ABSTRACT
Acute kidney injury induced by ischemia/reperfusion is an independent risk factor for chronic kidney disease. Macrophage recruitment plays an essential role during the injury and repair phases after an ischemic episode in the kidney. Here we show that the novel non-steroidal mineralocorticoid receptor antagonist finerenone or selective myeloid mineralocorticoid receptor ablation protects against subsequent chronic dysfunction and fibrosis induced by an episode of bilateral kidney ischemia/reperfusion in mice. This protection was associated with increased expression of M2-antiinflamatory markers in macrophages from finerenone-treated or myeloid mineralocorticoid receptor-deficient mice. Moreover, the inflammatory population of CD11b+, F4/80+, Ly6Chigh macrophages was also reduced. Mineralocorticoid receptor inhibition promoted increased IL-4 receptor expression and activation in the whole kidney and in isolated macrophages, thereby facilitating macrophage polarization to an M2 phenotype. The long-term protection conferred by mineralocorticoid receptor antagonism was also translated to the Large White pig pre-clinical model. Thus, our studies support the rationale for using mineralocorticoid receptor antagonists in clinical practice to prevent transition of acute kidney injury to chronic kidney disease.
Subject(s)
Acute Kidney Injury/metabolism , Inflammation Mediators/metabolism , Kidney/metabolism , Macrophages, Peritoneal/metabolism , Receptors, Cell Surface/metabolism , Receptors, Mineralocorticoid/metabolism , Reperfusion Injury/metabolism , Acute Kidney Injury/genetics , Acute Kidney Injury/pathology , Acute Kidney Injury/prevention & control , Animals , Cells, Cultured , Disease Models, Animal , Fibrosis , Kidney/drug effects , Kidney/pathology , Macrophages, Peritoneal/drug effects , Macrophages, Peritoneal/pathology , Male , Mice, Inbred C57BL , Mice, Knockout , Mineralocorticoid Receptor Antagonists/pharmacology , Naphthyridines/pharmacology , Phenotype , Receptors, Mineralocorticoid/drug effects , Receptors, Mineralocorticoid/genetics , Reperfusion Injury/genetics , Reperfusion Injury/pathology , Reperfusion Injury/prevention & control , Signal Transduction , Sus scrofaABSTRACT
AKI is a frequent complication in hospitalized patients. Unfortunately, there is no effective pharmacologic approach for treating or preventing AKI. In rodents, mineralocorticoid receptor (MR) antagonism prevents AKI induced by ischemia-reperfusion (IR). We investigated the specific role of vascular MR in mediating AKI induced by IR. We also assessed the protective effect of MR antagonism in IR-induced AKI in the Large White pig, a model of human AKI. In mice, MR deficiency in smooth muscle cells (SMCs) protected against kidney IR injury. MR blockade by the novel nonsteroidal MR antagonist, finerenone, or genetic deletion of MR in SMCs associated with weaker oxidative stress production. Moreover, ischemic kidneys had higher levels of Rac1-GTP, required for NADPH oxidase activation, than sham control kidneys, and genetic deletion of Rac1 in SMCs protected against AKI. Furthermore, genetic deletion of MR in SMCs blunted the production of Rac1-GTP after IR. Pharmacologic inhibition of MR also prevented AKI induced by IR in the Large White pig. Altogether, we show that MR antagonism, or deletion of the MR gene in SMCs, limited the renal injury induced by IR through effects on Rac1-mediated MR signaling. The benefits of MR antagonism in the pig provide a rational basis for future clinical trials assessing the benefits of this approach in patients with IR-mediated AKI.
Subject(s)
Acute Kidney Injury/drug therapy , Mineralocorticoid Receptor Antagonists/therapeutic use , Neuropeptides/physiology , rac1 GTP-Binding Protein/physiology , Acute Kidney Injury/etiology , Animals , Cells, Cultured , Male , Mice , Muscle, Smooth, Vascular/cytology , Myocytes, Smooth Muscle , Reperfusion Injury/complications , SwineABSTRACT
IgA nephropathy (IgAN), characterized by mesangial IgA1 deposits, is a leading cause of renal failure worldwide. IgAN pathogenesis involves circulating hypogalactosylated IgA1 complexed with soluble IgA Fc receptor I (sCD89) and/or anti-hypogalactosylated-IgA1 autoantibodies, but no specific treatment is available for IgAN. The absence of IgA1 and CD89 homologs in the mouse has precluded in vivo proof-of-concept studies of specific therapies targeting IgA1. However, the α1KICD89Tg mouse model of IgAN, which expresses human IgA1 and human CD89, allows in vivo testing of recombinant IgA1 protease (IgA1P), a bacterial protein that selectively cleaves human IgA1. Mice injected with IgA1P (1-10 mg/kg) had Fc fragments of IgA1 in both serum and urine, associated with a decrease in IgA1-sCD89 complexes. Levels of mesangial IgA1 deposits and the binding partners of these deposits (sCD89, transferrin receptor, and transglutaminase 2) decreased markedly 1 week after treatment, as did the levels of C3 deposition, CD11b(+) infiltrating cells, and fibronectin. Antiprotease antibodies did not significantly alter IgA1P activity. Moreover, hematuria consistently decreased after treatment. In conclusion, IgA1P strongly diminishes human IgA1 mesangial deposits and reduces inflammation, fibrosis, and hematuria in a mouse IgAN model, and therefore may be a plausible treatment for patients with IgAN.
Subject(s)
Glomerular Mesangium/metabolism , Glomerulonephritis, IGA/drug therapy , Hematuria/drug therapy , Immunoglobulin A/drug effects , Immunoglobulin A/metabolism , Serine Endopeptidases/pharmacology , Animals , Disease Models, Animal , Mice , Serine Endopeptidases/therapeutic useABSTRACT
Acute kidney injury induced by ischemia/reperfusion (IR) is a frequent complication in hospitalized patients. Mineralocorticoid receptor antagonism has shown to be helpful against renal IR consequences; however, the potential benefit of novel nonsteroidal mineralocorticoid receptor antagonists such as finerenone has to be further explored. In this study, we evaluated the efficacy of finerenone to prevent the acute and chronic consequences of ischemic acute kidney injury. For the acute study (24 hours), 18 rats were divided into sham, bilateral renal ischemia of 25 minutes, and rats that received 3 doses of finerenone at 48, 24, and 1 hour before the ischemia. For the chronic study (4 months), 23 rats were divided into sham, rats that underwent 45 minutes of bilateral ischemia, and rats treated with finerenone at days 2 and 1 and 1 hour before IR. We found that after 24 hours of reperfusion, the untreated IR rats presented kidney dysfunction and tubular injury. Kidney injury molecule-1 and neutrophil gelatinase associated to lipolacin mRNA levels were increased. In contrast, the rats treated with finerenone displayed normal kidney function and significantly lesser tubular injury and kidney injury molecule-1 and neutrophil gelatinase associated to lipolacin levels. After 4 months, the IR rats developed chronic kidney disease, evidenced by kidney dysfunction, increased proteinuria and renal vascular resistance, tubular dilation, extensive tubule-interstitial fibrosis, and an increase in kidney transforming growth factor-ß and collagen-I mRNA. The transition from acute kidney injury to chronic kidney disease was fully prevented by finerenone. Altogether, our data show that in the rat, finerenone is able to prevent acute kidney injury induced by IR and the chronic and progressive deterioration of kidney function and structure.
Subject(s)
Acute Kidney Injury/metabolism , Mineralocorticoid Receptor Antagonists/therapeutic use , Naphthyridines/therapeutic use , Oxidative Stress/drug effects , Renal Insufficiency, Chronic/prevention & control , Reperfusion Injury/metabolism , Acute Kidney Injury/complications , Animals , Cell Adhesion Molecules/metabolism , Disease Models, Animal , Kidney/drug effects , Kidney/metabolism , Lipocalin-2/metabolism , Male , Malondialdehyde/metabolism , Mineralocorticoid Receptor Antagonists/pharmacology , Naphthyridines/pharmacology , Rats , Rats, Wistar , Renal Insufficiency, Chronic/etiology , Renal Insufficiency, Chronic/metabolism , Reperfusion Injury/complicationsABSTRACT
Immunoglobulin A nephropathy (IgAN) or Berger's disease is the most common form of primary glomerulonephritis in the world and one of the first causes of end-stage renal failure. IgAN is characterized by the accumulation of immune complexes containing polymeric IgA1 in mesangial areas. The pathogenesis of this disease involves the deposition of polymeric and hypogalactosylated IgA1 (Gd-IgA1) in the mesangium. Quantitative and structural changes of Gd-IgA1 play a key role in the development of the disease due to functional abnormalities of two IgA receptors: the FcαRI (CD89) expressed by blood myeloid cells and the transferrin receptor (CD71) on mesangial cells. Abnormal Gd-IgA1 induces release of soluble CD89, which participates in the formation of circulating IgA1 complexes. These complexes are trapped by CD71 that is overexpressed on mesangial cells in IgAN patients together with the crosslinking enzyme transglutaminase 2 allowing pathogenic IgA complex formation in situ and mesangial cell activation. A humanized mouse model expressing IgA1 and CD89 develops IgAN in a similar manner as patients. In this model, a food antigen, the gliadin, was shown to be crucial for circulating IgA1 complex formation and deposition, which could be prevented by a gluten-free diet. Identification of these new partners opens new therapeutic prospects for IgAN treatment.