Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0033687 (
proteinuria
)
24,015
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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 Keap1
FA/FA
mice lacked baseline
proteinuria
but exhibited increased;
proteinuria
in experimental models evoked by adriamycin, angiotensin II, or protein overload. After injury, Keap1
FA/FA
mice had increased glomerulosclerosis, nephrin disruption and shedding, podocyte injury, foot process effacement, and interstitial fibrosis. Keap1
FA/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.
...
PMID:Genetic or Pharmacologic Nrf2 Activation Increases Proteinuria in Chronic Kidney Disease in Mice. 3281 18
