Reversible dysregulation of renal circadian rhythm in lupus nephritis

Rakesh Mishra,Anne Davidson,Ramalingam Bethunaickan,Weijia Zhang,Joshua J Strohl,Zhengzi Yi,Patricio T Huerta,Celine C Berthier

doi:10.1186/s10020-021-00361-9

Abstract

BackgroundWe 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.MethodsMolecular 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.ResultsWe 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.ConclusionsOur 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.

Highlights

Circadian rhythm is a universal phenomenon by which organisms anticipate and respond to environmental changes by regulating sleep and feeding patterns, blood pressure, metabolism, detoxification and response to pathogens
In the course of molecular profiling studies of kidney mRNA from three mouse models of lupus nephritis (LN) using samples collected in the mornings we found altered expression of transcriptional regulators of circadian rhythm in nephritic kidneys (Bethunaickan et al 2013)
To determine whether renal circadian disturbance is a general feature of aging, samples from 8 and 36- weekold C57BL/6 mice obtained at Zeitgeiber times (ZT) 0 and 12 were included in the RNASeq analysis

Summary

Introduction

Circadian rhythm is a universal phenomenon by which organisms anticipate and respond to environmental changes by regulating sleep and feeding patterns, blood pressure, metabolism, detoxification and response to pathogens. Circadian rhythms are controlled by a set of core clock genes that regulate their own expression through a series of feedback loops. Ror that activates and Rev-erbα (Nrd1) that represses Bmal transcription. These core genes control the expression of many other genes which drive cascades of rhythmic gene expression (Stow and Gumz 2011; Reddy and O’Neill 2010; Levi and Schibler 2007; Kyriacou and Hastings 2010; Feng and Lazar 2012; Bechtold et al 2010). We have found disruption of expression of major transcriptional regulators of circadian rhythm in the kidneys of several mouse models of lupus nephritis. 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

Results

Conclusion