Targeting REDD1 in Podocytes: A Promising Strategy for Mitigating Diabetic Kidney Injury

Diabetic nephropathy (DN) is a common and severe complication of diabetes, characterized by progressive decline of kidney function leading to end-stage kidney disease. High glucose levels induce structural and functional damage in the kidneys, with podocytes, which are essential for maintaining the integrity and permeability of the glomerular filtration barrier, especially susceptible to injury in DN (1). The damage or loss of these cells significantly contributes to disease progression, making therapeutic strategies targeting podocytes a key focus in treating DN.

In a recent study by Sunilkumar et al. published in this issue of Diabetes (2), the stress response protein regulated in development and DNA damage response 1 (REDD1) was identified as a potential therapeutic target for DN. REDD1 expression is activated by a variety of cellular stressors, including hypoxia, energy depletion, endoplasmic reticulum stress, insulin signaling, and oxidative stress (3,4). As a crucial endogenous regulator of the Akt/mTOR pathway, REDD1 typically acts as a repressor under stress conditions (3,5,6). Extensive evidence links REDD1 to various diseases, highlighting its role as a key mediator of cellular stress responses. A recent review by the same group of authors summarized findings on the role of REDD1 in the development of diabetes complications and discussed potential opportunities for targeting this signaling pathway as a therapeutic approach (7). For instance, it was reported that diabetes enhances REDD1-dependent activation of glycogen synthase kinase 3β (GSK3β) to promote canonical nuclear factor-κB (NF-κB) signaling and macrophage infiltration in the retina of diabetic mice (8). While REDD1 has been examined in many studies in different contexts, its role in kidney pathology remains incompletely understood. Research in this area remains highly relevant and necessary, as understanding the precise mechanisms of REDD1’s involvement could lead to new therapeutic strategies for a range of kidney diseases.

The study discussed here provides evidence for REDD1’s involvement in the pathogenesis of DN and podocyte injury. Using a combination of in vivo and in vitro loss-of-function approaches, the authors demonstrated that podocyte-specific expression of the stress response protein REDD1 is essential for podocyte loss, deterioration of the glomerular filtration barrier, and the subsequent decline in kidney filtration function in a mouse model of type 1 diabetes. The study first showed that, following streptozotocin (STZ)-induced diabetes in mice, elevated REDD1 levels in the kidney were linked to a reduction in podocin expression. The deletion of REDD1 prevented this reduction in podocin in both diabetic mice and human podocyte cultures under hyperglycemic conditions (2). These findings suggest that REDD1 expression in podocytes is crucial for the progression of renal injury in diabetes. To further investigate, the authors generated podocyte-specific REDD1 knockout (podKO) mice and found that, following STZ-induced diabetes, both diabetic and nondiabetic podKO mice maintained blood glucose levels comparable with those of controls. However, deletion of REDD1 in podocytes led to reduced glomerular REDD1 protein levels and prevented the diabetes-induced increase in REDD1 expression. It also mitigated the reduction in Nphs2 mRNA and podocin protein levels observed in diabetes conditions, indicating that podocyte-specific REDD1 contributes to decreased podocin. Additionally, with the deletion the architecture of podocyte foot processes was preserved and the thickness of the glomerular basement membrane was maintained in diabetic mice (2). These findings indicate that REDD1 contributes to disrupting podocyte structure and function under hyperglycemic conditions.

Interestingly, the authors found that REDD1 plays a role in regulating the transient receptor potential canonical type 6 (TRPC6) expression and altering podocyte structure. They demonstrated that REDD1 promotes NF-κB–dependent transcription of TRPC6, a cation channel involved in calcium influx into podocytes under hyperglycemic conditions (Fig. 1) (9,10). This mechanism resulted in elevated intracellular calcium levels, potentially contributing to cytoskeletal remodeling and podocyte injury in diabetes conditions (2). By deleting REDD1 in podocytes, the authors demonstrated a reduction in TRPC6 expression and stabilization of intracellular calcium levels, suggesting a potential pathway through which REDD1 exacerbates podocyte damage. This finding is particularly significant because TRPC6 is abundantly expressed in podocytes, where it plays a crucial role in maintaining their morphology and function. As the primary calcium channel in podocytes, TRPC6 serves as a key regulator of calcium homeostasis, which is essential for various cellular processes, including cytoskeletal organization, signaling pathways, and cell survival (1,9). TRPC6 is implicated in various kidney pathologies, including glomerulosclerosis and DN, where its dysregulation contributes to podocyte injury and impaired kidney function (11–13). This mechanism underscores REDD1’s role in disrupting podocyte function and exacerbating glomerular damage under hyperglycemic conditions. The findings support the hypothesis that targeting REDD1 in podocytes could be a promising therapeutic strategy for mitigating the progression of DN. By reducing REDD1 expression or inhibiting its downstream effects, it may be possible to preserve podocyte function and prevent severe renal complications associated with diabetes. This highlights a potential new direction for developing therapies to protect kidney function in patients with diabetes.

This study provides valuable insights into the role of REDD1 in DN and highlights its potential as a therapeutic target. However, several limitations should be considered. The research primarily used male C57BL/6 mice with STZ-induced diabetes, a common model for type 1 diabetes. C57BL/6 mice, however, typically exhibit relatively mild glomerular pathology and albuminuria. Moreover, only male mice were studied due to the resistance of female mice to STZ-induced diabetes. These factors may limit the applicability of the findings to more advanced forms of DN observed in human patients with complex pathophysiology of glomeruli injury. Future studies should investigate different mouse strains that exhibit more pronounced glomerular damage and albuminuria to better replicate the aggressive forms of DN observed in humans. Another limitation is that the study focused exclusively on type 1 DN, whereas type 2 is more prevalent and may involve different pathological mechanisms. Additionally, although the study focused on the podocyte-specific deletion of REDD1, other kidney cell types also express REDD1 and may contribute to the progression of DN. This focus limits the ability to draw broader conclusions about the overall role of REDD1 in DN. Another important question raised by the authors, REDD1 promotes NF-κB–dependent TRPC6 expression but other transcription factors may also regulate TRPC6 through NF-κB–independent mechanisms, suggesting that TRPC6 regulation may be more complex than initially proposed. Further research is needed to fully elucidate the pathways involved. Moreover, the study did not explore the interaction between REDD1 and the Akt/mTOR pathway, a key regulator of cell stress response (14), which may be important under diabetes conditions. The progression of DN involves intricate mechanisms and pathways, with REDD1’s functions potentially varying significantly depending on cell type, context, interaction partners, and cellular localization.

Despite these limitations, this study provides crucial insights into the role of REDD1 in mediating podocyte dysfunction and glomerular damage in DN, highlighting it as an important area for future research. The findings underscore REDD1’s potential as a therapeutic target, suggesting that modulating its activity could help protect against kidney damage in patients with diabetes. Future research could focus on extending these findings to more complex models and investigating how REDD1 interacts with other signaling pathways involved in DN development. Such efforts could ultimately lead to new strategies for preventing or treating DN, thereby improving patient outcomes.