7 in DN [37].…”

“…Whereas BMP-4 has been shown to contribute to renal fibrosis, conflicting evidence exists for the pro-or anti-fibrotic role of BMP-2 in this process [8][9][10][11]. BMP-7 is thought of as anti-fibrotic, and has been the focus of many groups who demonstrated its anti-fibrotic activity in models of diabetic nephropathy and other kidney fibrotic diseases [5,[12][13][14][15][16][17]. To date, however, efforts to translate these data into BMP-7-centred treatment of fibrosis have been rather slow to develop [18,19] Canonical BMPs signalling involves the Smad pathway, where BMP dimers bind to type I and type II BMP receptors leading to the formation of a hexameric complex, triggering receptor phosphorylation.…”