Abstract
Treatment with rhBMP7 exerts profound protective effects in a wide variety of experimental models of renal disease. However, little is known about how these protective effects are mediated, and which cells in the kidney are targeted by exogenous rhBMP7 treatment. To determine if rhBMP7 increases glomerular and tubulointerstitial canonical BMP signaling, we performed Unilateral Ureteral Obstruction (UUO, a widely used obstructive nephropathy model) in mice reporting transcriptional activity downstream of canonical BMP signaling by the expression of GFP under the BMP Responsive Element of the Id1 promoter (BRE:gfp mice). We also analysed the impact of rhBMP7 treatment on severity of the UUO phenotype, on TGFβ signaling, and on expression of CCN2 (CTGF). Despite profound protective effects with respect to morphological damage, macrophage infiltration, and fibrosis, no significant difference in GFP-expression was observed upon rhBMP7 administration. Also TGFβ signalling was similar in rhBMP7 and vehicle treated mice, but CCN2 expression in obstructed kidneys was significantly reduced by rhBMP7 treatment. Of note, in heterozygous CCN2 mice (CCN2+/−) treatment with rhBMP7 did not (further) reduce the severity of kidney damage in the UUO-model. These data suggest that protection against obstructive nephropathy by exogenous rhBMP7 treatment relies primarily on non-canonical BMP signaling, and may be mediated in large part by downregulation of CCN2 expression.
Highlights
Irrespective of underlying aetiology, chronic kidney disease (CKD) involves structural changes, and loss of function and fibrosis
The present study confirms that recombinant human BMP7 (rhBMP7) treatment reduces the severity of kidney damage, macrophage infiltration, and myofibroblast accumulation in a mouse model of obstructive nephropathy (UUO)
Transcriptional activity downstream of canonical BMP signaling, and TGFβ expression and transcriptional activity, appeared not to be altered by rhBMP7 treatment, while the expression of CCN2 was significantly reduced in the obstructed kidneys (OBK) of BMP7-treated mice
Summary
Irrespective of underlying aetiology, chronic kidney disease (CKD) involves structural changes, and loss of function and fibrosis. Numerous studies targeting TGFβ in various experimental diseases have yielded favourable results, but recent clinical trials have questioned efficacy of available interventions in human CKD (Akhurst and Hata 2012; Muñoz-Félix et al 2015) (Clinicaltrial.gov numbers NCT00464321 and NCT01113801). Several landmark papers have shown efficacy of BMP7 treatment in a wide range of experimental models of renal disease including diabetic nephropathy, obstructive uropathy, nephron loss and ischemic injury (Vukicevic et al 1998; Hruska et al 2000; Morrissey et al 2002; Wang et al 2003; Zeisberg et al 2003; Dube et al 2004; Sugimoto et al 2007), and a BMP-mimetic (THR-185) is under study in a phase II clinical trial (Clinicaltrial.gov number NCT01830920). Several other BMPs are expressed in the kidney throughout development and adulthood, including BMP4 and BMP6, the potential therapeutic effects of BMP7 are considered most potent (Zeisberg et al 2003; Dendooven et al 2011)
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