Marinobufagenin in Chronic Kidney Disease: From Na⁺/K⁺-ATPase Dysfunction to Fibrosis and Targeted Neutralization

Abstract

1. Chronic Kidney Disease Is More Than Progressive Loss of Filtration

Chronic kidney disease is characterized by persistent abnormalities of kidney structure or function. Clinical assessment commonly includes estimated glomerular filtration rate (eGFR) and markers of kidney damage such as albuminuria. Its consequences, however, extend far beyond the kidney [5].

As CKD progresses, patients can develop profound changes in sodium and fluid balance, vascular function, blood-pressure regulation, cardiac structure, oxidative stress, inflammation, and extracellular-matrix turnover. Cardiovascular disease remains a major cause of morbidity and mortality among people with impaired kidney function [5].

Fibrotic remodeling is an important common pathway connecting many of these processes. Within the kidney, progressive extracellular-matrix deposition contributes to nephron loss and structural deterioration. Vascular fibrosis increases arterial stiffness, while myocardial fibrosis and hypertrophy contribute to CKD-associated cardiomyopathy [5,8].

Understanding the molecular signals that connect renal dysfunction with systemic vascular and cardiac remodeling is therefore particularly important. One such signal is marinobufagenin.

2. Marinobufagenin: From Physiological Sodium Regulation to Pathological Signaling

Marinobufagenin is an endogenous cardiotonic steroid belonging to the bufadienolide family. Under physiological conditions, MBG participates in sodium and volume regulation. When sodium retention or extracellular-volume expansion occurs, increased MBG activity can promote natriuresis through interaction with Na⁺/K⁺-ATPase [1]. This response may initially be compensatory.

In chronic disease, however, sustained or dysregulated MBG activity can become maladaptive. Altered circulating MBG has been documented in experimental and clinical kidney disease. Patients with CKD, including individuals receiving hemodialysis, have shown higher plasma MBG immunoreactivity than people with preserved renal function; experimental chronic renal failure produces a similar increase [2].

The importance of this elevation extends beyond sodium transport because Na⁺/K⁺-ATPase is more than a membrane ion pump: it also participates in cellular signaling [1].

3. The MBG–Na⁺/K⁺-ATPase Signaling Axis

Na⁺/K⁺-ATPase maintains the transmembrane sodium and potassium gradients required for normal cell function. Interaction between cardiotonic steroids and Na⁺/K⁺-ATPase can additionally influence pathways associated with oxidative stress, cell growth and differentiation, and extracellular-matrix production [1].

In experimental models, MBG-associated signaling involves Src/EGFR signaling and protein kinase C delta (PKCδ). A particularly important downstream target is Friend leukemia integration-1 (Fli1), a transcription factor that normally acts as a negative regulator of collagen-1 synthesis. When MBG-dependent signaling reduces nuclear Fli1 activity, repression of collagen-gene transcription is weakened [3,5].

The proposed sequence can be summarized as follows:

This pathway provides a mechanistic explanation for how a circulating endogenous steroid involved in sodium homeostasis may also contribute to structural remodeling of the kidney, vasculature, and heart [3,5,6,8].

4. MBG, Fibrosis, and the Cardiorenal Complications of CKD

The pathological consequences of sustained MBG activity have been investigated in several experimental models of renal disease.

Vascular Fibrosis

In CKD, arterial stiffness is a major cardiovascular risk factor. MBG-associated suppression of Fli1 promotes collagen-1 accumulation within the vascular wall, altering the balance between collagen and elastic components and producing a structurally stiffer vessel with impaired relaxation [5,6].

A 2024 study in partially nephrectomized rats found that renal injury was accompanied by increased vascular collagen, decreased Fli1 expression, and severely impaired vasorelaxation. Treatment with an anti-MBG antibody counteracted changes in the Fli1–collagen-1 pathway and restored vascular relaxation [6].

Cardiac Remodeling

The MBG pathway also appears to contribute to experimental uremic cardiomyopathy. In chronic renal failure models, elevated MBG has been associated with oxidative stress, cardiac hypertrophy, suppression of cardiac Fli1, and increased collagen-1 [3].

In a partial-nephrectomy model, a monoclonal antibody against MBG reduced blood pressure, decreased oxidative stress, restored Fli1 expression, and substantially reduced cardiac fibrosis [3]. These findings support the interpretation that MBG is not simply a marker accompanying renal failure but may participate directly in pathological cardiorenal remodeling.

Renal Fibrosis

Fibrosis within the kidney is a central mechanism behind the progressive loss of functioning renal tissue. In an experimental renal-disease model, passive immunization against MBG attenuated renal fibrosis and improved renal function, further supporting a causal role for endogenous cardiotonic-steroid signaling in CKD progression [8].

Taken together, these studies suggest that the MBG–Na⁺/K⁺-ATPase pathway may connect renal dysfunction with vascular and cardiac disease through a shared pro-fibrotic mechanism.

5. Human Evidence: Plasma and Urinary MBG Tell Different Parts of the Story

Clinical research adds an important dimension to the understanding of MBG in kidney disease. Circulating and urinary MBG should not necessarily be interpreted in the same way.

A cross-sectional study of 108 patients with non-advanced CKD found that urinary MBG excretion was lower than in 25 matched healthy controls and was associated with measures of renal-disease severity [4]. The same CKD cohort was then followed prospectively for up to 24 months.

During a mean follow-up of 21 months, 35 patients (32.4%) reached a composite renal-progression endpoint. Their baseline urinary MBG excretion was lower than in participants who did not reach the endpoint. Very low urinary MBG was strongly associated with subsequent CKD progression, but the study authors emphasized that larger, heterogeneous validation cohorts are needed before urinary MBG can be considered an established clinical biomarker [7].

The apparent contrast—elevated circulating MBG in advanced disease but reduced urinary MBG excretion in patients at high risk of progression—does not necessarily represent a contradiction. Plasma concentrations reflect systemic exposure, whereas urinary levels are influenced by renal handling and excretion. Studying both compartments may help clarify how MBG production, circulation, clearance, and biological activity change across CKD progression.

6. Why Selective MBG Neutralization Is Therapeutically Interesting

Current CKD treatments can slow progression and reduce cardiovascular complications, yet substantial residual renal and cardiovascular risk remains [5]. Targeting MBG would address a different part of the disease pathway.

Rather than broadly suppressing sodium transport or systemic signaling pathways, selective anti-MBG antibodies are designed to bind the circulating molecule itself. Across experimental and ex vivo studies, MBG neutralization has been reported to:

• restore Na⁺/K⁺-ATPase activity in erythrocytes from patients with CKD [2];
• normalize Fli1 signaling and reduce collagen-1 expression [3,6];
• decrease renal, vascular, and cardiac fibrosis in animal models [3,6,8];
• restore vascular relaxation in experimental CKD [6];
• reduce pathological cardiovascular remodeling in experimental renal failure [3].

Evidence boundary. The reported therapeutic effects come from animal models or ex vivo experiments. They establish a mechanistic and translational rationale, not clinical efficacy or safety in patients.

7. From Experimental Evidence to Human-Sample Validation

Padakonn Pharma is developing monoclonal antibodies that target marinobufagenin and an extracorporeal platform intended to remove circulating MBG from the bloodstream.

The next translational question is whether selective MBG neutralization can restore Na⁺/K⁺-ATPase function and reverse MBG-driven pathological signaling in human CKD samples.

Padakonn Pharma has begun a TRL5 study with the University of Tartu and Tartu University Hospital to investigate this question using blood samples from patients with chronic kidney disease. The study evaluates anti-MBG monoclonal antibodies in a clinically relevant human-sample setting, with a focus on restoration of Na⁺/K⁺-ATPase function and reversal of MBG-associated signaling. The antibodies are not being administered to patients as part of this work. See the company’s TRL5 validation update for the programme context.

This work represents a transition from mechanistic and preclinical evidence toward validation of the therapeutic concept in human disease samples.

8. Conclusion

Marinobufagenin may connect sodium and volume dysregulation, Na⁺/K⁺-ATPase signaling, fibrosis, and cardiovascular complications in chronic kidney disease.

The accumulated evidence supports a proposed disease pathway:

CKD and volume dysregulation → altered MBG activity → Na⁺/K⁺-ATPase dysfunction and signaling → Fli1 suppression → collagen accumulation → renal, vascular, and cardiac remodeling.

Experimental reversal of these processes through selective anti-MBG antibodies provides a rationale for further translational investigation [2,3,6,8]. At the same time, clinical studies of circulating and urinary MBG indicate that this endogenous cardiotonic steroid may have future value both as a therapeutic target and as a biomarker of CKD biology and progression [2,4,7].

Studies using clinically relevant human CKD samples will help determine whether targeting the MBG–Na⁺/K⁺-ATPase axis can advance toward a therapeutic approach to cardiorenal disease.

References