Hepatocyte growth factor attenuates high glucose-disturbed mitochondrial dynamics in podocytes by decreasing ARF6-dependent DRP1 translocation

by Selleckchem | Dec 23 2023

Diabetic nephropathy (DN), one of the most common complications of Diabetes Mellitus, is the leading cause of end-stage renal diseases worldwide. Our previous study proved that hepatocyte growth factor (HGF) alleviated renal damages in mice with type 1 Diabetes Mellitus by suppressing overproduction of reactive oxygen species (ROS) in podocytes, while the further mechanism of how HGF lessens ROS production had not been clarified yet. ADP-ribosylation factor 6 (ARF6), the member of the small GTPases superfamilies, is widely spread among epithelial cells and can be activated by the HGF/c-Met signaling. Thus, this study was aimed to explore whether HGF could function on mitochondrial homeostasis, the main resource of ROS, in podocytes exposed to diabetic conditions via ARF6 activation. Our in vivo data showed that HGF markedly ameliorated the pathological damages in kidneys of db/db mice, especially the sharp decline of podocyte number, which was mostly blocked by the ARF6 inhibitor SecinH3. Correspondingly, our in vitro data revealed that HGF protected against high glucose-induced podocyte injuries by increasing ARF6 activity. Besides, this ARF6-dependent beneficial effect of HGF on podocytes was accompanied by improved mitochondrial dynamics and declined DRP1 translocation from cytosol to mitochondria. Collectively, our findings confirm the ability of HGF maintaining mitochondrial homeostasis in diabetic podocytes via decreasing ARF6-dependent DRP1 translocation and shed light on the novel mechanism of HGF treatment for DN.

Comments:

That's an intriguing study! It seems like your research delves into the intricate mechanisms by which HGF (hepatocyte growth factor) mitigates renal damage in diabetic nephropathy (DN) by focusing on podocytes and their mitochondrial homeostasis.

Your findings suggest a compelling link between HGF and the regulation of mitochondrial dynamics in podocytes under diabetic conditions via the activation of ADP-ribosylation factor 6 (ARF6). This activation seems to contribute to the protection of podocytes against high glucose-induced injuries, ultimately leading to a decline in podocyte loss and improved kidney function in diabetic mice.

The involvement of ARF6 in this process is particularly interesting, as it appears to mediate the beneficial effects of HGF on podocytes, possibly by modulating mitochondrial dynamics and inhibiting the translocation of DRP1 (dynamin-related protein 1) from the cytosol to mitochondria. This action might play a crucial role in reducing reactive oxygen species (ROS) production within podocytes, thereby preventing renal damage in diabetes.

Understanding the role of HGF in maintaining mitochondrial homeostasis and its interplay with ARF6 could indeed pave the way for novel therapeutic approaches in treating diabetic nephropathy. The connection between growth factors like HGF and intracellular signaling pathways within podocytes sheds light on potential targets for interventions aimed at preserving kidney function in diabetes.

Have you considered any further experiments or investigations to delve deeper into the specific molecular pathways involved in this process?