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Genetic or pharmacologic Nrf2 activation increases proteinuria in chronic kidney disease in mice
Brittney M Rush1, Corry D Bondi1, Sean D Stocker1
1Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Abstract:
The nuclear factor erythroid 2-related factor 2 (Nrf2) pathway upregulates key cellular defenses. Clinical trials are utilizing pharmacologic Nrf2 inducers such as bardoxolone methyl to treat chronic kidney disease, but Nrf2 activation has been linked to a paradoxical increase in proteinuria. To understand this effect, we examined genetically engineered mice with elevated Nrf2 signaling due to reduced expression of the Nrf2 inhibitor, Kelch-like ECH-associated protein 1 (Keap1). These Keap1FA/FA mice lacked baseline proteinuria but exhibited increased proteinuria in experimental models evoked by adriamycin, angiotensin II, or protein overload. After injury, Keap1FA/FA mice had increased glomerulosclerosis, nephrin disruption and shedding, podocyte injury, foot process effacement, and interstitial fibrosis. Keap1FA/FA mice also had higher daytime blood pressures and lower heart rates measured by radiotelemetry. Conversely, Nrf2 knockout mice were protected from proteinuria. We also examined the pharmacologic Nrf2 inducer CDDO-Im. Compared to angiotensin II alone, the combination of angiotensin II and CDDO-Im significantly increased proteinuria, a phenomenon not observed in Nrf2 knockout mice. This effect was not accompanied by additional increases in blood pressure. Finally, Nrf2 was found to be upregulated in the glomeruli of patients with focal segmental glomerulosclerosis, diabetic nephropathy, fibrillary glomerulonephritis, and membranous nephropathy. Thus, our studies demonstrate that Nrf2 induction in mice may exacerbate proteinuria in chronic kidney disease.
Insights
Nuclear factor erythroid 2-related factor 2 (Nrf2) activation may worsen proteinuria in chronic kidney disease. Studies show Nrf2 inducers increased kidney injury markers and proteinuria in mouse models and human kidney disease patients.
Area of Science:
- Nephrology
- Molecular Biology
- Pathology
Background:
- The nuclear factor erythroid 2-related factor 2 (Nrf2) pathway is crucial for cellular defense mechanisms.
- Pharmacologic Nrf2 inducers are being investigated for chronic kidney disease (CKD) treatment.
- However, Nrf2 activation has been paradoxically linked to increased proteinuria in CKD.
Purpose of the Study:
- To investigate the role of elevated Nrf2 signaling in exacerbating proteinuria and kidney damage.
- To examine the effects of pharmacologic Nrf2 induction in experimental models of kidney injury.
- To assess Nrf2 expression in human kidney disease glomeruli.
Main Methods:
- Utilized genetically engineered Keap1(FA/FA) mice with elevated Nrf2 signaling and Nrf2 knockout mice.
- Induced kidney injury using adriamycin, angiotensin II, and protein overload models.
- Administered pharmacologic Nrf2 inducer CDDO-Im in conjunction with angiotensin II.
- Measured proteinuria, blood pressure, heart rate, and performed histological analysis.
- Examined Nrf2 expression in glomeruli from patients with various kidney diseases.
Main Results:
- Keap1(FA/FA) mice exhibited increased proteinuria, glomerulosclerosis, podocyte injury, and interstitial fibrosis after injury.
- Elevated Nrf2 signaling was associated with higher blood pressure and lower heart rate.
- Nrf2 knockout mice were protected from proteinuria.
- CDDO-Im combined with angiotensin II significantly increased proteinuria in wild-type but not Nrf2 knockout mice.
- Nrf2 was upregulated in glomeruli of patients with focal segmental glomerulosclerosis, diabetic nephropathy, fibrillary glomerulonephritis, and membranous nephropathy.
Conclusions:
- Nrf2 induction can exacerbate proteinuria and kidney damage in experimental CKD models.
- Pharmacologic Nrf2 activation may pose a risk for proteinuria in CKD patients.
- Elevated Nrf2 signaling is present in human proteinuric kidney diseases, suggesting a potential role in disease progression.
