Activation of Bone Morphogenetic Protein 4 Signaling Leads to Glomerulosclerosis That Mimics Diabetic Nephropathy

Abstract

Diabetic nephropathy (DN) is the most common cause of chronic kidney disease. We have previously reported that Smad1 transcriptionally regulates the expression of extracellular matrix (ECM) proteins in DN. However, little is known about the regulatory mechanisms that induce and activate Smad1. Here, bone morphogenetic protein 4 (Bmp4) was found to up-regulate the expression of Smad1 in mesangial cells and subsequently to phosphorylate Smad1 downstream of the advanced glycation end product-receptor for advanced glycation end product signaling pathway. Moreover, Bmp4 utilized Alk3 and affected the activation of Smad1 and Col4 expressions in mesangial cells. In the diabetic mouse, Bmp4 was remarkably activated in the glomeruli, and the mesangial area was expanded. To elucidate the direct function of Bmp4 action in the kidneys, we generated transgenic mice inducible for the expression of Bmp4. Tamoxifen treatment dramatically induced the expression of Bmp4, especially in the glomeruli of the mice. Notably, in the nondiabetic condition, the mice exhibited not only an expansion of the mesangial area and thickening of the basement membrane but also remarkable albuminuria, which are consistent with the distinct glomerular injuries in DN. ECM protein overexpression and activation of Smad1 in the glomeruli were also observed in the mice. The mesangial expansion in the mice was significantly correlated with albuminuria. Furthermore, the heterozygous Bmp4 knock-out mice inhibited the glomerular injuries compared with wild type mice in diabetic conditions. Here, we show that BMP4 may act as an upstream regulatory molecule for the process of ECM accumulation in DN and thereby reveals a new aspect of the molecular mechanisms involved in DN.

Bone morphogenetic protein 4 inhibits insulin secretion from rodent beta cells through regulation of calbindin1 expression and reduced voltage-dependent calcium currents

“…Generally, BMP2/4 may be considered as inflammatory markers in several metabolic tissues. Under diabetic conditions, expression of BMP2 or BMP4 has been reported to increase in the arteries, kidney, bones and islets [4,14,18,19]. Increased BMP4 expression was reflected by increased circulating levels of BMP4 in type 2 diabetic patients in one study [13].…”

“…In contrast, deficiency of inhibitor of differentiation 1 (Id1), encoding a central BMP-regulated transcription factor, resulted in enhanced insulin secretion and protection from diet-induced glucose intolerance, suggesting that BMPs and ID1 normally inhibit adult beta cell function [17]. BMPs are both released from and affect several metabolically relevant tissues, including fat, liver and kidney, thus adding to the complexity of the role of BMPs in metabolism [14,18,19]. To characterise the direct effects of BMPs on beta cells, we recently reported BMP4-mediated inhibition of beta cell proliferation and repression of GSIS from mouse, rat and human islets [4].…”

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

“…BMPs have a critical role in kidney development as evidenced by data showing that BMP-7 null mice are postnatal lethal due to various developmental abnormalities including kidney agenesis [6,7]. 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].…”

Bone Morphogenetic Protein 4 and Smad1 Mediate Extracellular Matrix Production in the Development of Diabetic Nephropathy

“…Although a previous report indicated that this promoter could be transactivated in glomerular epithelial cells (16), another report showed that the transgene under this promoter is expressed ubiquitously in glomeruli (17); therefore, it could still work in mesangial cells. Transgenic mice expressing SMAD1 were generated as described (18). Integration of the transgene into host genome was confirmed by Southern blot analysis of DNA using a 32 P-labeled SMAD1 cDNA fragment as a probe (Fig.…”