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Updated: Oct 21, 2025
Analyses of Proteinuria, Renal Infiltration of Leukocytes, and Renal Deposition of Proteins in Lupus-prone MRL/lpr Mice
Published on: June 8, 2022
Reversible dysregulation of renal circadian rhythm in lupus nephritis
Rakesh Mishra1, Ramalingam Bethunaickan1, Celine C Berthier2
1Institute for Molecular Medicine, Feinstein Institutes for Medical Research, 350 Community Drive, Manhasset, NY, 11030, USA.
Background:
We have found disruption of expression of major transcriptional regulators of circadian rhythm in the kidneys of several mouse models of lupus nephritis. Here we define the consequence of this disturbance with respect to circadian gene expression and renal homeostatic function in a mouse model of lupus nephritis.
Methods:
Molecular profiling of kidneys from 47 young and 41 nephritic female NZB/W F1 mice was performed at 4 hourly intervals over a 24 h period. Disruption of major circadian transcriptional regulators was confirmed by qPCR. Molecular data was normalized and analyzed for rhythmicity using RAIN analysis. Serum aldosterone and glucose and urine sodium and potassium were measured at 4 hourly intervals in pre-nephritic and nephritic mice and blood pressure was measured every 4 h. Analyses were repeated after induction of complete remission of nephritis using combination cyclophosphamide and costimulatory blockade.
Results:
We show a profound alteration of renal circadian rhythms in mice with lupus nephritis affecting multiple renal pathways. Using Cosinor analysis we identified consequent alterations of renal homeostasis and metabolism as well as blood pressure dipper status. This circadian dysregulation was partially reversed by remission induction therapy.
Conclusions:
Our studies indicate the role of inflammation in causing the circadian disruption and suggest that screening for loss of normal blood pressure dipping should be incorporated into LN management. The data also suggest a potential role for circadian agonists in the treatment of lupus nephritis.
Insights
Lupus nephritis disrupts kidney circadian rhythms, altering gene expression and function. Treatment can partially restore these rhythms, suggesting potential therapies targeting circadian health.
Area of Science:
- Nephrology
- Chronobiology
- Immunology
Background:
- Circadian rhythm regulators are disrupted in mouse models of lupus nephritis.
- This study investigates the impact of this disruption on kidney function and gene expression.
Purpose of the Study:
- To define the consequences of circadian rhythm disturbance in lupus nephritis.
- To explore potential therapeutic targets related to circadian regulation.
Main Methods:
- Molecular profiling of kidneys from NZB/W F1 mice over 24 hours.
- qPCR to confirm disruption of circadian regulators; RAIN analysis for rhythmicity.
- Measurement of serum/urine electrolytes, glucose, aldosterone, and blood pressure.
Main Results:
- Profound alterations in renal circadian rhythms and multiple affected pathways observed in lupus nephritis.
- Consequent changes in renal homeostasis, metabolism, and blood pressure dipping status identified.
- Circadian dysregulation was partially reversed following nephritis remission induction therapy.
Conclusions:
- Inflammation likely causes circadian disruption in lupus nephritis.
- Loss of normal blood pressure dipping may indicate disease progression and warrant monitoring.
- Circadian agonists show potential as a novel treatment strategy for lupus nephritis.
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