Novel Renal-cardiac Disease Model: Podocyte-specific MafB Conditional Knockout Mice

Chronic kidney disease (CKD) progresses through glomerular and tubular injury and causes complications such as albuminuria, hypertension, renal anemia, cardiac hypertrophy, and fibrosis. About half of CKD patients die from cardiovascular events, making understanding reno-cardiac disorder (RCD) mechanisms crucial. Conventional RCD models are insufficient to induce cardiac hypertrophy or fibrosis via renal injury alone, and no reproducible model exists that simultaneously develops renal–cardiac interaction, hypertension, and renal anemia. Most current models combine multiple stressors through surgery or drugs, making it difficult to clarify interorgan crosstalk or causal links between glomerular injury and systemic complications.
MafB is essential for podocyte maintenance, and MafB-deficient mice (MafB CKO) develop progressive glomerulosclerosis and renal failure. Because this model induces severe renal injury with high reproducibility through a tissue-specific single-gene deletion, we investigated whether these mice also develop cardiac disease, hypertension, and renal anemia, as seen in CKD patients.

Using this mouse model, we evaluated cardiac function, hypertrophy, and fibrosis by echocardiography and histopathology. In addition, blood pressure, renal anemia, and serum FGF23 and phosphate levels were measured to determine whether glomerular injury alone could induce cardiac remodeling and systemic complications.

Male and female mice with podocyte-specific MafB deletion (MafB CKO), induced by tamoxifen at 8 weeks of age, were analyzed at 18 and 23–28 weeks post-treatment. Echocardiography revealed a significant increase in body weight–normalized left ventricular (LV) wall mass in MafB CKO mice (Fig1), while ejection fraction (EF) was unchanged (Fig2), consistent with features of HFpEF. HE staining confirmed cardiac hypertrophy, with fibrosis and necrosis in some regions (Fig3). MafB CKO mice also developed hypertension (Fig4), reductions in hemoglobin and hematocrit (Fig5,6), and elevated serum FGF23 and phosphate levels (Fig7), indicating renal anemia and increased LV hypertrophy risk. These results demonstrate frequent cardiac remodeling and comorbidities in MafB CKO mice during progressive kidney disease.

To confirm the utility of MafB CKO mice as a model for evaluating novel therapeutics, we examined the effects of sacubitril/valsartan on cardiac remodeling and blood pressure. Although no significant improvements were observed in CRE, serum urea nitrogen (S-UN) (Fig8), and quantitative analyses of glomerulosclerosis (PAS staining) and tubulointerstitial injury (MT staining) (Fig9), blood pressure was significantly reduced in the treatment group (Fig10). While there was no significant change in overall heart weight, left ventricular wall mass and its longitudinal change showed a decreasing trend (Fig11).

In conclusion, MafB CKO mice represent a disease model that reproduces the pathophysiology of human CKD, as well as RCD and comorbidities such as hypertension and renal anemia, in a simple and highly reproducible manner without the need for multiple interventions. Furthermore, the results of ARNI administration in this model were consistent with previous preclinical and clinical studies, suggesting that MafB CKO mice are also a suitable model for evaluating the efficacy of novel therapeutic agents.