VEGFR1 Blockade Reverses Advanced Diabetic Kidney Damage in Mice

The Challenge of Reversing Advanced Diabetic Renal Injury

Diabetic kidney disease remains the primary driver of chronic kidney failure, necessitating aggressive management of glycemic control and blood pressure to slow progression [1, 2]. While the vascular endothelial growth factor (VEGF) pathway is a known regulator of glomerular filtration and microvascular integrity, clinical attempts to modulate these signals have often yielded inconsistent outcomes [3, 4]. Recent phase 2 trials targeting related pathways have failed to significantly reduce albuminuria (the presence of excess albumin in the urine, a key clinical marker of kidney damage); for instance, the vascular endothelial growth factor B inhibitor CSL346 showed only a 4.0% difference in the urinary albumin-creatinine ratio compared to placebo (95% confidence interval, -14.7 to 26.8) [5]. Similarly, the interleukin-33 inhibitor tozorakimab demonstrated no significant benefit, with a 23% to 25% reduction in albuminuria compared to 22% in the placebo group [6]. Furthermore, systemic anti-angiogenic therapy is frequently complicated by hypertension, as seen with CSL346, which increased diastolic blood pressure by up to 5.3 mm Hg (p = 0.002) [5, 4]. A recent study now investigates whether selective targeting of vascular endothelial growth factor receptor 1 (VEGFR1) can move beyond disease stabilization to achieve the regression of established renal lesions [7].

Divergent Outcomes of VEGF-A and VEGFR2 Inhibition

Diabetic kidney disease remains the primary cause of kidney failure worldwide, yet therapeutic strategies targeting the vascular endothelial growth factor A (VEGF-A) pathway have historically yielded conflicting results in preclinical models. To address these inconsistencies, researchers conducted a comprehensive evaluation of neutralizing antibodies targeting VEGF-A and its primary receptors, vascular endothelial growth factor receptor 1 (VEGFR1) and vascular endothelial growth factor receptor 2 (VEGFR2). The study utilized four distinct mouse models of diabetic and chronic kidney disease to assess how different components of this signaling pathway influence renal outcomes. These included uninephrectomized diabetic db/db mice (a model where one kidney is surgically removed to accelerate the progression of diabetic nephropathy), as well as hypertensive models involving renin-AAV injections (an adeno-associated virus used to induce high renin levels) or eNOS-deficient mice (which lack endothelial nitric oxide synthase and develop severe hypertension). The findings revealed that broad inhibition of the VEGF pathway may be counterproductive in the context of advanced renal disease. In uninephrectomized diabetic db/db mice, the administration of an anti-VEGF-A monoclonal antibody worsened albuminuria and exacerbated kidney injury, contrary to previous reports suggesting a protective role for VEGF-A blockade. A similar detrimental effect was observed when the researchers targeted the VEGFR2 receptor specifically. Using the anti-VEGFR2 antibody DC101, the study demonstrated that VEGFR2 inhibition also increased albuminuria and intensified histological kidney damage in the uninephrectomized diabetic mice. For practicing nephrologists, these results suggest that maintaining a baseline level of VEGF-A and VEGFR2 signaling is essential for preserving the integrity of the glomerular filtration barrier, and that non-selective blockade of these signals can actually accelerate the progression of diabetic kidney disease.

Selective VEGFR1 Blockade and Renal Recovery

In contrast to the deleterious effects observed with broad vascular endothelial growth factor A inhibition, targeted intervention using MF1, a selective monoclonal blocking antibody against vascular endothelial growth factor receptor 1 (VEGFR1), yielded significant therapeutic benefits. In models of advanced renal impairment, including the mouse remnant kidney model (where renal mass is surgically reduced to induce failure) and uninephrectomized db/db mice, administration of the MF1 antibody dramatically decreased albuminuria. Beyond reducing protein excretion, MF1 treatment improved kidney function and histological injury in these cohorts, suggesting a reversal of established structural damage within the nephrons. The efficacy of VEGFR1 blockade extended to high-risk hypertensive settings, which frequently complicate the clinical management of diabetic nephropathy. In eNOS-deficient db/db mice, a model characterized by severe hypertension and accelerated renal decline, MF1 treatment improved kidney function and reduced histological injury. These physiological improvements translated into a clear clinical benefit, as MF1 improved animal survival across all tested models of progressive chronic kidney disease. This survival benefit is particularly notable given the advanced stage of disease at which treatment was initiated in several of the experimental arms. The physiological impact of MF1 was observed both acutely and over long-term follow-up. In db/db mice, the antibody acutely increased the glomerular filtration rate (the rate at which the kidneys filter waste from the blood), indicating an immediate hemodynamic or functional improvement in renal clearance. Ultimately, the study demonstrated that blocking VEGFR1 improved kidney function and microvascular structure (the integrity of the small blood vessels and capillaries within the glomerulus) in models of progressive chronic kidney disease. These findings suggest that selective inhibition of the VEGFR1 receptor may preserve the microvasculature and stabilize renal filtration in a way that non-selective blockade cannot, offering a potential future pathway for treating patients with progressive renal decline.

Regression of Established Histological Lesions

The researchers further evaluated the therapeutic impact of MF1 in uninephrectomized db/db mice complicated by high renin states. In these subjects, MF1 improved kidney function and histological injury regardless of whether the mice received a renin-AAV injection to accelerate renal damage. This consistency across different levels of disease severity suggests that vascular endothelial growth factor receptor 1 blockade addresses core mechanisms of renal decline even when complicated by severe hypertension. To simulate a more clinically relevant scenario where patients present with existing renal impairment, the study utilized a delayed treatment protocol in renin-AAV uninephrectomized db/db mice with advanced diabetic kidney disease. Even when initiated after significant damage had occurred, delayed MF1 treatment improved survival in these cohorts. This survival benefit was accompanied by objective improvements in biochemical markers of filtration; specifically, delayed MF1 treatment reduced serum creatinine (a primary clinical indicator of renal clearance) in the mice with advanced disease. Most notably, the intervention demonstrated the potential for structural recovery in the renal parenchyma. In the renin-AAV uninephrectomized db/db mice, delayed MF1 treatment led to the regression of established kidney histological changes. This finding indicates that vascular endothelial growth factor receptor 1 inhibition does not merely arrest the progression of diabetic kidney disease but may facilitate the repair of existing microvascular and tissue damage. By reversing established lesions, this targeted therapy addresses a critical need in the management of advanced chronic kidney disease, where current standards of care typically only delay the eventual requirement for dialysis or transplantation.

Mechanisms of Action and Hemodynamic Effects

The therapeutic efficacy of the MF1 antibody appears to stem from its ability to modulate the availability of circulating ligands within the vascular endothelial growth factor pathway. In the treated models, the administration of the VEGFR1 antibody increased circulating placental growth factor (PlGF) and increased circulating VEGF-A. Because VEGFR1 normally acts as a decoy receptor that sequesters these proteins, its blockade prevents this binding, thereby increasing the systemic concentration of these growth factors. This shift in ligand availability led to increased phosphorylation of kidney VEGFR2, a process involving the addition of a phosphate group to the receptor to activate its downstream signaling. This suggests that the renal protection observed with MF1 may be mediated by the redirection of VEGF-A to the VEGFR2 receptor, which supports endothelial cell survival and maintains the integrity of the glomerular filtration barrier. Further investigation into the intracellular requirements for this effect revealed that the MF1 benefit persisted in albuminuric transgenic mice lacking the VEGFR1 cytoplasmic tyrosine kinase domain, which is the internal portion of the receptor responsible for initiating intracellular signaling cascades. This finding indicates that the primary mechanism of action is likely the neutralization of the receptor's decoy function rather than the inhibition of direct signaling through the VEGFR1 protein itself. Beyond molecular signaling, the intervention demonstrated significant hemodynamic advantages in models of severe vascular dysfunction. Specifically, MF1 reduced blood pressure in diabetic eNOS-deficient mice, a strain that typically exhibits accelerated hypertension and renal decline. For the clinician, this suggests that VEGFR1 blockade may offer a dual benefit by simultaneously addressing molecular drivers of microvascular damage and improving systemic hemodynamic parameters that contribute to the progression of chronic kidney disease.

References

1. Visseren FL, Mach F, Smulders YM, et al. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice. European Heart Journal. 2021. doi:10.1093/eurheartj/ehab484

2. Standards of Medical Care in Diabetes—2013. Diabetes Care. 2012. doi:10.2337/dc13-s011

3. Ferrara N. Vascular Endothelial Growth Factor: Basic Science and Clinical Progress. Endocrine Reviews. 2004. doi:10.1210/er.2003-0027

4. Liu Z, Chen H, Zheng L, Sun L, Shi L. Angiogenic signaling pathways and anti-angiogenic therapy for cancer. Signal Transduction and Targeted Therapy. 2023. doi:10.1038/s41392-023-01460-1

5. Cooper M, Cherney DZI, Greene TH, et al. Vascular Endothelial Growth Factor-B Blockade with CSL346 in Diabetic Kidney Disease: A Phase 2A Randomized Controlled Trial.. Journal of the American Society of Nephrology : JASN. 2024. doi:10.1681/ASN.0000000000000438

6. Hofherr A, Mäki-Petäjä K, Selvarajah V, et al. Inhibition of IL-33 in Diabetic Kidney Disease: A Randomized, Placebo-Controlled Phase 2b Trial.. Journal of the American Society of Nephrology. 2025. doi:10.1681/asn.0000000966

7. Qi Z, Tang Y, Croy JE, et al. Reversal of advanced diabetic kidney disease in mice treated with a monoclonal anti-VEGFR1 antibody.. Kidney international. 2026. doi:10.1016/j.kint.2026.03.016