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Persistent Inflammation, Maladaptive Remodeling, and Fibrosis in the Kidney Following Long COVID-like MHV-1 Mouse
Rajalakshmi Ramamoorthy1, Anna Rosa Speciale1,2, Emily M West1
1Department of Obstetrics, Gynecology and Reproductive Sciences, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Background:
Accumulating evidence indicates that SARS-CoV-2 infection results in long-term multiorgan complications, with the kidney being a primary target. This study aimed to characterize the long-term transcriptomic changes in the kidney following coronavirus infection using a murine model of MHV-1-induced SARS-like illness and to evaluate the therapeutic efficacy of SPIKENET (SPK).
Methods:
A/J mice were infected with MHV-1. Renal tissues were collected and subjected to immunofluorescence analysis and Next Generation RNA Sequencing to identify differentially expressed genes associated with acute and chronic infection. Bioinformatic analyses, including PCA, volcano plots, and GO/KEGG pathway enrichment, were performed. A separate cohort received SPK treatment, and comparative transcriptomic profiling was conducted. Gene expression profile was further confirmed using real-time PCR.
Results:
Acute infection showed the upregulation of genes involved in inflammation and fibrosis. Long-term MHV-1 infection led to the sustained upregulation of genes involved in muscle regeneration, cytoskeletal remodeling, and fibrotic responses. Notably, both expression and variability of SLC22 and SLC22A8, key proximal tubule transporters, were reduced, suggesting a loss of segment-specific identity. Further, SLC12A1, a critical regulator of sodium reabsorption and blood pressure, was downregulated and is associated with the onset of polyuria and hydronephrosis. SLC transporters exhibited expression patterns consistent with tubular dysfunction and inflammation. These findings suggest aberrant activation of myogenic pathways and structural proteins in renal tissues, consistent with a pro-fibrotic phenotype. In contrast, SPK treatment reversed the expression of most genes, thereby restoring the gene profiles to those observed in control mice.
Conclusions:
MHV-1-induced long COVID is associated with persistent transcriptional reprogramming in the kidney, indicative of chronic inflammation, cytoskeletal dysregulation, and fibrogenesis. SPK demonstrates robust therapeutic potential by normalizing these molecular signatures and preventing long-term renal damage. These findings underscore the relevance of the MHV-1 model and support further investigation of SPK as a candidate therapy for COVID-19-associated renal sequelae.
Insights
Long COVID causes persistent kidney damage by altering gene expression, leading to inflammation and fibrosis. SPIKENET (SPK) treatment effectively reversed these molecular changes, offering therapeutic potential for COVID-19-associated kidney problems.
Area of Science:
- Molecular biology
- Renal pathophysiology
- Virology
Background:
- SARS-CoV-2 infection is linked to long-term kidney damage.
- Understanding the molecular mechanisms of kidney complications is crucial.
- A murine model of MHV-1-induced SARS-like illness was used to study chronic kidney changes.
Purpose of the Study:
- To characterize long-term kidney transcriptomic changes after coronavirus infection.
- To evaluate the therapeutic efficacy of SPIKENET (SPK) in mitigating these changes.
Main Methods:
- Infection of A/J mice with MHV-1, followed by renal tissue collection.
- Immunofluorescence and Next Generation RNA Sequencing for gene expression analysis.
- Bioinformatic analyses (PCA, volcano plots, GO/KEGG) and real-time PCR validation.
- Assessment of SPK treatment efficacy through comparative transcriptomic profiling.
Main Results:
- Long-term MHV-1 infection sustained upregulation of genes involved in inflammation, fibrosis, muscle regeneration, and cytoskeletal remodeling.
- Reduced expression and variability of proximal tubule transporters (SLC22, SLC22A8) indicated loss of segment-specific identity.
- Downregulation of SLC12A1 was associated with polyuria and hydronephrosis, suggesting tubular dysfunction and a pro-fibrotic phenotype.
- SPK treatment reversed most gene expression changes, restoring profiles similar to control mice.
Conclusions:
- MHV-1-induced long COVID causes persistent kidney transcriptional reprogramming, marked by chronic inflammation, cytoskeletal dysregulation, and fibrogenesis.
- SPK demonstrated significant therapeutic potential by normalizing molecular signatures and preventing long-term renal damage.
- The MHV-1 model is relevant for studying COVID-19-associated renal sequelae, and SPK warrants further investigation as a potential therapy.
