Bone morphogenetic protein-7 attenuates pancreatic damage under diabetic conditions and prevents progression to diabetic nephropathy via inhibition of ferroptosis

Abstract

BackgroundApproximately 30% of diabetic patients develop diabetic nephropathy, a representative microvascular complication. Although the etiological mechanism has not yet been fully elucidated, renal tubular damage by hyperglycemia-induced expression of transforming growth factor-β (TGF-β) is known to be involved. Recently, a new type of cell death by iron metabolism called ferroptosis was reported to be involved in kidney damage in animal models of diabetic nephropathy, which could be induced by TGF-β. Bone morphogenetic protein-7 (BMP7) is a well-known antagonist of TGF-β inhibiting TGF-β-induced fibrosis in many organs. Further, BMP7 has been reported to play a role in the regeneration of pancreatic beta cells in diabetic animal models.MethodsWe used protein transduction domain (PTD)-fused BMP7 in micelles (mPTD-BMP7) for long-lasting in vivo effects and effective in vitro transduction and secretion.ResultsmPTD-BMP7 successfully accelerated the regeneration of diabetic pancreas and impeded progression to diabetic nephropathy. With the administration of mPTD-BMP7, clinical parameters and representative markers of pancreatic damage were alleviated in a mouse model of streptozotocin-induced diabetes. It not only inhibited the downstream genes of TGF-β but also attenuated ferroptosis in the kidney of the diabetic mouse and TGF-β-stimulated rat kidney tubular cells.ConclusionBMP7 impedes the progression of diabetic nephropathy by inhibiting the canonical TGF-β pathway, attenuating ferroptosis, and helping regenerate diabetic pancreas.

Broadening horizons: the multifaceted functions of ferroptosis in kidney diseases

“…Therefore, further investigation of the ferroptotic biomarkers has broad prospects for performing targeted therapies in kidney diseases. With advances of studies, many new regulators related to ferroptosis have been confirmed, such as ACSL4 61 , bone morphogenetic protein-7 (BMP7) 164 and ZRT/IRT-like protein 14 (ZIP14) 126 , which will further promote the understanding of the regulatory mechanism of ferroptosis and provide promising directions for expanding novel drugs for the treatment of kidney diseases in the future.…”

Targeting ferroptosis as a prospective therapeutic approach for diabetic nephropathy

“…Further experiments demonstrated that N-acetylcysteine (NAC) and insulin combination therapy had an anti-ferroptosis ability in renal TEC, likely by binding Sirt3 and increasing the expression of Sirt3 and GPX4 expression while inhibiting that of sod2, indicating a novel signaling SIRT3-SOD2-Gpx4 in ameliorating DN through preserving the mitochondrial homeostasis and alleviating ferroptosis [ 49 ]. In mice RTECs, Bone morphogenetic protein-7 (BMP7), an antagonist of TGF-β, has been shown to accelerate the regeneration of pancreatic beta cells to inhibit ferroptosis through GPX4 signaling [ 50 ].…”