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Recent advances in understanding the mechanisms by which sodium-glucose co-transporter type 2 inhibitors protect podocytes in diabetic nephropathy

Diabetology & Metabolic Syndrome volume 17, Article number: 84 (2025) Cite this article

This article has been updated

Abstract

Background

Diabetes mellitus is associated with systemic damage across multiple organ systems, and an increasing number of patients are presenting with diabetic kidney disease as its initial manifestation. The onset and progression of diabetic nephropathy is closely associated with podocyte injury.

Main body

Sodium-glucose cotransporter type 2 (SGLT2) inhibitors, which can significantly reduce glucose levels as well as protecting against kidney damage, are therefore widely used for the clinical treatment of patients with diabetic kidney disease. An increasing body of research has revealed that the renal protective effect of SGLT2 inhibitors is primarily derived from their enhancement of podocyte autophagy and their inhibition of inflammation and podocyte apoptosis. Multiple signaling pathways are involved in these processes.

Conclusion

A deeper exploration of the renal protective effects of SGLT2 inhibitors and the underlying mechanisms will provide more solid theoretical support for their application in the prevention and treatment of diabetic kidney disease.

Background

Diabetes mellitus(DM), a metabolic disease characterized by chronic hyperglycemia, is typically caused by defective insulin secretion and/or utilization that can be due to various etiological factors. Long-term disorders of carbohydrate, fat, and protein metabolism, can damage multiple systems, leading to chronic progressive lesions, functional decompensation, and failure of tissues and organs such as the eyes, kidneys, nerves, heart, and blood vessels. DM often co-occurs with microangiopathy, with diabetic kidney disease (DKD) a common complication.DKD is often the first symptom of chronic kidney disease (CKD), the incidence of which has increased to 10.8% of Chinese adults [1], part of the DM patients are often diagnosed with DKD and other complications as the first symptom. Early identification of DKD and its early treatment are therefore of great prognostic significance in patients with DM.

The 2024 American Diabetes Association Standards for the Management of Diabetes Mellitus [2] recommends the use of a sodium-glucose co-transporter (SGLT) 2 inhibitor in patients with type 2 DM and CKD (defined as an estimated glomerular filtration rate of 20–60 mL/min/1.73 m2 and/or albuminuria), to minimize the deterioration of DN and reduce the incidence of cardiovascular events and hospitalization for heart failure.In addition, the KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease and the KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease both recommend treating patients with type 2 DM, CKD, and an estimated glomerular filtration rate (eGFR) ≥ 20 ml/min/1.73 m² with a SGLT2 inhibitor [3, 4].This review aimed to explore the mechanisms by which SGLT2 inhibitors protect podocytes from DKD-induced damage.

Podocyte damage due to hyperglycemia

Podocytes are unique and highly differentiated terminal glomerular epithelial cells that attach to the outside of the glomerular basement membrane. Along with endothelial cells and the glomerular basement membrane, they form the glomerular filtration barrier, and are an indispensable component of this barrier [5]. An impaired glomerular filtration barrier can lead to proteinuria. DKD is associated with significant structural and functional changes to glomeruli and podocytes. In the glomeruli, hyperglycemia induces glomerular basement membrane thickening, hypertrophy and proliferation of mesangial cells, and sedimentation of the mesangial matrix.During this prossess, podocytes undergo a series of morphological changes, including hypertrophy, epithelial–mesenchymal transition (EMT), detachment, and apoptosis [1]. These alterations damage the glomerular filtration barrier and ultimately lead to proteinuria; thus, podocyte injury is key to the development and progression of DKD [6].

Hara et al. [7] found that levels of the urinary podocyte marker, podocalyxin (PODXL), directly correlated with the degree of podocyte damage in IgA nephropathy and purpura nephritis. PODXL has been used to detect glomerular diseases with a sensitivity of 88.4% and a specificity of up to 100% [8]. A clinical study by Kostovska et al. [9] showed that urinary PODXL identified early DKD with a specificity of 93.3% and sensitivity of 73.3%, compared with a sensitivity of 41.5% and specificity of 90% for the urinary albumin-to-creatinine ratio. Because PODXL originates from the apical membrane region of podocytes, it appears at an early stage of glomerular injury, and is therefore an earlier marker of renal injury than the urinary albumin-to-creatinine ratio. As the early detection of podocyte injury and DN are vital for the prognosis of DN, the detection of urinary podocyte marker proteins represents a valuable clinical tool.

DM induces a high glucose and high fat environment. High glucose levels cause the accumulation of harmful substances such as advanced glycation end product(AGEs)and reactive oxygen species (ROS), which induce kidney damage via the fusion of podocyte foot processes and their apoptosis. Abnormalities in lipid metabolism can further damage renal cells. Long-term oxidative stress and glucose and lipid metabolism dysfunction can induce inflammation and promote the progression of DKD to end-stage renal disease [10].

SGLT2 inhibitors and podocyte injury in DN

Under physiological conditions, glucose reabsorption in renal tubules is performed by two types of transporter proteins: glucose transporters (GLUTs) and SGLTs [11]. SGLT2, a low-affinity, high-transporting protein mainly expressed in proximal tubules, is responsible for 90% of glucose reabsorption. SGLT2 inhibitors suppress glucose reabsorption and promote its excretion in urine. In addition, they exert renal protective effects through multiple mechanisms, including anti-inflammatory effects and the reduction of oxidative stress, as well as the normalization of glomerular hyperfiltration [12]. SGLT2 inhibitors, including empagliflozin (EMPA-REG Outcome), canagliflozin (CREDENCE trial), and dapagliflozin (DAPA-CKD), have been shown to cause a significant and clinically relevant reduction in the risks of albuminuria and progression of nephropathy, doubling of serum creatinine levels, and initiation of renal replacement therapy [13].Wanner et al. [14] studied 4124 patients with DN and found that those patients who received 10 or 25 mg oral empagliflozin daily had a significantly lower risk of progression to macroalbuminuria or clinically relevant renal outcomes, such as a doubling of the serum creatinine level and initiation of renal-replacement therapy, than that of those in the placebo group.Oraby et al. [15] used a rat model of DN to show that the SGLT2 inhibitor dapagliflozin was able to reduce the levels of renal injury markers, including kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL), as well as the activities of malondialdehyde, a biomarker of oxidative stress, and inflammation in kidney tissues.These results suggest that dapagliflozin can prevent hyperglycemia-induced renal tubular and podocyte injury, attenuating inflammation and oxidative stress and inhibiting podocyte apoptosis.

Mechanisms underlying the protection of podocytes by SGLT2 inhibitors

Previous studies have identified several pathological mechanisms of podocyte injury, including hypertrophy, EMT, apoptosis, autophagy, and pyroptosis [6]. These can be regulated by SGLT2 inhibitors.

Inhibition of podocyte apoptosis

Apoptosis, a type of programmed cell death, is regulated under normal physiological conditions by balancing pro- and anti-apoptotic factors [16]. In a high-glucose environment, this homeostasis is disrupted and podocyte apoptosis occurs [17]. Podocyte apoptosis has been shown to involve the transforming growth factor-β1 (TGF-β1), angiotensin II(Ang II), adenosine 5’-monophosphate (AMP)-activated protein kinase (AMPK), ROS, endoplasmic reticulum stress, p53, phosphatase and tensin homolog/phosphoinositide-dependent kinase-1/Akt/mammalian target of rapamycin (mTOR), and B-cell lymphoma (Bcl)-2/Bcl-2 associated X (Bax) signaling pathways [18,19,20,21]. Mima et al. [22] demonstrated that podocyte apoptosis induced by high glucose was reduced by 25 ± 20% following the addition of 50 nM linagliptin.Linagliptin treatment also ameliorated the effects of high glouse levels on insulin receptor substrate 1 (IRS1) and Akt phosphorylation. Similarly, SGLT-2 inhibitors exhibit anti-apoptotic effects through multiple pathways.Sun et al. [23] established a cellular model of glucose-induced injury using an HK-2 human renal tubular epithelial cell line. Adding dapagliflozin significantly reduced apoptosis, indicating that SGLT2 inhibitors suppress apoptosis induced by hyperglycemia.

Regulation of Bax/Bcl-2 expression

Caspases are a family of cysteine proteases that regulate apoptosis. Promoter caspases (including caspase-2, -8, -9, -10, -11 and − 12) bind tightly to pro-apoptotic signals. Initiator caspases (caspase-2, -8, -9, and − 10) are activated in response to apoptotic stimuli; these proteolytically cleave and activate effector or executioner caspases (caspase-3, -6, and − 7), which induce apoptosis by shearing cellular proteins at specific aspartate residues [24]. The Bcl-2 family also plays crucial roles in the regulation of apoptosis, with pro-apoptotic family members including Bax, Bcl-2 homologous antagonist/killer, and Bcl-2 related ovarian killer, and anti-apoptotic family members including Bcl-2, Bcl-extra large, and Bcl-w [25]. Cleavage of the caspase-3 zymogen by activated caspase-8 promotes the activation of Bax proteins and therefore apoptosis. Wei [26] used a mouse model of diabetes to show that treatment with the SGLT2 inhibitor canagliflozin significantly reduced the protein expression levels of Bax, cleaved-caspase-3, and Bc1-2. Sun et al. [27] used human podocytes cultured under hyperglycemic conditions and a rat model of diabetes to establish that dapagliflozin reduced the protein expression levels of Bax and caspase-3, increased the protein expression levels of Bcl-2, and significantly reduced apoptosis of podocytes and renal tissue damage. These studies suggest that SGLT2 inhibitors reduce podocyte apoptosis and kidney injury by regulating Bax/Bcl-2 expression.

Suppression of the mitogen-activated protein kinase signaling pathway

The mitogen-activated protein kinase (MAPK) signaling pathway plays crucial roles in a variety of cellular processes, including proliferation, differentiation, apoptosis, and the stress response. It includes four major branches: extracellular signal-regulated kinase, c-Jun N-terminal kinase, p38 MAPK, and extracellular signal-regulated kinase 5, of which p38 MAPK and c-Jun N-terminal kinase are mainly associated with stress responses and apoptosis [28];the activation of these two pathways can be involved in a variety forms of stress-mediated cell apoptosis.Recent research [29] suggests that vascular endothelial growth factor (VEGF) is expressed in podocytes and plays a role in maintaining the filtration barrier.Mima et al. [30] found that elevated glucose levels induced protein kinase Cδ and p38 MAPK to increase Src homology-2 domain-containing phosphatase-1 expression, increased podocyte apoptosis, and inhibited VEGF activation in podocytes and glomerular endothelial cells. Chen et al. [31] studied 47 patients with DN and found that those patients who received daily oral 5 ~ 10 mg dapagliflozin had a significantly reduced urinary albumin-to-creatinine ratio. In addition, HK-2 cells cultured in hyperglycemic conditions were used to conduct in vitro experiments. The addition of dapagliflozin to the cells significantly reduced the expression of calcium channel, voltage dependent, L-type, alpha 1D subunit; calcium channel, voltage dependent, L-type, alpha 1 C subunit; cAMP responsive element binding protein 3 like 1; ATPase Na+/K + transporting subunit beta 2; nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 4; solute carrier family 8 member A2 gene; and calmodulin-like protein 4, suggesting that dapagliflozin inhibits inflammation and podocyte apoptosis through the inhibition of the MAPK signaling pathway. Luo et al. [32] cultured human glomerular podocytes in vitro and found that dapagliflozin decreased apoptosis, as well as protein expression levels of beclin-1, light chain (LC) 3-II, p53, p38 MAPK, and phosphorylated p38 MAPK, suggesting that dapagliflozin downregulates the p38 MAPK signaling pathway to prevent podocyte apoptosis. The above studies demonstrate that dapagliflozin can inhibit apoptosis, reduce inflammation, and improve podocyte function by inhibiting the MAPK signaling pathway.

Enhancement of autophagy in podocytes

Autophagy, a defense mechanism in podocytes, is a highly conserved process of intracellular protein recycling, in which damaged proteins and organelles are transferred to lysosomes for degradation [33] under the control of numerous autophagy-related (ATG) genes. Autophagy has five key processes: (1) formation of autophagic vacuoles; (2) formation of the ATG5-ATG12-ATG16L complex and its fusion with autophagic vacuoles; (3) transformation of microtubule-associated protein LC3 from a soluble (LC3-I) to a lipid-soluble (LC3-II) form, which binds to autophagic vacuoles to create autophagosomes; (4) capture of proteins, organelles, and other materials that require degradation or clearance by autophagosomes; and (5) fusion of autophagosomes with lysosomes to form autophagolysosomes, the contents of which are degraded [34]. Under physiological conditions, autophagy is maintained at a high level in podocytes, but DM and other forms of overnutrition inhibit autophagy, preventing the removal of damaged proteins and other substances. The continuous accumulation of harmful material results in irreversible damage to podocyte [35, 36]. Several autophagy-related pathways have been identified in podocytes, including the mTOR signaling pathway, AMPK signaling pathway, sirtuin (SIRT) l signaling pathway coupled with the ATG12-ATG5 system, MAPK signaling pathway, and actin cytoskeletal pathway [37].

Activation of the AMPK pathway

AMPK is an important metabolic stress protein kinase in DN [9]. Activated AMPK promotes catabolism and reduces anabolism, decreasing ATP consumption and increasing ATP synthesis to increase energy levels. AMPK activation also result in the phosphorylation of tuberous sclerosis complex 2, which leads to the phosphorylation of regulatory associated protein of mTOR, inhibiting mTOR complex 1 activity and inducing autophagy.In addition, AMPK activation can initiate autophagy through the phosphorylation of unc-51 like autophagy activating kinase 1. Lee et al. [38] used a mouse model of diabetes and a cell model to show that the SGLT2 inhibitor empagliflozin downregulated expression levels of mTOR complex 1, enhanced the expression levels of LC3-II, and restored the phosphorylation of AMPK. An increase in the ratio of cellular AMP/ATP also contributed to the activation of AMPK. Yang et al. [39] showed that dapagliflozin reversed AGEs-induced podocyte apoptosis and significantly increased the ratio of LC3-II/LC3-I and the expression of beclin-1, indicating that dapagliflozin induced autophagy in podocytes. Dapagliflozin also reversed the AGEs -induced enhancement of mTOR activity and inhibition of AMPK, suggesting that dapagliflozin restored autophagy in podocytes by activating the AMPK/mTOR signaling pathway. The above studies suggest that SGLT2 inhibitors induce autophagy by regulating the activity of AMPK/mTOR and thus exert a protective effect on podocytes.

Activation of the SIRT1 signaling pathway

SIRT1 is a nicotinamide adenine dinucleotide-dependent histone deacetylase that regulates various cellular processes, including autophagy and proliferation. In response to nutrient deprivation, SIRT1 directly deacetylates ATG5, ATG7, and ATG12, promoting the formation of the ATG12-ATG5-ATG16L complex. It also promotes the translocation of LC3-I from the nucleus to the cytoplasm and its transformation to LC3-II, thereby driving autophagy. Additionally, SIRT1 enhances autophagy through the deacetylation and activation of forkhead box O3. SIRT1 therefore regulates autophagy through deacetylation [34]. Xiong et al. [40] showed using a rat model of diabetes that dapagliflozin increased the protein expression levels of SIRT1, beclin-1, and podocin, as well as the LC3-II: LC3-I ratio, suggesting that dapagliflozin can induce autophagy in podocytes through the SIRT1 signaling pathway. Faridvand et al. [41] demonstrated that in human umbilical vein endothelial cells cultured under hyperglycemic conditions, treatment with dapagliflozin reduced the expression of ROS and the pro-inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor-α, and increased the expression of SIRT1 and the phosphorylation of AMPK, indicating that dapagliflozin increased autophagy and reduced apoptosis by upregulating the SIRT1/AMPK pathway.

Inhibition of Toll-like receptor expression

Toll-like receptors (TLRs) recognize pathogens, triggering immune responses; they have also been shown to regulate autophagy, with TLR activation inhibiting autophagy [42]. Ashrafi Jigheh et al. [43] demonstrated using a rat model of diabetes that empagliflozin reduced the mRNA expression levels of the pro-inflammatory genes tumor necrosis factor-α and monocyte chemotactic protein-1 and the pro-fibrotic genes TGF-β, type IV collagen, and fibronectin in the kidney, as well as reducing the protein expression levels of TLR-4. Chen et al. [44] established a rat model of DKD, in which dapagliflozin treatment significantly inhibited inflammatory responses, induced autophagy in podocytes, and ameliorated renal injury, via regulation of the TLR/MyD88 signaling pathway. These studies suggest that SGLT2 inhibitors induce autophagy and reduce inflammation in podocytes by inhibiting TLR expression and signaling.

Inhibition of podocyte EMT

Podocytes develop from the renal mesenchyme, and undergo EMT when the renal filtration barrier is impaired by hyperglycemia [45]. EMT can lead to podocyte dysfunction, and consequently, proteinuria. During EMT, renal tubular cells lose their epithelial phenotype and acquire mesenchymal cell characteristics, downregulating the key epithelial markers E-cadherin, mucin-1, cytokeratins (such as CK19, CK18,andCK8), occludin, and desmoplakin, and upregulating the mesenchymal markers N-cadherin, fibronectin, α-smooth muscle actin (α-SMA), and vimentin. Previous studies [10] have shown that podocyte EMT in response to hyperglycemia involves the TGF-β/Smad, Wnt/β-catenin, and integrin-linked kinase signaling pathways. Das et al. [46] showed that in HK-2 cells cultured under hyperglycemic conditions, empagliflozin restored the expression of E-cadherin and reduced the expression of fibronectin, α-SMA, and vimentin, suggesting that empagliflozin inhibited EMT.

Inhibition of the signal transducer and activator of transcription 1/TGF-β1 signaling pathway

Signal transducer and activator of transcription (STAT) 1 is a member of the STAT family of transcription factors, which is associated with hyperglycemia-induced oxidative stress and TGF-β1 expression, as well as with the production of extracellular matrix, collagen IV, and fibronectin [47]. The high glucose environment in DN activates STAT1 and TGF-β, promoting tubulointerstitial fibrosis. Huang et al. [48] demonstrated using cell and mouse models of DN that expression levels of STAT1 and TGF-β1 were significantly reduced by dapagliflozin, as were protein expression levels of collagen IV and fibronectin and tubular atrophy. Dapagliflozin also reversed the reduction of E-cadherin expression, suggesting that dapagliflozin attenuated EMT through the inhibition of the STAT1/TGF-β1 signaling pathway.

Restoration of SIRT3 expression

SIRT3 participates in cell metabolism and the stress response; mice deficient in SIRT3 develop fibrosis in various organs and exhibit hypoxia-inducible factor 1α accumulation, which can induce EMT of renal tubular cells [49, 50]. Wang et al. [51] showed using a rat model of hypertensive renal injury that canagliflozin decreased the protein expression levels of vimentin and αSMA and increased the protein expression levels of E-cadherin, and restored the expression of SIRT3, inhibiting renal EMT. Results from an HK-2 cell model showed that canagliflozin significantly inhibited Ang II-induced EMT, suggesting that canagliflozin ameliorates oxidative stress and EMT in the kidney through a SIRT3-dependent pathway. Similarly, SGLT2 inhibitors can improve EMT in DN. Li et al. [52] induced renal fibrosis in a mouse model of diabetes, and showed that treatment with empagliflozin reduced the expression of αSMA, smooth muscle protein 22α, and vimentin, restored SIRT3 expression, decreased hypoxia-inducible factor 1 expression, and ameliorated renal fibrosis. This suggests that SGLT2 inhibitors prevent EMT by restoring the expression of SIRT3, which is suppressed by hyperglycemia.

Inhibition of the insulin-like growth factor 1 receptor/phosphoinositide 3-kinase signaling pathway

Guo et al. [53] established an animal model of DN and collected samples from patients with DN, and showed that dapagliflozin significantly reduced the expression levels of insulin-like growth factor (IGF) 1 receptor, phosphorylated phosphoinositide 3-kinase, α-SMA, snail family transcriptional repressor 1, and zinc ginger E-box binding homeobox 2 in podocytes. In patients with DN receiving SGLT2 inhibitors, IGF1 and IGF2 levels were reduced, suggesting that SGLT2 inhibitors inhibit EMT by downregulating the IGF1 receptor/phosphoinositide 3-kinase signaling pathway, thereby reducing glomerular proteinuria and slowing DN progression.

Inhibition of podocyte pyroptosis

Pyroptosis is a novel type of programmed cell death dependent on caspase-1 and accompanied by the release of pro-inflammatory factors including IL-1β and IL-18, which induce and amplify inflammatory responses. Pyroptosis involves inflammatory vesicles formed of nucleotide-binding oligomerization domain-like receptor protein (NLRP) 3, NLRP1, NLRP4, absent in melanoma 2(PYHIN4), and pyrin.

Regulation of Heme oxygenase-1 expression

Heme oxygenase-1 is an important antioxidant enzyme, the expression of which is up-regulated in response to oxidative stress and cellular injury. Zhang et al. [54] induced disordered lipid metabolism in mouse podocytes, and found that dapagliflozin treatment reduced the protein expression levels of NLRP3, caspase-1, IL-18, and IL-1β, and increased the expression levels of heme oxygenase-1, inhibiting pyroptosis. This suggests that dapagliflozin suppresses pyroptosis of mouse podocytes by regulating the expression of heme oxygenase-1; however, studies on this mechanism are lacking and further research is required to fully elucidate it.

Reduction of NLRP3 expression

The NLRP3 inflammasome cleaves caspase-1, causing a cascade of reactions and inducing renal inflammatory injury [55]. Shahzad et al. [56] showed that mouse models of both type 1 and 2 DM exhibited intrarenal inflammasome activation with increased mRNA expression levels of IL-1β and NLRP3. Zhao et al. [57] used gene editing technology to generate SGLT2 knockout podocytes, and determined that empagliflozin reduced pyroptosis by down-regulating the protein expression levels of NLRP3, caspase-1, and IL-1β. NLRP3-mediated pyroptosis is a key factor in the development of nonalcoholic fatty liver disease, a common complication of diabetes [58]. Huang et al. [59] established a mouse model of diabetes and nonalcoholic fatty liver disease, and showed that canagliflozin treatment significantly attenuated hepatic fat accumulation; improved liver function, inflammation, and fibrosis; increased insulin sensitivity; and inhibited NLRP3-associated pyroptosis. Canagliflozin also reduced the expression of inflammatory and fibrotic factors. These studies suggest that SGLT2 inhibitors can inhibit pyroptosis by decreasing NLRP3 expression, thereby attenuating renal injury; however, whether other mechanisms exist requires further investigation.

Fig. 1
figure 1

Protective effects of SGLT2 inhibitors on podocytes. AMPK, adenosine 5’-monophosphate-activated protein kinase; Bax, B-cell lymphoma 2-associated X; Bcl-2, B-cell lymphoma 2; EMT, epithelial–mesenchymal transition; HO-1, heme oxygenase-1; IGF1R, insulin-like growth factor 1 receptor; MAPK, mitogen-activated protein kinase; NLRP3, nucleotide-binding oligomerization domain-like receptor protein 3; PI3K, phosphoinositide 3-kinase; SGLT2, sodium-glucose cotransporter type 2; Sirt, sirtuin; STAT, signal transducer and activator of transcription; TGF-β1, transforming growth factor-β1; TLR, Toll-like receptor

Full size image

Discussion

In vitro and in vivo studies have shown that SGLT2 inhibitors have multiple protective effects on renal podocytes, which are important for the prevention of CKD. The renal protection provided by SGLT2 inhibitors not only relies on their ability to lower glucose levels but also on their ability to inhibit podocyte apoptosis, pyroptosis, and EMT, as well as their promotion of autophagy and inhibition of inflammation. Therefore, SGLT2 inhibitors, the treatment of choice for DN, greatly improve the prognosis of patients. Whether SGLT2 inhibitors prevent podocyte pyroptosis via signaling pathways other than those described here requires further investigation, as does the question of whether SGLT2 inhibitors can ameliorate and reverse early podocyte damage and, if so, by which mechanisms.

Although SGLT2 inhibitors provide protection for the kidney through multiple mechanisms, they are associated with adverse effects that must be taken into consideration The US Food and Drug Administration published a warning in 2016 [60] indicating that the use of SGLT2 inhibitors may lead to acute kidney injury, dehydration, and hyperosmolarity. Therefore, in clinical practice, SGLT2 inhibitors should be administered with caution, in a way that is tailored to the condition of the patient.

Beyond podocyte damage, diffuse mesangial expansion with mesangial cell proliferation provides another method for treating DKD.Araoka et al. [61] demonstrated that AGEs induced the expression of transcription factor 7-like 2(TCF7L2 ) in mouse mesangial cells via TGF-β. This resulted in a significant increase in diabetic glomerulosclerosis in mice. Furthermore, TCF7L2 can increase activin receptor-like kinase 1(ALK1) expression, which enhances the effects of TGF-β and further promotes the phosphorylation of Smad1. These changes contribute to the development of glomerulosclerosis. Consequently, the AGEs/TGF-β/TCF7L2/ALK1/Smad1 signaling pathway plays a crucial role in the development of DKD. Previous research [62] has demonstrated that the glomerular expression of Smad1 is significantly increased in diabetic rats with mesangial matrix expansion.The results of a study by Mima et al. [63] indicate that Ang II can modulate Smad1-mediated signaling in the expansion of the diabetic mesangial matrix via a Src-dependent pathway. Activation of the Ang II-Src/Smad1 pathway can induce mesangial matrix expansion, leading to DKD. Additionally, the use of an Ang II type 1 receptor blocker can suppress the expression of phospho-Src and phospho-Smad1, thereby regulating mesangial matrix expansion.Combining insights from the previous research, we can regulate these two pathways to inhibit mesangial matrix expansion and subsequent glomerulosclerosis.Therefore, investigating the modulatory effect of SGLT2 inhibitors on these dual signaling pathways may provide a mechanistic basis for early intervention in DKD.

Data availability

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.

Change history

  • 12 April 2025

    Funding statement has been updated in the original article.

Abbreviations

AGEs:

Advanced glycation end products

ALK1:

Activin receptor-like kinase 1

AMP:

Adenosine 5’-monophosphate

AMPK:

Adenosine 5’-monophosphate-activated protein kinase

Ang II:

Angiotensin II

α-SMA:

α-smooth muscle actin

ATG:

Autophagy-related

Bax:

B-cell lymphoma associated X

Bcl:

B-cell lymphoma

CKD:

Chronic kidney disease

DKD:

Diabetic kidney disease

DM:

Diabetes mellitus

EMT:

Epithelial-mesenchymal transition

IGF:

Insulin-like growth factor

IL:

Interleukin

LC:

Light chain

MAPK:

Mitogen-activated protein kinase

mTOR:

Mammalian target of rapamycin

NLRP:

Nucleotide-binding oligomerization domain-like receptor protein

PODXL:

Podocalyxin

ROS:

Reactive oxygen species

SGLT:

Sodium-glucose co-transporter

SIRT:

Sirtuin

STAT:

Signal transducer and activator of transcription

TCF7L2:

Transcription factor 7-like 2

TGF-β1:

Transforming growth factor-β1

TLR:

Toll-like receptor

VEGF:

Vascular endothelial growth factor

ALK1:

Activin receptor-like kinase 1 ALK1

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This work was supported by the Natural Science Foundation of Inner Mongolia Autonomous Region (2022SHZR2220), 2022 Inner Mongolia Autonomous Region Medical and Health Science and Technology Plan Project (202201317) and 2022 Inner Mongolia Autonomous Region Medical and Health Science and Technology Plan Project (202202190).

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  1. Department of Endocrinology, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China

    Xinqi Chen, Mingjie Wang & Zhaoli Yan

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Chen, X., Wang, M. & Yan, Z. Recent advances in understanding the mechanisms by which sodium-glucose co-transporter type 2 inhibitors protect podocytes in diabetic nephropathy. Diabetol Metab Syndr 17, 84 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13098-025-01655-2

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Diabetology & Metabolic Syndrome

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