Post-myocardial infarction (MI), overactive inflammation is the hallmark of aging, however, the mechanism is unclear. We hypothesized that excess influx of omega 6 fatty acids may impair resolution, thus impacting the cardiosplenic and cardiorenal network post-MI. Young and aging mice were fed on standard lab chow (LC) and excess fatty acid (safflower oil; SO)-enriched diet for 2 months and were then subjected to MI surgery. Despite similar infarct areas and left ventricle (LV) dysfunction post-MI, splenic mass spectrometry data revealed higher levels of arachidonic acid (AA) derived pro-inflammatory metabolites in young-SO, but minimal formation of docosanoids, D- and E- series resolvins in SO-fed aged mice. The aged mice receiving excess intake of fatty acids exhibit; 1) decreased lipoxygenases (5-,12-, and 15) in the infarcted LV; 2) lower levels of 14HDHA, RvD1, RvD5, protectin D1, 7(S)maresin1, 8-,11-,18-HEPE and RvE3 with high levels of tetranor-12-HETEs; 3) dual population of macrophages (CD11blow/F480high and CD11bhigh/F480high) with increased pro-inflammatory (CD11b+F4/80+Ly6Chi) phenotype and; 4) increased kidney injury marker NGAL with increased expression of TNF-ɑ and IL-1β indicating MI-induced non-resolving response compared with LC-group. Thus, excess fatty acid intake magnifies the post-MI chemokine signaling and inflames the cardiosplenic and cardiorenal network towards a non-resolving microenvironment in aging.
Conflict of interest: MM reports grants and consulting fees from Otsuka Pharmaceutical and Sanofi. AA serves as a consultant for DynaMed and is on the advisory board of Goldilocks Therapeutics.
Renal tissue injury initiates inflammatory and fibrotic processes that occur to promote regeneration and repair. After renal injury, damaged tissue releases cytokines and chemokines, which stimulate activation and infiltration of inflammatory cells to the kidney. Normal tissue repair processes occur simultaneously with activation of myofibroblasts, collagen deposition, and wound healing responses; however, prolonged activation of pro-inflammatory and pro-fibrotic cell types causes excess extracellular matrix deposition. This review focuses on the physiological and pathophysiological roles of specialized cell types, cytokines/chemokines, and growth factors, and their implications in recovery or exacerbation of acute kidney injury.
Despite the prevalence and recognition of its detrimental impact, clinical complications of sepsis remain a major challenge. Here, we investigated the effects of myeloid ferritin heavy chain (FtH) in regulating the pathogenic sequelae of sepsis. We demonstrate that deletion of myeloid FtH leads to protection against lipopolysaccharide-induced endotoxemia and cecal ligation and puncture (CLP)-induced model of sepsis as evidenced by reduced cytokine levels, multi-organ dysfunction and mortality. We identified that such protection is predominantly mediated by the compensatory increase in circulating ferritin (ferritin light chain; FtL) in the absence of myeloid FtH. Our in vitro and in vivo studies indicate that prior exposure to ferritin light chain restrains an otherwise dysregulated response to infection. These findings are mediated by an inhibitory action of FtL on NF-κB activation, a key signaling pathway that is implicated in the pathogenesis of sepsis. We further identified that LPS mediated activation of MAPK pathways, specifically, JNK, and ERK were also reduced with FtL pre-treatment. Taken together, our findings elucidate a crucial immunomodulatory function for circulating ferritin that challenges the traditional view of this protein as a mere marker of body iron stores. Accordingly, these findings will stimulate investigations to the adaptive nature of this protein in diverse clinical settings.
Chronic kidney disease (CKD) is a condition with significant morbidity and mortality that affects 15% of adults in the United States. One cause of CKD is acute kidney injury (AKI), which commonly occurs secondary to sepsis, ischemic events, and drug-induced nephrotoxicity. Unilateral ischemia-reperfusion injury (UIRI) without contralateral nephrectomy (CLN) and repeated low-dose cisplatin (RLDC) models of AKI to CKD demonstrate responses characteristic of the transition; however, previous studies have not effectively compared the pathogenesis. We demonstrate both models instigate renal dysfunction, inflammatory cytokine responses, and fibrosis. However, the models exhibit differences in urinary excretory function, inflammatory cell infiltration, and degree of fibrotic response. UIRI without CLN demonstrated worsening perfusion and function, measured with Tc-mercaptoacetyltriglycine-3 imaging, and physiologic compensation in the contralateral kidney. Furthermore, UIRI without CLN elicited a robust inflammatory response that was characterized by a prolonged polymorphonuclear cell and natural killer cell infiltrate and an early expansion of kidney resident macrophages, followed by T-cell infiltration. Symmetrical diminished function occurred in RLDC kidneys and progressively worsened until day 17 of the study. Surprisingly, RLDC mice demonstrated a decrease in inflammatory cell numbers relative to controls. However, RLDC kidneys expressed increased levels of kidney injury molecule-1 (KIM-1), high mobility group box-1 ( HMGB1), and colony stimulating factor-1 ( CSF-1), which likely recruits inflammatory cells in response to injury. These data emphasize how the divergent etiologies of AKI to CKD models affect the kidney microenvironment and outcomes. This study provides support for subtyping AKI by etiology in human studies, aiding in the elucidation of injury-specific pathophysiologic mechanisms of the AKI to CKD transition.
Acute kidney injury (AKI) and chronic kidney disease (CKD) are interconnected syndromes with significant attributable morbidity and mortality. The disturbing trend of increasing incidence and prevalence of these clinical conditions highlights the urgent need for better understanding of the underlying mechanisms that are involved in pathogenesis of these conditions. Lymphangiogenesis and its involvement in various inflammatory conditions is increasingly recognized while its role in AKI and CKD remains to be fully elucidated. Here, we studied lymphangiogenesis in three models of kidney injury. Our results demonstrate that the main ligands for lymphangiogenesis, VEGF-C and VEGF-D, are abundantly present in tubules at baseline conditions and the expression pattern of these ligands is significantly altered following injury. In addition, we show that both of these ligands increase in serum and urine post-injury and suggest that such increment may serve as novel urinary biomarkers of AKI as well as in progression of kidney disease. We also provide evidence that irrespective of the nature of initial insult, lymphangiogenic pathways are rapidly and robustly induced as evidenced by higher expression of lymphatic markers within the kidney.
Fatty acid drug discovery (FADD) is defined as the identification of novel, specialized bioactive mediators that are derived from fatty acids and have precise pharmacological/therapeutic potential. A number of reports indicate that dietary intake of omega-3 fatty acids and limited intake of omega-6 promotes overall health benefits. In 1929, Burr and Burr indicated the significant role of essential fatty acids for survival and functional health of many organs. In reference to specific dietary benefits of differential omega-3 fatty acids, docosahexaenoic and eicosapentaenoic acids (DHA and EPA) are transformed to monohydroxy, dihydroxy, trihydroxy, and other complex mediators during infection, injury, and exercise to resolve inflammation. The presented FADD approach describes the metabolic transformation of DHA and EPA in response to injury, infection, and exercise to govern uncontrolled inflammation. Metabolic transformation of DHA and EPA into a number of pro-resolving molecules exemplifies a novel, inexpensive approach compared to traditional, expensive drug discovery. DHA and EPA have been recommended for prevention of cardiovascular disease since 1970. Therefore, the FADD approach is relevant to cardiovascular disease and resolution of inflammation in many injury models. Future research demands identification of novel action targets, receptors for biomolecules, mechanism(s), and drug-interactions with resolvins in order to maintain homeostasis.
Cellular metabolic rates in the kidney are critical for maintaining renal function. In a hypoxic milieu, cells rely on glycolysis to meet energy needs, resulting in the generation of pyruvate and NADH. In the absence of oxidative phosphorylation, the continuation of glycolysis is dependent on the regeneration of NAD+ from NADH accompanied by the fermentation of pyruvate to lactate. This reaction is catalyzed by lactate dehydrogenase (LDH) isoform A (LDHA), while isoform B (LDHB) catalyzes the opposite reaction. LDH is widely used as a potential injury marker, yet the precise isoform-specific cellular localization of the enzyme along the nephron has not been characterized. By combining immunohistochemistry and single-cell RNA sequencing data on healthy mouse kidneys we identified that LDHA is primarily expressed in proximal segments while LDHB is expressed in the distal parts of the nephron. In vitro studies in mouse and human renal proximal tubule cells show an increase in LDHA following hypoxia with no change in LDHB. We observed that the overall expression of both LDHA and LDHB decreased following renal ischemia-reperfusion injury (IRI) as well as in the adenine-diet induced model of chronic kidney disease. Single-nucleus RNA sequencing analyses of kidneys following IRI revealed a significant decline in the number of cells expressing Ldha and Ldhb, however, cells that were positive showed increased average expression post-injury which subsided during the recovery phase. These data provide information on the cell-specific expression of LDHA and LDHB in the normal kidney as well as following acute and chronic kidney disease.
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