Loss of Endogenous Bone Morphogenetic Protein-6 Aggravates Renal Fibrosis

Abstract

Bone morphogenetic protein-6 (BMP-6) suppresses inflammatory genes in renal proximal tubular cells and regulates iron metabolism by inducing hepcidin. In diabetic patients, an increase of myofibroblast progenitor cells (MFPCs), also known as fibrocytes, was found to be associated with decreased BMP-6 expression. We hypothesized that loss of endogenous BMP-6 would aggravate renal injury and fibrosis. Wild type (WT) and BMP-6 null mice underwent unilateral ureteral obstruction. In WT mice, ureteral obstruction down-regulated BMP-6. Obstructed kidneys of BMP-6 null mice showed more casts (1.5-fold), epithelial necrosis (1.4-fold), and brush border loss (1.3-fold). This was associated with more inflammation (1.8-fold more CD45(+) cells) and more pronounced overexpression of profibrotic genes for αSMA (2.0-fold), collagen I (6.8-fold), fibronectin (4.3-fold), CTGF (1.8-fold), and PAI-1 (3.8-fold), despite similar BMP-7 expression. Also, 1.3-fold more MFPCs were obtained from BMP-6 null than from WT mononuclear cell cultures, but in vivo only very few MFPCs were observed in obstructed kidneys, irrespective of BMP-6 genotype. The obstructed kidneys of BMP-6 null mice showed 2.2-fold more iron deposition, in association with 3.3-fold higher expression of the oxidative stress marker HO-1. Thus, ureteral obstruction leads to down-regulation of BMP-6 expression, and BMP-6 deficiency aggravates tubulointerstitial damage and fibrosis independent of BMP-7. This process appears to involve loss of both direct anti-inflammatory and antifibrotic action and indirect suppressive effects on renal iron deposition, oxidative stress, and MFPCs.

MicroRNA-22 Is a Master Regulator of Bone Morphogenetic Protein-7/6 Homeostasis in the Kidney

“…Screening of miRNAs That Target BMP-7/6 in the Kidney-BMP-7 and BMP-6 have recently emerged as key anti-fibrogenic proteins in several experimental models of kidney fibrosis (5)(6)(7)(8)(9)(10)(11). Although it is known that BMP signaling is tightly regulated at various layers, the potential interaction between miRNAs and BMP-7/6 signaling in the kidney has not been established.…”

“…Emerging evidence suggests that BMP-7/6, members of the TGF-␤ superfamily of cysteine knot cytokines, play pivotal roles in kidney homeostasis mainly by antagonizing TGF-␤-induced profibrogenic signaling that contribute to the accumulation of the extracellular matrix (5)(6)(7)(8)(9)(10)(11). In this study, we uncover a critical role of miR-22 on BMP signaling and renal fibrosis by providing strong evidence that miR-22 directly targets BMP-7, BMP-6, and BMPR1B.…”

“…Although the origin of the activated fibroblasts pool in the kidney remains controversial, a growing body of evidence indicates that fibrogenic cues in the kidney evoke multiple intracellular signaling pathways that ultimately lead to phenotypic changes in the fibroblasts, resulting in their activation with characteristic expression of several smooth muscle cell markers (1)(2)(3). Among the many fibrogenic factors that regulate renal fibrotic processes, TGF-␤ and connective tissue growth factor are regarded as key fibrogenic cytokines (1-4), whereas bone morphogenic protein-7 (BMP-7) 3 and BMP-6, have been known as natural antagonists of TGF-␤ signaling and anti-fibrogenic factors that have been shown to prevent renal fibrosis in several experimental models (5)(6)(7)(8)(9)(10)(11).…”

BMPS and Liver: More Questions than Answers

“…Altogether these studies suggest a central role for BMP7 in the progress of liver fibrosis. What is the role of other BMP ligands awaits further studies but it is plausible that other members of the family could participate in liver fibrosis as it has been recently described for renal fibrosis [125,126].…”

BMP-6 Emerges as a Potential Major Regulator of Fibrosis in the Kidney

“…In this issue of The American Journal of Pathology, Dendooven et al 9 have examined expression of BMP-6 in the adult murine kidney and the effect of genetic deletion of BMP-6 on renal BMP signaling and response to renal injury. They found BMP-6 expression in the renal cortex, predominantly the tubulo-interstitium.…”