Unveiling the podocyte-protective effect of sodium-glucose cotransporter-2 inhibitors

Podocyte-protective effect of SGLT2 inhibitors

Article information

Korean J Nephrol. 2024;.j.krcp.24.144

Publication date (electronic) : 2024 December 5

doi : https://doi.org/10.23876/j.krcp.24.144

Buchun Jiang ¹^,²

, Zhiwen Cheng ²^,³

, Dongjie Wang ¹^,²

, Fei Liu ¹^,²

, Jingjing Wang ¹^,²

, Haidong Fu^,¹^,²^,^*

, Jianhua Mao^,¹^,²^,^*

¹Department of Nephrology, The Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China

²National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou, China

³Department of General Pediatrics, The Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China

Correspondence: Haidong Fu Department of Nephrology, The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, 3333 Bingsheng Rd., Hangzhou, Zhejiang 310052, China. E-mail: fhdhz@163.com

Jianhua Mao The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, 3333 Bingsheng Rd., Hangzhou, Zhejiang 310052, China. E-mail: maojh88@zju.edu.cn

*Haidong Fu and Jianhua Mao contributed equally to this study as co-corresponding authors.

Received 2024 May 25; Revised 2024 August 28; Accepted 2024 October 7.

Abstract

The renoprotective effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors in both diabetic and nondiabetic nephropathy are widely recognized due to results from randomized controlled trials notably the DAPA-CKD and EMPA-KIDNEY trials. Research exploring the mechanisms of renoprotection indicates that SGLT2 inhibitors exert protective effects on podocytes by enhancing autophagy and stabilizing the structure of podocytes and basement membranes. Furthermore, reductions in lipotoxicity, oxidative stress, and inflammation have been confirmed with SGLT2 inhibitor treatment. Recent clinical studies have also begun to explore the effects of SGLT2 inhibitors on nondiabetic podocytopathies, such as focal segmental glomerulosclerosis. In this review, we summarize clinical and laboratory studies that focus on the podocyte-protective effects of SGLT2 inhibitors, exploring the potential for broader applications of this novel therapeutic agent in kidney disease.

Keywords: Podocytes; podocytopathies; Renal protection; Sodium-glucose transporter 2 inhibitors

Introduction

Sodium-glucose cotransporter-2 (SGLT2) serves as a critical glucose transporter, is predominantly expressed in the kidney, and is responsible for reabsorbing 80% to 90% of glucose in urine. SGLT2 inhibitors, a novel class of pharmacological agents targeting this transporter, have proven effective in the management of both diabetic and nondiabetic nephropathy. Evidence from randomized controlled trials (RCTs) demonstrates that SGLT2 inhibitors can significantly reduce albuminuria and slow the decline in estimated glomerular filtration rate (eGFR), thereby decelerating the progression of kidney disease [1–3]. However, the mechanisms of such kidney protective effects remain poorly understood. It is widely accepted that the renal protection afforded by SGLT2 inhibitors results from multiple factors.

As one of the most important mechanisms of renoprotection, SGLT2 inhibitors enhance tubuloglomerular feedback, a process triggered by natriuresis, which consequently results in a decrease of glomerular hyperfiltration and albuminuria [4]. Furthermore, several studies have demonstrated that SGLT2 inhibitors modulate renal energy metabolism through metabolic reprogramming, analogous to fasting-induced metabolic paradigms or aestivation-metabolism [5,6]. Additionally, SGLT2 inhibitors have been shown to reduce inflammation and oxidative stress in kidney diseases [7,8].

Podocytopathy is a kidney disease caused by direct or indirect damage to podocytes, leading to clinical manifestations such as proteinuria and potentially progressing to nephrotic syndrome [9]. This condition can result from single factors, such as hereditary influences, or multiple factors including infections, diabetes, and autoimmune disorders. The DAPA-CKD trial showed that patients with focal segmental glomerulosclerosis (FSGS), a typical type of podocytopathy, may also benefit from treatment with SGLT2 inhibitors [10,11]. Primarily utilized in managing diabetic nephropathy—a systemic disease characterized by podocyte injury, SGLT2 inhibitors are also thought to mitigate podocyte injury, potentially another crucial renoprotective mechanism. This review examines the role of SGLT2 inhibitors in reducing podocyte injury, aiming to uncover further potential of this novel therapeutic agent.

Mechanism of the protective effect on podocytes

Autophagy activation

Autophagy is generally considered a process by which intracellular components are transported to the lysosomal compartment for degradation and recycling. Autophagy can remove damaged organelles, misfolded proteins, and pathogens. This process is primarily governed by the energy and nutrient status of cells, with starvation being the most potent inducer. Conversely, nutritional excess, such as in diabetes, inhibits autophagy. The regulatory signaling pathways triggered by starvation and stress include the serine/threonine protein kinase mammalian target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), and sirtuins [12]. Previous studies have demonstrated that both starvation and energy depletion activate AMPK and sirtuins while simultaneously inhibiting mTOR, thereby promoting autophagy [13,14].

Early research in mice revealed that podocytes, as terminally differentiated cells, exhibit high levels of autophagy [15]. Atg5-knockout mice, characterized by deficient autophagy activity, develop proteinuria by 12 weeks and glomerular sclerosis by 20 to 24 months, underscoring the critical role of autophagy in podocyte function [15]. In type 2 diabetic mice, transmission electron microscopy studies investigating the effects of the SGLT2 inhibitor empagliflozin and the DPP4 inhibitor linagliptin have demonstrated that both medications enhance the volume density of autophagosomes and autolysosomes in podocytes [16]. Further research in podocyte injury in diabetic nephropathy demonstrated that dapagliflozin could enhance AMPK activity and suppress mTOR, thus boosting autophagy in podocytes [17]. Additionally, Lv et al. [18] observed that canagliflozin inhibited mTOR activity and mitigated immune-induced podocyte autophagy impairment in rats with membranous nephropathy. The most recent promising findings on the impact of SGLT2 inhibitors on podocyte autophagy observed that empagliflozin decreases mTOR activity and reduces podocyte damage in systemic lupus erythematosus (SLE) in a mouse model of lupus nephritis (LN) [19]. The results indicated that SGLT2 inhibitors have potential for treatment of LN, which is usually not included in large RCTs. This autophagy signaling pathway of SGLT2 inhibitors in LN may also be an important factor underlying the renoprotective effects in other nondiabetic nephropathy.

In summary, SGLT2 inhibitors facilitate podocyte autophagy by modulating the AMPK/mTOR signaling pathway, thereby mitigating podocyte injury. This represents one of the protective mechanisms of SGLT2 inhibitors against podocyte injury and may also contribute to their renoprotective effects.

Maintenance of podocyte structure

The early features of podocyte injury primarily include foot process simplification and effacement [9]. A study investigating the effects of dapagliflozin on podocyte injury in mice with diabetic nephropathy demonstrated that dapagliflozin reduced podocyte foot process width by 44.9% and glomerular basement membrane thickness by 37.7% compared to db/db control mice receiving vehicle [20]. Additionally, empagliflozin increased the number and density of podocytes, reduced the width of foot processes, and alleviated foot process effacement in an animal model of diabetic nephropathy [21]. It has been suggested that empagliflozin enhances the activation of parietal epithelial cells, considered a potential renewable source of podocytes [21]. The reversal of podocyte morphology and number by empagliflozin highlights the potential of SGLT2 inhibitors as promising agents to reverse renal pathological changes in diabetic nephropathy.

Moreover, the benefits of SGLT2 inhibitors on podocytes extend beyond diabetic nephropathy. Numerous clinical studies have shown that SGLT2 inhibitors can improve renal outcomes in various podocytopathies. A study of dapagliflozin in an animal model of proteinuric nondiabetic nephropathy induced by bovine serum albumin injection indicated that SGLT2 was expressed in podocytes of mice with proteinuric nephropathy and was upregulated following bovine serum albumin injection [22]. Significantly, that study demonstrated that dapagliflozin could decrease foot process effacement and prevent podocyte loss. Using confocal microscopy, they observed that dapagliflozin prevents structural rearrangement induced by albumin in cultured podocytes [22].

It is imperative to consider cytoskeletal proteins to comprehensively analyze the impact of SGLT2 inhibitors on the structure of podocytes. Nephrin, an essential transmembrane protein of the slit diaphragm, is critical for maintaining the integrity of the glomerular filtration barrier. Experimental studies in animals have indicated that SGLT2 inhibitors may prevent the loss of nephrin in both diabetic and nondiabetic nephropathy [22–24]. In an animal model of proteinuric nondiabetic nephropathy induced by albumin overload, dapagliflozin improved the expression of nephrin [22]. Human studies on the effects of SGLT2 inhibitors on nephrin are limited. A randomized, placebo-controlled trial in patients with type 2 diabetes suggested that 12 weeks of SGLT2 inhibitor treatment could decrease nephrin levels in urine and increase urinary excretion of transforming growth factor-beta 1, a fibrogenic cytokine known to promote podocyte apoptosis [25]. However, due to the small sample size and lack of renal biopsy, the evidence remains inconclusive [25]. The detailed signaling mechanism underlying the effect of SGLT2 inhibitors on nephrin remains unclear and needs further study.

F-actin is a critical cytoskeletal protein in podocytes. Confocal microscopy revealed that dapagliflozin could mitigate albumin-induced redistribution of F-actin fibers in cultured podocytes [22]. Besides F-actin, podocyte foot processes contain several actin-related proteins, such as α-actinin-4, synaptopodin, and CD2-associated protein. α-actinin-4 is an important actin-related protein that plays a role in fixing podocytes alongside integrins. Studies of cultured podocytes suggest that dapagliflozin prevents α-actinin-4 remodeling induced by albumin exposure [22]. Synaptopodin, a proline-rich protein that interacts with F-actin in podocyte foot processes, is crucial for protecting podocytes from F-actin redistribution [26]. A study of the effects of advanced glycation end products on podocytes indicated that dapagliflozin enhances synaptopodin expression [17]. Recent research on SGLT2 inhibitors in LN demonstrated a decrease in synaptopodin levels in the kidneys of Murphy Roths Large/lymphoproliferation (MRL/lpr) mice and patients, with empagliflozin treatment boosting synaptopodin expression in MRL/lpr mice [19]. Cassis et al. [22] observed that SGLT2 inhibitors reduced the loss of β1-integrin, an essential adhesion molecule between podocytes and the glomerular basement membrane.

In conclusion, SGLT2 inhibitors protect the foot process and maintain the normal structure of podocytes in both diabetic and nondiabetic nephropathy. The beneficial effects of SGLT2 inhibitors on podocyte foot processes may be related to their influence on key cytoskeletal proteins.

Alleviation of lipotoxicity

Lipotoxicity, a significant area of research in diabetic nephropathy and obesity-related glomerulopathy, results from the accumulation of lipids such as cholesterol and triglycerides. This accumulation can exacerbate oxidative stress and mitochondrial dysfunction, leading to cellular injury and death. The kidney is an often overlooked target of lipotoxicity. The precise mechanisms of renal injury due to lipid accumulation remain unclear, but oxidative stress, organelle dysfunction, inflammation, and dysregulated autophagy are widely acknowledged as potential contributors [27]. Szeto et al. [28] conducted an animal study to investigate the mechanisms of renal damage caused by lipid accumulation, finding that a high-fat diet for 28 weeks induces mitochondrial damage and endoplasmic reticulum stress in podocytes, leading to foot process effacement and podocyte loss.

Previous research on the metabolic effects of SGLT2 inhibitors has demonstrated that this class of drugs enhances the consumption of free fatty acids and reduces the accumulation of toxic lipid metabolites [29–31]. However, investigations into the impact of SGLT2 inhibitors on podocyte lipotoxicity are sparse. A study involving a Western diet-induced mouse obesity model showed that dapagliflozin could reduce lipid accumulation in the kidney and decrease markers of podocyte injury. Moreover, in Western diet-fed mice, dapagliflozin decreased the expression of sterol regulatory element-binding protein-1c transcript, a triglyceride synthesis master transcription factor [32]. In addition, empagliflozin decreased the intracellular lipid droplets and apoptosis of podocytes in a mouse model of Alport syndrome [33]. This study found that empagliflozin could inhibit the utilization of pyruvate, decrease glycolysis, and upregulate the activity of carnitine palmitoyltransferase 1A, which is the rate-limiting enzyme of fatty acid oxidation. Empagliflozin changes the substrate of podocyte energy metabolism from glucose to fatty acid [33].

In sum, the primary mechanisms of SGLT2 inhibitors in combating podocyte lipotoxicity include increased utilization of free fatty acids and reduced lipid accumulation, thereby preventing the escalation of podocyte detachment and apoptosis due to lipotoxicity.

Reduction of oxidative stress and inflammation

Increased oxidative stress is a critical component of pathogenesis in diabetic nephropathy. Previous studies using animal models demonstrated that SGLT2 inhibitors are able to reduce oxidative stress in kidney disease [34]. Recent research involving patients with diabetic nephropathy has indicated that treatment with SGLT2 inhibitors can lower urinary levels of 8-hydroxy-2′-deoxyguanosine, a useful marker of oxidative stress [35]. A study of SGLT2 inhibitors in type 2 diabetic mice found that ipraglifozin reduced the urinary excretion of 8-hydroxy-2′-deoxyguanosine and decreased reactive oxygen species overproduction in tubular epithelia and glomeruli. Furthermore, in isolated glomerular samples, high-dose ipraglifozin decreased the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 and subsequent podocyte injury [36]. NADPH oxidase 4 plays a significant role in podocyte injury, and its podocyte-specific induction in vivo can lead to podocyte injury similar to diabetic nephropathy [37].

Additionally, SGLT2 inhibitors exhibit anti-inflammatory properties [38] and can reduce various pro-inflammatory cytokines in human proximal tubular cells, including tumor necrosis factor-alpha, interleukin (IL)-1β, and IL-6 [39]. SGLT2 inhibitors also decreased levels of NLR family pyrin domain containing 3 (NLRP3), which is crucial in the progression of diabetic nephropathy and LN [40,41], in a preclinical study [15]. In recent research on LN, empagliflozin was administered to cultured podocytes exposed to IgG extracted from the serum of LN patients. This treatment resulted in reduced levels of NLRP3 and IL-1β [19]. Clinical studies of SGLT2 inhibitors on anti-inflammatory effects have primarily focused on diabetes and cardiovascular diseases. A post-hoc analysis of dapagliflozin in patients with type 2 diabetes showed that dapagliflozin could decrease urinary IL-6 excretion [42]. An analysis based on the CANVAS study evaluated plasma samples and kidney outcomes in patients with type 2 diabetes, finding that canagliflozin could mitigate the increase in plasma IL-6 levels. Notably, patients with lower plasma IL-6 in the canagliflozin group had a lower risk of kidney outcomes [43]. Unfortunately, these clinical studies did not specifically address the effects on podocytes.

Other proposed potential effects

In 2021, Fang et al. [44] demonstrated that β-hydroxybutyrate treatment could mitigate podocyte injury and senescence by enhancing Nrf2 activation and inhibiting GSK3β activation in podocytes. Research on metabolic effects has shown that SGLT2 inhibitors can elevate levels of ketone bodies, including β-hydroxybutyrate [5,45]. In a study involving proteinuric diabetic kidney disease (DKD), researchers administered empagliflozin and 1,3-butanediol—a precursor of ketone bodies—to db/db mice. The findings indicated that empagliflozin increased β-hydroxybutyrate levels and alleviated mTORC1-associated podocyte damage, similar to the effects seen with 1,3-butanediol treatment. Additionally, the renoprotective effects of empagliflozin were absent in mice with a gene deletion of Hmgcs2, which is a rate-limiting enzyme in ketogenesis [46]. Therefore, the elevation of ketone bodies may be linked to the protective effects of SGLT2 inhibitors on podocytes.

Epithelial-mesenchymal transition (EMT) is an important pathological change in kidney fibrosis. Studies have indicated that SGLT2 inhibitors suppress EMT in renal tubular epithelial cells and prevent the development of kidney fibrosis in mice with DKD or hypertensive renal injury [47,48]. Podocyte EMT is a significant aspect of podocyte injury, yet studies on this topic are limited. In a pilot study combining human and mouse models of DKD, dapagliflozin was observed to reduce the levels of mesenchymal markers and prevent the loss of podocyte markers by decreasing insulin-like growth factor 1 receptor/phosphoinositide 3-kinase (PI3K) activity. This effect contributes to the inhibition of podocyte EMT in both in vitro and in vivo experiments [49]. More research is needed to confirm the effect of SGLT2 inhibitors on EMT in podocytes.

Clinical studies on podocytopathies

Numerous clinical studies have investigated the effects of SGLT2 inhibitors on podocytopathies (Table 1), with a particular focus on DKD, which is considered a secondary podocytopathy. Large RCTs such as EMPA-REG OUTCOME [50], CANVAS [51], DECLARE-TIMI 58 [52], and CREDENCE [53] have all demonstrated protective effects against diabetic nephropathy. FSGS is a classic nephropathy characterized by podocyte damage due to multiple factors, including genetic mutations and infections [54]. The pivotal DAPA-CKD trial highlighted that dapagliflozin could reduce the risk of adverse outcomes in nondiabetic chronic kidney disease [55], with a subgroup analysis of 104 participants with biopsy-confirmed FSGS showing that dapagliflozin decreased the rate of chronic decline in eGFR compared to placebo [10]. However, secondary analyses from the EMPA-KIDNEY trial did not demonstrate superiority of the empagliflozin group over placebo in glomerular diseases, including FSGS, as empagliflozin did not reduce the risk of kidney disease progression [2]. Previous studies, including a combined human-rodent pilot study, failed to show the benefits of dapagliflozin in FSGS, noting that SGLT2 messenger RNA expression was lower in FSGS [56]. The DIAMOND RCT, which included non-DKDs such as FSGS and immunoglobulin A (IgA) nephropathy, also found that 6 weeks of dapagliflozin treatment did not reduce 24-hour proteinuria compared to placebo [57]. The effectiveness of SGLT2 inhibitors in treating FSGS remains controversial and necessitates more targeted research for confirmation. Moreover, stratifying FSGS into primary and secondary categories based on etiology in RCTs may yield more convincing and successful outcomes.

Table 1.

Primary clinical studies of SGLT2 inhibitors on podocytopathies

Research on SGLT2 inhibitors in hereditary podocytopathies is limited, yet shows promising results. A case series involving patients with hereditary disorders such as X-linked Alport syndrome and FSGS demonstrated that treatment with SGLT2 inhibitors could effectively reduce albuminuria [58]. A cohort study of dapagliflozin in inherited proteinuric kidney diseases, which included five pediatric patients with Alport syndrome and one with FSGS, found that dapagliflozin reduced proteinuria by 33.3% from baseline at 4 weeks and 22.6% at 12 weeks [59]. However, these studies are constrained by their small sample sizes and the absence of a placebo control group. Additionally, two studies with small cohorts investigated the efficacy of SGLT2 inhibitors in SLE, focusing on their cardioprotective and renoprotective effects [19,60]. Despite yielding conflicting results, these studies provided some evidence of safety.

Perspectives on the protective effect of sodium-glucose cotransporter-2 inhibitors on podocytes

Current research suggests that the protective effects of SGLT2 inhibitors on podocytes arise from the interactions and cumulative impact of multiple factors. Specifically targeting podocytes, SGLT2 inhibitors enhance autophagy, stabilize the cytoskeleton, reduce foot process loss, decrease lipotoxicity, and alleviate oxidative stress and inflammation (Fig. 1). These effects, such as oxidative stress, inflammation, and autophagy interact and influence one another. The direct impact on the foot process and cytoskeleton is particularly crucial for podocytes. Similar to their mechanism of renoprotection, the influence of SGLT2 inhibitors on podocytes is also “all-round.” These multiple benefits may be the foundation for renoprotection by SGLT2 inhibitors in kidney diseases, including nondiabetic podocytopathies. Consequently, there is substantial reason to believe that SGLT2 inhibitors will be a promising and revolutionary treatment for podocytopathies beyond DKD.

Figure 1.

Protective effects of SGLT2 inhibitors on podocytes.

Based on the results of the present study, SGLT2 inhibitors enhance autophagy, decrease lipotoxicity, alleviate foot process damage, and reduce oxidative stress and inflammation. Moreover, SGLT2 inhibitors have direct effects on cytoskeletal proteins and stabilize the podocyte structure. Limited research shows that SGLT2 inhibitors could also increase the level of ketone bodies and decrease EMT, which may be associated with their protective effect on podocytes.

AMPK, AMP-activated protein kinase; EMT, epithelial-mesenchymal transition; IGF1R, insulin-like growth factor 1 receptor; IL, interleukin; mTOR, mammalian target of rapamycin; NLRP3, NLR family pyrin domain containing 3; SGLT2, sodium-glucose cotransporter-2; PI3K, phosphoinositide 3-kinase.

Results from large RCTs indicate significant benefits of SGLT2 inhibitors for DKD. However, their demonstrated effects in nondiabetic podocytopathies, particularly FSGS, have been less than satisfactory, possibly due to small sample sizes and short follow-up periods. There is also a need for a more detailed classification of podocytopathies in clinical studies, distinguishing between primary and secondary forms. SGLT2 inhibitors are a potential treatment option for minimal change disease, though no clinical studies currently support this hypothesis. Additionally, research on cardioprotection has shown that SGLT2 inhibitors affect cell apoptosis through various signaling pathways, including JAK/STAT, PI3K/AKT, and mitogen-activated protein kinase pathways [61–63]. However, few studies have specifically focused on podocytes. Further investigation into the effects of SGLT2 inhibitors on the cytoskeleton and inflammation in podocytes is needed. Compared to their significant renoprotective effects in DKD, the outcomes of clinical studies on other podocytopathies have been disappointing. More focused research on the role of SGLT2 inhibitors in podocyte health could potentially break this impasse and broaden the therapeutic applications of this novel class of medications in kidney diseases.

Conclusion

Research indicates that SGLT2 inhibitors can protect podocytes by enhancing autophagy, maintaining structural integrity, and reducing inflammation and oxidative stress. It is reasonable to posit that these protective effects on podocytes represent a crucial mechanism of renoprotection, particularly in podocytopathies. Beyond diabetes, however, clinical studies focusing on podocytopathies are sparse. To acquire more robust evidence of their protective effects on podocytes, high-quality RCTs of nondiabetic podocytopathies involving SGLT2 inhibitors are essential.

Notes

Conflicts of interest

All authors have no conflicts of interest to declare.

Data sharing statement

The data presented in this study are available from the corresponding author upon reasonable request.

Authors’ contributions

Conceptualization: JM

Data curation: DW, FL, JW

Formal analysis: ZC, DW, FL, JW, HF

Writing–original draft: BJ

Writing–review & editing: All authors

All authors read and approved the final manuscript.

References

1. Jongs N, Greene T, Chertow GM, et al. Effect of dapagliflozin on urinary albumin excretion in patients with chronic kidney disease with and without type 2 diabetes: a prespecified analysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol 2021;9:755–766. 10.1016/s2213-8587(21)00243-6. 34619106.

2. EMPA-KIDNEY Collaborative Group. Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial. Lancet Diabetes Endocrinol 2024;12:51–60. 38061372.

3. Jardine M, Zhou Z, Lambers Heerspink HJ, et al. Kidney, Cardiovascular, and safety outcomes of canagliflozin according to baseline albuminuria: a CREDENCE secondary analysis. Clin J Am Soc Nephrol 2021;16:384–395. 33619120.

4. DeFronzo RA, Reeves WB, Awad AS. Pathophysiology of diabetic kidney disease: impact of SGLT2 inhibitors. Nat Rev Nephrol 2021;17:319–334. 10.1038/s41581-021-00393-8. 33547417.

5. Marton A, Kaneko T, Kovalik JP, et al. Organ protection by SGLT2 inhibitors: role of metabolic energy and water conservation. Nat Rev Nephrol 2021;17:65–77. 10.1038/s41581-020-00350-x. 33005037.

6. Gao YM, Feng ST, Wen Y, Tang TT, Wang B, Liu BC. Cardiorenal protection of SGLT2 inhibitors-perspectives from metabolic reprogramming. EBioMedicine 2022;83:104215. 10.1016/j.ebiom.2022.104215. 35973390.

7. Heerspink HJ, Perco P, Mulder S, et al. Canagliflozin reduces inflammation and fibrosis biomarkers: a potential mechanism of action for beneficial effects of SGLT2 inhibitors in diabetic kidney disease. Diabetologia 2019;62:1154–1166. 10.1007/s00125-019-4859-4. 31001673.

8. Jaikumkao K, Pongchaidecha A, Chueakula N, et al. Dapagliflozin, a sodium-glucose co-transporter-2 inhibitor, slows the progression of renal complications through the suppression of renal inflammation, endoplasmic reticulum stress and apoptosis in prediabetic rats. Diabetes Obes Metab 2018;20:2617–2626. 10.1111/dom.13441. 29923295.

9. Kopp JB, Anders HJ, Susztak K, et al. Podocytopathies. Nat Rev Dis Primers 2020;6:68. 10.1038/s41572-020-0196-7. 32792490.

10. Wheeler DC, Jongs N, Stefansson BV, et al. Safety and efficacy of dapagliflozin in patients with focal segmental glomerulosclerosis: a prespecified analysis of the dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trial. Nephrol Dial Transplant 2022;37:1647–1656. 10.1093/ndt/gfab335. 34850160.

11. Heerspink HJ, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med 2020;383:1436–1446. 10.1056/nejmoa2024816. 32970396.

12. Tang C, Livingston MJ, Liu Z, Dong Z. Autophagy in kidney homeostasis and disease. Nat Rev Nephrol 2020;16:489–508. 10.1038/s41581-020-0309-2. 32704047.

13. Kroemer G, Mariño G, Levine B. Autophagy and the integrated stress response. Mol Cell 2010;40:280–293. 10.1016/j.molcel.2010.09.023. 20965422.

14. Kim J, Kundu M, Viollet B, Guan KL. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 2011;13:132–141. 10.1038/ncb2152. 21258367.

15. Hartleben B, Gödel M, Meyer-Schwesinger C, et al. Autophagy influences glomerular disease susceptibility and maintains podocyte homeostasis in aging mice. J Clin Invest 2010;120:1084–1096. 10.1172/jci39492. 20200449.

16. Korbut AI, Taskaeva IS, Bgatova NP, et al. SGLT2 inhibitor empagliflozin and DPP4 inhibitor linagliptin reactivate glomerular autophagy in db/db mice, a model of type 2 diabetes. Int J Mol Sci 2020;21:2987. 10.3390/ijms21082987. 32340263.

17. Yang L, Liang B, Li J, et al. Dapagliflozin alleviates advanced glycation end product induced podocyte injury through AMPK/mTOR mediated autophagy pathway. Cell Signal 2022;90:110206. 10.1016/j.cellsig.2021.110206. 34856357.

18. Lv X, Wang J, Zhang L, et al. Canagliflozin reverses Th1/Th2 imbalance and promotes podocyte autophagy in rats with membranous nephropathy. Front Immunol 2022;13:993869. 10.3389/fimmu.2022.993869. 36531996.

19. Zhao XY, Li SS, He YX, et al. SGLT2 inhibitors alleviated podocyte damage in lupus nephritis by decreasing inflammation and enhancing autophagy. Ann Rheum Dis 2023;82:1328–1340. 10.1136/ard-2023-224242. 37487609.

20. Han E, Shin E, Kim G, et al. Combining SGLT2 inhibition with a thiazolidinedione additively attenuate the very early phase of diabetic nephropathy progression in type 2 diabetes mellitus. Front Endocrinol (Lausanne) 2018;9:412. 10.3389/fendo.2018.00412. 30072956.

21. Hudkins KL, Li X, Holland AL, Swaminathan S, Alpers CE. Regression of diabetic nephropathy by treatment with empagliflozin in BTBR ob/ob mice. Nephrol Dial Transplant 2022;37:847–859. 10.1093/ndt/gfab330. 34865099.

22. Cassis P, Locatelli M, Cerullo D, et al. SGLT2 inhibitor dapagliflozin limits podocyte damage in proteinuric nondiabetic nephropathy. JCI Insight 2018;3e98720. 10.1172/jci.insight.98720. 30089717.

23. Oraby MA, El-Yamany MF, Safar MM, Assaf N, Ghoneim HA. Dapagliflozin attenuates early markers of diabetic nephropathy in fructose-streptozotocin-induced diabetes in rats. Biomed Pharmacother 2019;109:910–920. 10.1016/j.biopha.2018.10.100. 30551545.

24. Klimontov VV, Korbut AI, Taskaeva IS, et al. Empagliflozin alleviates podocytopathy and enhances glomerular nephrin expression in db/db diabetic mice. World J Diabetes 2020;11:596–610. 10.4239/wjd.v11.i12.596. 33384767.

25. Tian Y, Chen XM, Liang XM, Wu XB, Yao CM. SGLT2 inhibitors attenuate nephrin loss and enhance TGF-β1 secretion in type 2 diabetes patients with albuminuria: a randomized clinical trial. Sci Rep 2022;12:15695. 10.1038/s41598-022-19988-7. 36127497.

26. Ning L, Suleiman HY, Miner JH. Synaptopodin is dispensable for normal podocyte homeostasis but is protective in the context of acute podocyte injury. J Am Soc Nephrol 2020;31:2815–2832. 10.1681/asn.2020050572. 32938649.

27. Ren L, Cui H, Wang Y, et al. The role of lipotoxicity in kidney disease: from molecular mechanisms to therapeutic prospects. Biomed Pharmacother 2023;161:114465. 10.1016/j.biopha.2023.114465. 36870280.

28. Szeto HH, Liu S, Soong Y, Alam N, Prusky GT, Seshan SV. Protection of mitochondria prevents high-fat diet-induced glomerulopathy and proximal tubular injury. Kidney Int 2016;90:997–1011. 10.1016/j.kint.2016.06.013. 27519664.

29. Daniele G, Xiong J, Solis-Herrera C, et al. Dapagliflozin enhances fat oxidation and ketone production in patients with type 2 diabetes. Diabetes Care 2016;39:2036–2041. 10.2337/dc15-2688. 27561923.

30. Wallenius K, Kroon T, Hagstedt T, et al. The SGLT2 inhibitor dapagliflozin promotes systemic FFA mobilization, enhances hepatic β-oxidation, and induces ketosis. J Lipid Res 2022;63:100176. 10.1016/j.jlr.2022.100176. 35120993.

31. Zhu Q, Zhou Q, Luo XL, Zhang XJ, Li SY. Combination of canagliflozin and puerarin alleviates the lipotoxicity to diabetic kidney in mice. Korean J Physiol Pharmacol 2023;27:221–230. 10.4196/kjpp.2023.27.3.221. 37078296.

32. Wang D, Luo Y, Wang X, et al. The sodium-glucose cotransporter 2 inhibitor dapagliflozin prevents renal and liver disease in western diet induced obesity mice. Int J Mol Sci 2018;19:137. 10.3390/ijms19010137. 29301371.

33. Ge M, Molina J, Kim JJ, et al. Empagliflozin reduces podocyte lipotoxicity in experimental Alport syndrome. Elife 2023;12e83353. 10.7554/elife.83353. 37129368.

34. Hasan R, Lasker S, Hasan A, et al. Canagliflozin ameliorates renal oxidative stress and inflammation by stimulating AMPK-Akt-eNOS pathway in the isoprenaline-induced oxidative stress model. Sci Rep 2020;10:14659. 10.1038/s41598-020-71599-2. 32887916.

35. Zeng XC, Tian Y, Liang XM, Wu XB, Yao CM, Chen XM. SGLT2i relieve proteinuria in diabetic nephropathy patients potentially by inhibiting renal oxidative stress rather than through AGEs pathway. Diabetol Metab Syndr 2024;16:46. 10.1186/s13098-024-01280-5. 38365853.

36. Kamezaki M, Kusaba T, Komaki K, et al. Comprehensive renoprotective effects of ipragliflozin on early diabetic nephropathy in mice. Sci Rep 2018;8:4029. 10.1038/s41598-018-22229-5. 29507299.

37. You YH, Quach T, Saito R, Pham J, Sharma K. Metabolomics reveals a key role for fumarate in mediating the effects of NADPH oxidase 4 in diabetic kidney disease. J Am Soc Nephrol 2016;27:466–481. 10.1681/asn.2015030302. 26203118.

38. Feijóo-Bandín S, Aragón-Herrera A, Otero-Santiago M, et al. Role of sodium-glucose co-transporter 2 inhibitors in the regulation of inflammatory processes in animal models. Int J Mol Sci 2022;23:5634. 10.3390/ijms23105634. 35628443.

39. Xu J, Kitada M, Ogura Y, Liu H, Koya D. Dapagliflozin restores impaired autophagy and suppresses inflammation in high glucose-treated HK-2 cells. Cells 2021;10:1457. 10.3390/cells10061457. 34200774.

40. Hou Y, Lin S, Qiu J, et al. NLRP3 inflammasome negatively regulates podocyte autophagy in diabetic nephropathy. Biochem Biophys Res Commun 2020;521:791–798. 10.1016/j.bbrc.2019.10.194. 31703838.

41. Fu R, Guo C, Wang S, et al. Podocyte activation of NLRP3 inflammasomes contributes to the development of proteinuria in lupus nephritis. Arthritis Rheumatol 2017;69:1636–1646. 10.1002/art.40155. 28544564.

42. Dekkers CC, Petrykiv S, Laverman GD, Cherney DZ, Gansevoort RT, Heerspink HJ. Effects of the SGLT-2 inhibitor dapagliflozin on glomerular and tubular injury markers. Diabetes Obes Metab 2018;20:1988–1993. 10.1111/dom.13301. 29573529.

43. Koshino A, Schechter M, Sen T, et al. Interleukin-6 and cardiovascular and kidney outcomes in patients with type 2 diabetes: new insights from CANVAS. Diabetes Care 2022;45:2644–2652. 10.2337/dc22-0866. 36134918.

44. Fang Y, Chen B, Gong AY, et al. The ketone body β-hydroxybutyrate mitigates the senescence response of glomerular podocytes to diabetic insults. Kidney Int 2021;100:1037–1053. 10.1016/j.kint.2021.06.031. 34246657.

45. Ferrannini E, Baldi S, Frascerra S, et al. Shift to fatty substrate utilization in response to sodium-glucose cotransporter 2 inhibition in subjects without diabetes and patients with type 2 diabetes. Diabetes 2016;65:1190–1195. 10.2337/db15-1356. 26861783.

46. Tomita I, Kume S, Sugahara S, et al. SGLT2 inhibition mediates protection from diabetic kidney disease by promoting ketone body-induced mTORC1 inhibition. Cell Metab 2020;32:404–419.e6. 10.1016/j.cmet.2020.06.020. 32726607.

47. Li J, Liu H, Takagi S, et al. Renal protective effects of empagliflozin via inhibition of EMT and aberrant glycolysis in proximal tubules. JCI Insight 2020;5e129034. 10.1172/jci.insight.129034. 32134397.

48. Wang Z, Zhai J, Zhang T, et al. Canagliflozin ameliorates epithelial-mesenchymal transition in high-salt diet-induced hypertensive renal injury through restoration of sirtuin 3 expression and the reduction of oxidative stress. Biochem Biophys Res Commun 2023;653:53–61. 10.1016/j.bbrc.2023.01.084. 36857900.

49. Guo R, Wang P, Zheng X, Cui W, Shang J, Zhao Z. SGLT2 inhibitors suppress epithelial-mesenchymal transition in podocytes under diabetic conditions via downregulating the IGF1R/PI3K pathway. Front Pharmacol 2022;13:897167. 10.3389/fphar.2022.897167. 36225569.

50. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016;375:323–334. 10.1056/nejmoa1515920. 27299675.

51. Perkovic V, de Zeeuw D, Mahaffey KW, et al. Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trials. Lancet Diabetes Endocrinol 2018;6:691–704. 10.1016/s2213-8587(18)30141-4. 29937267.

52. Mosenzon O, Wiviott SD, Cahn A, et al. Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE-TIMI 58 randomised trial. Lancet Diabetes Endocrinol 2019;7:606–617. 10.1016/s2213-8587(19)30180-9. 31196815.

53. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019;380:2295–2306. 10.1056/nejmoa1811744. 30990260.

54. Fogo AB. Causes and pathogenesis of focal segmental glomerulosclerosis. Nat Rev Nephrol 2015;11:76–87. 10.1038/nrneph.2014.216. 25447132.

55. Wheeler DC, Stefánsson BV, Jongs N, et al. Effects of dapagliflozin on major adverse kidney and cardiovascular events in patients with diabetic and non-diabetic chronic kidney disease: a prespecified analysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol 2021;9:22–31. 10.1016/s2213-8587(20)30369-7. 33338413.

56. Rajasekeran H, Reich HN, Hladunewich MA, et al. Dapagliflozin in focal segmental glomerulosclerosis: a combined human-rodent pilot study. Am J Physiol Renal Physiol 2018;314:F412–F422. 10.1152/ajprenal.00445.2017. 29141939.

57. Cherney DZ, Dekkers CC, Barbour SJ, et al. Effects of the SGLT2 inhibitor dapagliflozin on proteinuria in non-diabetic patients with chronic kidney disease (DIAMOND): a randomised, double-blind, crossover trial. Lancet Diabetes Endocrinol 2020;8:582–593. 10.1016/s2213-8587(20)30162-5. 32559474.

58. Boeckhaus J, Gross O. Sodium-glucose cotransporter-2 inhibitors in patients with hereditary podocytopathies, Alport syndrome, and FSGS: a case series to better plan a large-scale study. Cells 2021;10:1815. 10.3390/cells10071815. 34359984.

59. Liu J, Cui J, Fang X, et al. Efficacy and safety of dapagliflozin in children with inherited proteinuric kidney disease: a pilot study. Kidney Int Rep 2021;7:638–641. 10.1016/j.ekir.2021.12.019. 35257077.

60. Wang H, Li T, Sun F, et al. Safety and efficacy of the SGLT2 inhibitor dapagliflozin in patients with systemic lupus erythematosus: a phase I/II trial. RMD Open 2022;8e002686. 10.1136/rmdopen-2022-002686. 36288823.

61. Wood N, Straw S, Cheng CW, et al. Sodium-glucose cotransporter 2 inhibitors influence skeletal muscle pathology in patients with heart failure and reduced ejection fraction. Eur J Heart Fail 2024;26:925–935. 38468429.

62. El-Sayed N, Mostafa YM, AboGresha NM, Ahmed AA, Mahmoud IZ, El-Sayed NM. Dapagliflozin attenuates diabetic cardiomyopathy through erythropoietin up-regulation of AKT/JAK/MAPK pathways in streptozotocin-induced diabetic rats. Chem Biol Interact 2021;347:109617. 10.1016/j.cbi.2021.109617. 34391751.

63. Lin K, Yang N, Luo W, et al. Direct cardio-protection of dapagliflozin against obesity-related cardiomyopathy via NHE1/MAPK signaling. Acta Pharmacol Sin 2022;43:2624–2635. 10.1038/s41401-022-00885-8. 35217813.

Article information Continued

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial and No Derivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/) which permits unrestricted non-commercial use, distribution of the material without any modifications, and reproduction in any medium, provided the original works properly cited.

Study (clinical trial)	Year	No. of patients	Drug	Definition of renal outcomes	Results
Diabetic nephropathy
Wanner et al. [50] (EMPA-REG OUTCOME)	2016	7,028	Empagliflozin	Progression to macroalbuminuria; Doubling of the serum creatinine level; Initiation of renal-replacement therapy; Death from renal causes	Empagliflozin can reduce the risk of renal outcomes by 46% in patients with type 2 diabetes.
Perkovic et al. [51] (CANVAS)	2018	10,142	Canagliflozin	40% reduction in eGFR; New-onset macroalbuminuria; ESKD; Death from renal causes	Canagliflozin can reduce the risk of renal outcomes by 47% in patients with type 2 diabetes.
Mosenzon et al. [52] (DECLARE-TIMI 58)	2019	17,160	Dapagliflozin	Sustained decrease of 40% or more in eGFR; New ESKD; Death from renal causes	Dapagliflozin can reduce the risk of renal outcomes by 47% in patients with type 2 diabetes.
Perkovic et al. [53] (CREDENCE)	2019	4,401	Canagliflozin	ESKD; A doubling of the serum creatinine level; Death from renal causes	Canagliflozin can reduce the risk of renal outcomes by 34% in patients with type 2 diabetes and albuminuric chronic kidney disease.
Nondiabetic podocytopathies
Wheeler et al. [10] (DAPA-CKD)	2022	104	Dapagliflozin	Sustained decline in eGFR of at least 50%; ESKD; Death from renal or cardiovascular causes	Dapagliflozin can reduce the chronic eGFR slope in patients with FSGS.
Cherney et al. [57] (DIAMOND)	2020	53	Dapagliflozin	The percentage change from baseline in 24-hour proteinuria, changes in mGFR	Dapagliflozin does not reduce 24-hour proteinuria in patients with FSGS but leads to a reversible reduction of mGFR.
Rajasekeran et al. [56]	2018	10	Dapagliflozin	GFR; 24-hour proteinuria; Urine protein-to-creatinine ratio	Dapagliflozin did not reduce 24-hour proteinuria and GFR in patients with FSGS after treatment for 8 weeks.
The EMPA-KIDNEY Collaborative Group [2]	2024	6,609	Empagliflozin	A sustained ≥40% eGFR decline from randomization; ESKD, a sustained eGFR below 10 mL/min per 1.73 m²; Death from kidney failure	Empagliflozin can reduce the risk of renal outcomes by 29% in patients with chronic kidney disease but did not work in 195 patients with FSGS.
Liu et al. [59]	2021	8	Dapagliflozin	24-hour proteinuria	Dapagliflozin can reduce 24-hour proteinuria by 33.3% at 4 weeks of treatment and 22.6% at 12 weeks in patients with inherited proteinuric kidney disease.
Boeckhaus and Gross [58]	2021	6	Empagliflozin or dapagliflozin	Urinary albumin-creatinine ratio; eGFR	SGLT2 inhibitors can reduce the mean urinary albumin-creatinine ratio by 40% in patients with FSGS or Alport syndrome.
Wang et al. [60]	2022	38	Dapagliflozin	SLEDAI score; 24-hour proteinuria	Dapagliflozin cannot reduce the SLEDAI score and 24-hour proteinuria in patients with SLE after treatment for 6 months.
Zhao et al. [19]	2023	9	Empagliflozin	Proteinuria	Empagliflozin can reduce proteinuria by 29.6% to 96.3% in patients with lupus nephritis.