Maladaptation of renal hemodynamics contributes to kidney dysfunction resulting from thoracic spinal cord injury in mice

Abstract

Renal dysfunction is a hallmark of spinal cord injury (SCI). Several SCI sequalae are implicated, however, the exact pathogenic mechanism of renal dysfunction is unclear. Herein, we found that T3 (T3Tx) or T10 (T10Tx) complete thoracic spinal cord transection induced hypotension, bradycardia, and hypothermia immediately after injury. T3Tx-induced hypotension but not bradycardia or hypothermia slowly recovered to levels in T10Tx SCI and uninjured mice ~16 h after injury as determined by continuous radiotelemetry monitoring. Both types of thoracic SCI led to a marked decrease in albuminuria and proteinuria in all phases of SCI, while the kidney injury marker, NGAL, rapidly increased in the acute phase, remaining elevated in the chronic phase of T3Tx SCI. Renal interstitial and vascular elastin fragmentation after SCI were worsened during chronic T3Tx SCI. In the chronic phase, renal vascular resistance response to a step increase in renal perfusion pressure or a bolus injection of Ang II or NE was almost completely abolished after T3Tx SCI. Bulk RNAseq analysis showed enrichment of genes involved in extracellular matrix (ECM) remodeling and chemokine signaling in the kidney from T3Tx SCI mice. Serum levels of interleukin 6 was elevated in the acute but not chronic phase of T3Tx and T10Tx SCI, while serum amyloid A1 level was elevated in both acute and chronic phases. We conclude that tissue fibrosis and hemodynamic impairment are involved in renal dysfunction resulting from thoracic SCI; these pathological alterations, exacerbated by high thoracic-level injury, is mediated at least partly by renal microvascular ECM remodeling.

Phosphodiesterases Mediate the Augmentation of Myogenic Constriction by Inhibitory G Protein Signaling and is Negatively Modulated by the Dual Action of RGS2 and 5

“…Ribonucleic acid quality control and library preparation were performed by the Case Western Reserve University Genomics Core facility ( https://genomics.case.edu ) using an Invitrogen Qubit Fluorometer RNA assay with an AATI Fragment Analyzer RNA assay to determine concentration and the integrity of RNA and an Illumina NextSeq High Output Flow Cell—1 × 75 bp run, respectively, as previously described. 43 FastQ files were transferred to the Case Western Reserve University Institute for Computational Biology for sequence alignment and transcriptional analysis using ADVAITA next-generation bioinformatics software. Signaling pathway and gene ontology (GO) analysis for the identification of enriched terms and overrepresented genes in sets of genes with measured expression were performed using iPathwayGuide , as previously described.…”

“…Signaling pathway and gene ontology (GO) analysis for the identification of enriched terms and overrepresented genes in sets of genes with measured expression were performed using iPathwayGuide , as previously described. 43 Genes in WT samples were used as a reference to determine differential expression (DE) in each knockout genotype. Genes considered to have DE were those with ≥0.6-fold change in measured expression (ME) relative to the expression in WT tissue.…”

Consequences of spinal cord injury on the sympathetic nervous system

“…Surprisingly, after chronic high-level SCI in rodents, renal autoregulation is completely abolished; there was virtually no change in renal vascular resistance in response to an increase in blood pressure, allowing more blood to flow unimpeded into the kidney. This loss of renal autoregulation was associated with injury to the kidney, as indicated by higher levels of neutrophil gelatinaseassociated lipocalin, fibrosis, and inflammatory signaling than in animals with low-level SCI (Osei-Owusu et al, 2022).…”