Tissue injury can drive secondary organ injury; however, mechanisms and mediators are not well understood. To identify interorgan cross-talk mediators, we used acute kidney injury (AKI)–induced acute lung injury (ALI) as a clinically important example. Using kidney and lung single-cell RNA sequencing after AKI in mice followed by ligand-receptor pairing analysis across organs, kidney ligands to lung receptors, we identify kidney-released circulating osteopontin (OPN) as a novel AKI-ALI mediator. OPN release from kidney tubule cells triggered lung endothelial leakage, inflammation, and respiratory failure. Pharmacological or genetic OPN inhibition prevented AKI-ALI. Transplantation of ischemic wt kidneys caused AKI-ALI, but not of ischemic OPN–global knockout kidneys, identifying kidney-released OPN as necessary interorgan signal to cause AKI-ALI. We show that OPN serum levels are elevated in patients with AKI and correlate with kidney injury. Our results demonstrate feasibility of using ligand-receptor analysis across organs to identify interorgan cross-talk mediators and may have important therapeutic implications in human AKI-ALI and multiorgan failure.
BackgroundSynaptopodin (Synpo) is an actin-associated protein in podocytes and dendritic spines. Many functions in regulating the actin cytoskeleton via RhoA and other pathways have been ascribed to Synpo, yet no pathogenic mutations in the SYNPO gene have been discovered in patients. Naturally occurring Synpo isoforms are known (Synpo-short and -long), and a novel truncated version (Synpo-T) is upregulated in podocytes from Synpo mutant mice. Synpo-T maintains some Synpo functions, which may prevent a podocyte phenotype from emerging in unchallenged mutant mice.MethodsNovel mouse models were generated to further investigate the functions of Synpo. In one, CRISPR/Cas9 deleted most of the Synpo gene, preventing production of any detectable Synpo protein. Two other mutant strains made truncated versions of the protein. Adriamycin injections were used to challenge the mice, and Synpo functions were investigated in primary cultured podocytes.ResultsMice that could not make detectable Synpo (Synpo−/−) did not develop any kidney abnormalities up to 12 months of age. However, Synpo−/− mice were more susceptible to Adriamycin nephropathy. In cultured primary podocytes from mutant mice, the absence of Synpo caused loss of stress fibers, increased the number and size of focal adhesions, and impaired cell migration. Furthermore, loss of Synpo led to decreased RhoA activity and increased Rac1 activation.ConclusionsIn contrast to previous findings, podocytes can function normally in vivo in the absence of any Synpo isoform. Synpo plays a protective role in the context of podocyte injury through its involvement in actin reorganization and focal adhesion dynamics.
Lupus nephritis (LN) is one of the most common and severe manifestations of systemic lupus erythematosus, leading to permanent renal damage and chronic kidney disease. Hydroxychloroquine (HCQ) serves a protective role against lupus-associated clinical manifestations and medical complications; however, it results in numerous adverse reactions, limiting its long-term use. The aim of the present study was to investigate the combined effect of HCQ and artemisinin (ART) on LN, and to elucidate the underlying mechanisms. An in vivo LN mouse model was prepared, and the animals were administered prednisone (PDS; serving as a positive control), high-dose HCQ (H-HCQ) or low-dose HCQ combined with ART (L-HCQ + ART) once daily for 8 weeks. The body weight, serum biochemical parameters, immune and inflammatory indicators, renal and spleen histological alterations, and mRNA expression levels of Kruppel-like factor 15 (KLF15) and nuclear factor-κB (NF-κB) were analyzed. It was observed that L-HCQ + ART and H-HCQ ameliorated the LN-induced body weight decrease, and significantly decreased the levels of anti-double stranded DNA, antinuclear antibodies, immunoglobulin G, interferon γ, tumor necrosis factor-α and transforming growth factor-β1, as well as improved the kidney and spleen pathology, when compared with the model group. In addition, L-HCQ + ART and H-HCQ treatments induced KLF15 upregulation and NF-κB downregulation. These results indicated that treatment with L-HCQ + ART exerted renoprotective effects by regulating the expression levels of cytokines, KLF15 and NF-κB. This combination treatment may have a similar immunosuppressive effect as PDS and H-HCQ, and may be a promising alternative for LN treatment.
Synaptopodin (Synpo) is an actin-associated protein in podocyte foot processes. By generating mice that completely lack Synpo, we previously showed that Synpo is dispensable for normal kidney function. However, the lack of Synpo worsened Adriamycin nephropathy, indicating a protective role for Synpo in injured podocytes. Here we investigated whether the lack of Synpo directly impacts a genetic disease, Alport syndrome (AS), because Synpo is reduced in the podocytes of affected humans and mice; whether this is merely an association or pathogenic is unknown. We used Col4a5 mutant mice that model X-linked AS, showing glomerular basement membrane (GBM) abnormalities, eventual foot process effacement, and progression to ESKD. We intercrossed mice carrying mutations in Synpo and Col4a5 to produce doubly mutant mice. Urine and tissue were taken at select time points to evaluate albuminuria, histopathology, and glomerular capillary wall composition and ultrastructure. The lack of Synpo in Col4a5-/Y, Col4a5-/-, or Col4a5+/- Alport mice led to acceleration of disease progression, including more severe proteinuria and glomerulosclerosis. The absence of Synpo attenuated the shift of myosin IIA from the podocyte cell body and major processes to the actin cables near the GBM in the areas of effacement. We speculate that this is mechanistically associated with enhanced loss of podocytes due to easier detachment from the GBM. We conclude that Synpo deletion exacerbates the disease phenotype in Alport mice, revealing the podocyte actin cytoskeleton as a target for therapy in patients with AS.
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