Bone metabolism disorder has been identified to play a vital role in the pathogenesis of glucocorticoid-induced osteoporosis (GIOP). The local renin-angiotensin system (RAS) in bone is newly defined to be closely related to the bone metabolism. However, it is unknown whether the local RAS is involved in GIOP. Adult male New Zealand white rabbits were treated with saline, dexamethasone (DXM) alone, or DXM combined with perindopril. The expression of main RAS components in trabecular bone was examined at mRNA and/or protein levels. Bone metabolism was analyzed using dual-energy X-ray absorptiometry, histomorphometry, biomechanics, biochemical techniques, and quantitative RT-PCR. The expressions of local bone angiotensin II, angiotensin types 1 and 2 receptors, and angiotensin-converting enzyme at mRNA and/or protein levels increased when DXM-induced osteoporosis was present. Whereas, perindopril significantly blocked the activation of the local RAS and partially reversed GIOP. Mineralizing surface, mineral apposition rate, and bone formation rate were decreased by DXM, along with serum osteocalcin being downregulated. These changes were then reversed by the use of perindopril. Osteoclast number, osteoclast surface, and eroded surface increased after the administration of DXM, and urinary deoxypyridinoline was upregulated. These were also inhibited when perindopril was given. Quantitative RT-PCR using RNA isolated from the lumbar vertebrae revealed an increase in the SOST expression and a decrease in the Runx2 expression, whereas the receptor activator of nuclear factor-κB ligand/osteoprotegerin ratio and the expression of tartrate resistant acid phosphatase were increased, which were all inhibited by perindopril. The results of this study provide evidence for the role of local RAS is involved in GIOP, and GIOP may be ameliorated by blocking the activation of local RAS in the bone.
predict TNF activity by logistic regression. The cellular source(s) of urinary biomarkers was investigated in single cell (sc-) and single nuclear (sn-) RNAseq profiles. Results: Consensus clustering grouped subjects into 3 distinct molecular clusters. Statistically significant differences in eGFR and proteinuria were observed across clusters. Transcriptomic profiles of patients experiencing kidney failure were significantly associated with one cluster (p<0.001). A DEG analysis of this cluster identified 3262 transcripts up-regulated and 930 transcripts down-regulated in the tubulointerstitial compartment of this poor outcome cluster in biopsies from participants in the NEPTUNE cohort (FDR<0.05). DEG analysis in the replication cohorts validated the findings from NEPTUNE. Functional analysis of DEGs identified a transcriptional program consistent with activated TNF signaling. A TNF activation score was calculated from the patient transcriptomes. Urinary MCP1 and TIMP1, were correlated with, and predictive of a higher TNF activation score. Analysis of sc-RNAseq and sn-RNAseq profiles revealed TNF dependent transcripts in multiple cell lineages including resident renal cells. Furthermore, MCP1 and TIMP1 were also activated by TNF in iPSC-derived renal organoids. Conclusions: A highly conserved molecular classification of primary proteinuric kidney diseases was identified that can be linked to noninvasive biomarkers to aid in rational clinical trial design. The approach may be useful for identifying patients with activated signaling networks, who may be most likely to respond and benefit from targeted therapies in renal diseases.No conflict of interest
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