The kidney’s proximal tubule features two distinct segments responsible for glucose reabsorption: the S1 and S2 segments predominantly reabsorb glucose through SGLT2, handling approximately 97% of the filtered glucose load. Meanwhile, the S3 segment engages SGLT1 to reclaim the remaining glucose. While selective SGLT2 inhibitors like dapagliflozin primarily target these early segments, dual inhibition that includes SGLT1 presents an opportunity to influence downstream effects more comprehensively. This approach, until recently, was explored primarily for its potential in diabetes management. However, its implications for blood pressure regulation and renal protection have drawn significant attention owing to the complex interplay between sodium handling, glucose reabsorption, and vascular health.

Salt-sensitive hypertension, a prevalent condition affecting nearly half of hypertensive patients, is characterized by heightened blood pressure responses to excessive dietary salt intake. This pathology not only exacerbates cardiovascular risk but also accelerates kidney damage, ultimately contributing to chronic kidney disease (CKD) progression and renal failure. To model this condition experimentally, researchers utilized established rodent models subjected to high salt diets, mimicking the pathophysiological mechanisms underlying human salt-sensitive hypertension. In this model, the effects of selective SGLT2 inhibition were rigorously compared with those of dual SGLT1/2 inhibition through pharmacological agents dapagliflozin and sotagliflozin, respectively.

Findings demonstrated that while both dapagliflozin and sotagliflozin notably mitigated the severity of salt-induced hypertensive pathology, the dual SGLT1/2 inhibitor produced a more pronounced reduction in mean arterial pressure. This superior efficacy was accompanied by a striking attenuation in kidney injury markers, underscoring the enhanced renal protective capacity of dual inhibition. Interestingly, neither treatment exerted significant effects on blood pressure under normal salt intake, emphasizing the salt-dependent nature of their therapeutic impact. These results suggest a targeted mechanism by which dual inhibition modulates renal sodium and glucose handling, reducing volume overload and subsequent vascular strain.

Further mechanistic insights emerged as researchers observed that sotagliflozin uniquely influenced urinary electrolyte excretion. The drug enhanced sodium and chloride excretion more effectively than dapagliflozin, indicating a potentiation of natriuresis. Additionally, fractional glucose excretion nearly doubled with dual inhibition, signifying a more robust blockade of glucose reabsorption pathways throughout the proximal tubule segments. Despite these metabolic shifts, both drugs preserved overall kidney function, reassuring the renal safety profile of this therapeutic approach. The nuanced metabolic modulation was particularly evident in region-specific alterations in renal lipid metabolism and inflammatory signaling pathways, hallmarks of hypertension-induced kidney injury.

At the molecular level, SGLT2 inhibition demonstrated selective modulation of renal metabolic processes, especially affecting lipid utilization and inflammatory mediators within kidney tissues. These alterations hold substantial significance given the kidney’s high metabolic demands and the role of lipotoxicity in chronic kidney disease progression. By attenuating inflammatory signaling cascades, dual SGLT1/2 inhibition may quell the chronic low-grade inflammation that characterizes hypertensive kidney damage. Such molecular effects complement hemodynamic improvements, creating a multifactorial approach to renal and cardiovascular protection.

Olha Kravtsova, PhD, from the University of South Florida and the lead investigator of the study, emphasized the translational potential of these findings. The preclinical evidence supports broadening the clinical application of dual SGLT1/2 inhibitors beyond their conventional roles in heart failure and diabetes patients. Particularly for individuals grappling with salt-sensitive hypertension—a condition notoriously resistant to conventional antihypertensives—this therapeutic avenue heralds a promising alternative. Moreover, the newly uncovered metabolic pathways delineate exciting opportunities for further research, potentially unearthing novel drug targets centered on lipid metabolism and inflammatory modulation within the kidney.

The clinical implications extend beyond mere blood pressure control. By effectively lowering salt-induced hypertension and simultaneously reducing renal injury, dual SGLT1/2 inhibitors could alter the current management paradigms for chronic kidney disease. Given that hypertension remains a leading cause of CKD worldwide, a therapy that addresses the root contributors at a renal tubular level fits into a precision medicine framework. In light of these findings, nephrologists and cardiologists alike may soon consider the benefits of such combination inhibitors in comprehensive cardiovascular and renal care.

Intriguingly, the differential impact of SGLT1 versus SGLT2 blockade on sodium handling sheds light on the physiological role of proximal tubular segments in hypertensive pathophysiology. Whereas SGLT2 inhibition primarily affects early sodium and glucose reabsorption, the addition of SGLT1 blockade—localized to the more distal S3 segment—increases sodium excretion synergistically. This layered approach to disrupting sodium reabsorption pathways suggests a sophisticated mechanism for controlling volume overload and hypertension. These insights may also inform future drug development, guiding the design of agents with tailored segmental specificity.

Despite the promising outcomes, the study underscores the necessity for cautious progression toward human trials. Translational hurdles remain, given species differences in renal transporter expression and function. Nevertheless, the consistency of salt-sensitive hypertension mechanisms across mammals furnishes a robust preclinical foundation. The research presented at ASN Kidney Week 2025 invites the nephrology community to reassess the therapeutic landscape and fosters optimism for refined interventions in salt-related hypertensive and renal disorders.

The study titled “Dual SGLT1/2 Inhibition Attenuates Salt-Sensitive Hypertension and Kidney Injury More Effectively than SGLT2 Inhibition” represents a pivotal step in the nuanced understanding of renal glucose and sodium transport and its systemic effects. As researchers continue to unravel these complex interactions, the potential to transform clinical practice becomes increasingly tangible. This research signals a paradigm shift from singular to dual transporter inhibition, reflecting a comprehensive strategy to mitigate the multifactorial nature of hypertension and renal injury.

In conclusion, the dual inhibition of SGLT1 and SGLT2 by agents such as sotagliflozin offers a promising avenue for not only glycemic control but also for significant cardiovascular and renal protection. The findings from this rodent model study suggest that targeting multiple transporters in the kidney proximal tubule can more effectively suppress salt-sensitive hypertension and renal damage than current selective therapies. As new avenues open for addressing the metabolic and inflammatory underpinnings of hypertensive kidney disease, this line of research holds transformative potential for patients worldwide.

Join approximately 12,000 kidney specialists and healthcare professionals at ASN Kidney Week 2025 in Houston, TX, November 5–9, for the latest scientific discussions and updates in nephrology, including advances such as these that redefine kidney disease management. This global meeting remains a pivotal platform to exchange innovation, knowledge, and insight among leading experts aiming to improve patient outcomes in renal medicine.

Subject of Research: Effects of dual SGLT1/2 inhibition versus selective SGLT2 inhibition on salt-sensitive hypertension and kidney injury in a rat model
Article Title: Dual SGLT1/2 Inhibition Attenuates Salt-Sensitive Hypertension and Kidney Injury More Effectively than SGLT2 Inhibition
News Publication Date: November 7, 2025
Web References: www.asn-online.org
Keywords: Sodium-glucose co-transporter, SGLT1, SGLT2, salt-sensitive hypertension, kidney injury, dapagliflozin, sotagliflozin, proximal tubule, natriuresis, renal metabolism, lipid metabolism, inflammatory signaling

Type I diabetes arises primarily from the autoimmune destruction of β-cells, the insulin factories within the pancreatic islets of Langerhans. While this T cell–mediated β-cell assault has been extensively characterized, the role of resident immune cells, especially macrophages within the islets, has remained enigmatic. Macrophages possess the unique functional capacity to clear apoptotic cells through a process called efferocytosis, a key determinant of tissue homeostasis and immune regulation. Until now, how intra-islet macrophages influence the immunological landscape during the dynamic β-cell turnover and autoimmune attack was unclear.

Employing an integration of omics technologies alongside in vivo and ex vivo functional assays, the research team identified a subset of intra-islet macrophages displaying an efferocytic, anti-inflammatory phenotype—termed e-Mac—in both mouse models and human pancreatic tissue. Notably, these e-Macs were characterized by gene expression profiles indicative of enhanced clearance capacity and immunomodulatory functions, suggesting a fundamental role in counterbalancing islet inflammation.

A pivotal experimental approach involved inducing limited β-cell apoptosis in wild-type C57BL/6 mice and NOD mice, a standard model for autoimmune diabetes susceptibility. Rather than provoking macrophage proliferation, this apoptotic challenge triggered a phenotypic switch in resident islet macrophages towards the e-Mac state. Intriguingly, this modulation of macrophage phenotype coincided with a sustained suppression of autoimmune diabetes in the NOD model, underscoring the potential of harnessing efferocytosis-mediated immunomodulation to mitigate disease progression.

Delving deeper into mechanistic insights, co-culture experiments with macrophages and apoptotic β-cells recapitulated the e-Mac phenotype ex vivo, confirming that apoptotic cell signals are sufficient to reshape macrophage identity and function. This reprogramming heralds a shift in islet immune surveillance from inflammatory cytokine production towards an immunosuppressive milieu, which may prevent pathological activation of autoreactive lymphocytes.

One of the most striking findings involved the impact of e-Macs on CD4+ T cell responsiveness. Islet macrophages enriched in the e-Mac phenotype induced an anergic-like state in CD4+ T cells in ex vivo assays, rendering them hyporesponsive to antigenic stimuli. Parallel in vivo experiments corroborated these observations, revealing a local accumulation of anergic-like CD4+ T cells within the islets of treated mice. This phenomenon offers a plausible cellular basis for the observed attenuation of autoimmune aggression.

To unravel the molecular dialogue underpinning macrophage-T cell crosstalk, the investigators applied NicheNet, a cutting-edge computational framework for predicting ligand-receptor interactions and downstream signaling pathways. This analysis, validated by focused experimental interventions, pinpointed the insulin-like growth factor 1 (IGF-1) and its receptor IGF1R axis as a critical mediator driving the induction of T cell anergy by e-Macs. Therapeutic modulation of this axis could therefore provide a strategy to selectively re-educate pathogenic T cells.

Collectively, the data converge on a model wherein limited β-cell apoptosis initiates a beneficial feedback loop: dying β-cells instruct resident macrophages to adopt an efferocytic, anti-inflammatory program, which in turn enforces tolerance on autoreactive T cells. This paradigm underscores a previously underappreciated role of efferocytosis not merely as cellular debris clearance but as a pivotal immunoregulatory checkpoint maintaining islet homeostasis and preventing autoimmune diabetes onset.

This innovative study challenges the dogma that autoimmune diabetes is exclusively fueled by aberrant T cell activation and exposes intra-islet macrophages as critical gatekeepers capable of tempering immune aggression. By leveraging mechanisms intrinsic to tissue repair and immune resolution, future therapies could aim to bolster this natural immunosuppressive axis, potentially halting or even reversing β-cell destruction.

Further research is required to translate these findings into clinical intervention, particularly in decoding how to precisely manipulate e-Mac populations and the IGF-1–IGF1R pathway without disrupting systemic immune function. Moreover, the heterogeneity of macrophages across human pancreatic islets and the dynamics of efferocytosis in the context of symptomatic diabetes remain important areas for exploration.

Nevertheless, this study represents a paradigm shift, highlighting the interplay between cell death signals, macrophage plasticity, and adaptive immune modulation within a key metabolic organ. By framing β-cell apoptosis not as a purely detrimental event but also as an immunological cue for tolerance induction, these findings suggest novel avenues for diabetes prevention and management that transcend classical immune suppression.

The implications of this work extend beyond diabetes to broader contexts where chronic inflammation and failed apoptotic clearance drive disease. Therapeutic strategies promoting efferocytosis and anti-inflammatory macrophage states could revolutionize treatments for autoimmune and inflammatory disorders alike, capitalizing on endogenous repair mechanisms.

In essence, the research illuminates a sophisticated biological narrative: controlled cell death orchestrates a tailored immune response via macrophage remodeling, which in turn enforces tolerance and preserves tissue function. Such insight elevates the significance of macrophage efferocytosis from housekeeping to a potent immunological regulator and opens new frontiers in understanding and combating autoimmune diseases.

Subject of Research:
Efferocytosis-mediated immunoregulation by pancreatic islet macrophages in type I diabetes.

Article Title:
Efferocytic remodelling of pancreatic islet macrophages by limited β-cell death.

Article References:
Zakharov, P.N., Chowdhury, C.S., Peterson, O.J. et al. Efferocytic remodelling of pancreatic islet macrophages by limited β-cell death. Nature (2025). https://doi.org/10.1038/s41586-025-09560-4

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