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1.
Circ Res ; 132(9): 1226-1245, 2023 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-37104557

RESUMO

Kidney disease is associated with adverse consequences in many organs beyond the kidney, including the heart, lungs, brain, and intestines. The kidney-intestinal cross talk involves intestinal epithelial damage, dysbiosis, and generation of uremic toxins. Recent studies reveal that kidney injury expands the intestinal lymphatics, increases lymphatic flow, and alters the composition of mesenteric lymph. The intestinal lymphatics, like blood vessels, are a route for transporting potentially harmful substances generated by the intestines. The lymphatic architecture and actions are uniquely suited to take up and transport large macromolecules, functions that differentiate them from blood vessels, allowing them to play a distinct role in a variety of physiological and pathological processes. Here, we focus on the mechanisms by which kidney diseases result in deleterious changes in intestinal lymphatics and consider a novel paradigm of a vicious cycle of detrimental organ cross talk. This concept involves kidney injury-induced modulation of intestinal lymphatics that promotes production and distribution of harmful factors, which in turn contributes to disease progression in distant organ systems.


Assuntos
Nefropatias , Vasos Linfáticos , Humanos , Intestinos , Sistema Linfático
2.
Lab Invest ; 104(2): 100305, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38109999

RESUMO

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease in the United States and worldwide. Proteinuria is a major marker of the severity of injury. Dipeptidyl peptidase-4 inhibitor (DPP-4I) increases incretin-related insulin production and is, therefore, used to treat diabetes. We investigated whether DPP4I could have direct effect on kidney independent of its hypoglycemic activity. We, therefore, tested the effects of DPP4I with or without angiotensin-converting enzyme inhibitor (ACEI) on the progression of diabetic nephropathy and albuminuria in a murine model of DKD. eNOS-/-db/db mice were randomized to the following groups at age 10 weeks and treated until sacrifice: baseline (sacrificed at week 10), untreated control, ACEI, DPP4I, and combination of DPP4I and ACEI (Combo, sacrificed at week 18). Systemic parameters and urine albumin-creatinine ratio were assessed at baseline, weeks 14, and 18. Kidney morphology, glomerular filtration rate (GFR), WT-1, a marker for differentiated podocytes, podoplanin, a marker of foot process integrity, glomerular collagen IV, and alpha-smooth muscle actin were assessed at the end of the study. All mice had hyperglycemia and proteinuria at study entry at week 10. Untreated control mice had increased albuminuria, progression of glomerular injury, and reduced GFR at week 18 compared with baseline. DPP4I alone reduced blood glucose and kidney DPP-4 activity but failed to protect against kidney injury compared with untreated control. ACEI alone and combination groups showed significantly reduced albuminuria and glomerular injury, and maintained GFR and WT-1+ cells. Only the combination group had significantly less glomerular collagen IV deposition and more podoplanin preservation than the untreated control. DPP-4I alone does not decrease the progression of kidney injury in the eNOS-/-db/db mouse model, suggesting that targeting only hyperglycemia is not an optimal treatment strategy for DKD. Combined DPP-4I with ACEI added more benefit to reducing the glomerular matrix.


Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , Inibidores da Dipeptidil Peptidase IV , Hiperglicemia , Camundongos , Animais , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/etiologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Albuminúria/tratamento farmacológico , Albuminúria/complicações , Rim , Hipoglicemiantes/farmacologia , Camundongos Endogâmicos , Colágeno , Dipeptidil Peptidases e Tripeptidil Peptidases/farmacologia , Dipeptidil Peptidase 4
3.
Kidney Int ; 105(6): 1200-1211, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38423183

RESUMO

Podocyte injury and loss are hallmarks of diabetic nephropathy (DN). However, the molecular mechanisms underlying these phenomena remain poorly understood. YAP (Yes-associated protein) is an important transcriptional coactivator that binds with various other transcription factors, including the TEAD family members (nuclear effectors of the Hippo pathway), that regulate cell proliferation, differentiation, and apoptosis. The present study found an increase in YAP phosphorylation at S127 of YAP and a reduction of nuclear YAP localization in podocytes of diabetic mouse and human kidneys, suggesting dysregulation of YAP may play a role in diabetic podocyte injury. Tamoxifen-inducible podocyte-specific Yap gene knockout mice (YappodKO) exhibited accelerated and worsened diabetic kidney injury. YAP inactivation decreased transcription factor WT1 expression with subsequent reduction of Tead1 and other well-known targets of WT1 in diabetic podocytes. Thus, our study not only sheds light on the pathophysiological roles of the Hippo pathway in diabetic podocyte injury but may also lead to the development of new therapeutic strategies to prevent and/or treat DN by targeting the Hippo signaling pathway.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Diabetes Mellitus Experimental , Nefropatias Diabéticas , Camundongos Knockout , Fosfoproteínas , Podócitos , Transdução de Sinais , Fatores de Transcrição , Proteínas WT1 , Proteínas de Sinalização YAP , Podócitos/metabolismo , Podócitos/patologia , Animais , Proteínas WT1/metabolismo , Proteínas WT1/genética , Proteínas de Sinalização YAP/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/genética , Humanos , Fosforilação , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/complicações , Fosfoproteínas/metabolismo , Fosfoproteínas/genética , Fatores de Transcrição de Domínio TEA/metabolismo , Via de Sinalização Hippo , Camundongos , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Masculino , Camundongos Endogâmicos C57BL , Tamoxifeno/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética
4.
Pediatr Nephrol ; 39(8): 2301-2308, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38191938

RESUMO

The intricate relationship between tubular injury and glomerular dysfunction in kidney diseases has been a subject of extensive research. While the impact of glomerular injury on downstream tubules has been well-studied, the reverse influence of tubular injury on the glomerulus remains less explored. This paper provides a comprehensive review of recent advances in the field, focusing on key pathways and players implicated in the pathogenesis of tubular injury on glomerular dysfunction. Anatomical and physiological evidence supports the possibility of crosstalk from the tubule to the glomerulus, whereby various mechanisms contribute to glomerular injury following tubular injury. These mechanisms include tubular backleak, dysfunctional tubuloglomerular feedback, capillary rarefaction, atubular glomeruli, and the secretion of factors from damaged tubular epithelial cells. Clinical evidence further supports the association between even mild or recovered acute kidney injury and an increased risk of chronic kidney disease, including glomerular diseases. We also discuss potential therapeutic interventions aimed at mitigating acute tubular injury, thereby reducing the detrimental effects on glomerular function. By unraveling the complex interplay from tubular injury to glomerular dysfunction, we aim to provide insights that can enhance clinical management strategies and improve outcomes for patients with kidney disease.


Assuntos
Injúria Renal Aguda , Glomérulos Renais , Túbulos Renais , Humanos , Glomérulos Renais/patologia , Glomérulos Renais/fisiopatologia , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/fisiopatologia , Injúria Renal Aguda/patologia , Injúria Renal Aguda/metabolismo , Túbulos Renais/patologia , Animais
5.
Lab Invest ; 103(2): 100015, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-37039147

RESUMO

Exogenous erythropoietin (EPO) is used to treat anemia in patients with chronic kidney disease (CKD). Concerns about the possible adverse effect of EPO on the progression of CKD have been raised owing to nonerythroid cell effects. We investigated the effects of low-dose EPO, independent of correcting anemia, on existing glomerulosclerosis. Adult mice underwent 5/6 nephrectomy and were randomized into the following 4 groups at week 8 after surgery: vehicle (VEH), losartan (angiotensin II type 1 receptor blocker [ARB]), darbepoetin-α (DA), or combination (DA+ARB). Four weeks later, mice were euthanized, followed by evaluation of renal structure and function. Glomerular endothelial cells and podocytes were cultured to evaluate the effects of DA on cell migration, apoptosis, and Akt signaling. ARB reduced blood pressure, albuminuria, and the level of serum creatinine and increased hematocrit compared with VEH, whereas low-dose DA only reduced the level of serum creatinine. Combination treatment showed a trend to increase hematocrit and survival compared with ARB alone. Combination treatment but not ARB alone significantly reduced the progression of glomerulosclerosis compared with VEH. Low-dose DA resulted in more preserved glomerular and peritubular capillary endothelial cells with increased p-Akt and even further endothelial cell preservation in combination with ARB. In cultured glomerular endothelial cells, angiotensin II induced more apoptosis, reduced migration, and decreased p-Flk1, a receptor for the proangiogenic vascular endothelial growth factor. DA counteracted these injuries and increased p-Akt, a key factor in angiogenesis and cell survival. DA also protected cultured podocytes against transforming growth factor ß-induced apoptosis and synaptopodin loss. Low-dose EPO directly protects glomerular and peritubular endothelial cells via Akt phosphorylation. Therefore, treatment using a combination of low-dose EPO and ARB results in less progression of glomerulosclerosis in an experimental CKD model.


Assuntos
Eritropoetina , Insuficiência Renal Crônica , Camundongos , Animais , Angiotensina II/metabolismo , Creatinina , Proteínas Proto-Oncogênicas c-akt , Fator A de Crescimento do Endotélio Vascular , Células Endoteliais/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Eritropoetina/farmacologia , Insuficiência Renal Crônica/tratamento farmacológico
6.
Curr Hypertens Rep ; 24(10): 455-463, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35727522

RESUMO

PURPOSE OF REVIEW: Kidney disease is a strong modulator of the composition and metabolism of the intestinal microbiome that produces toxins and inflammatory factors. The primary pathways for these harmful factors are blood vessels and nerves. Although lymphatic vessels are responsible for clearance of interstitial fluids, macromolecules, and cells, little is known about whether and how kidney injury impacts the intestinal lymphatic network. RECENT FINDINGS: Kidney injury stimulates intestinal lymphangiogenesis, activates lymphatic endothelial cells, and increases mesenteric lymph flow. The mesenteric lymph of kidney-injured animals contains increased levels of cytokines, immune cells, isolevuglandin (IsoLG), a highly reactive dicarbonyl, and of apolipoprotein AI (apoAI). IsoLG is increased in the ileum of kidney injured animals, and intestinal epithelial cells exposed to myeloperoxidase produce more IsoLG. IsoLG-modified apoAI directly increases lymphatic vessel contractions and activates lymphatic endothelial cells. Inhibition of IsoLG by carbonyl scavenger treatment reduces intestinal lymphangiogenesis in kidney-injured animals. Research from our group and others suggests a novel mediator (IsoLG-modified apoAI) and a new pathway (intestinal lymphatic network) in the cross talk between kidneys and intestines and heart. Kidney injury activates intestinal lymphangiogenesis and increases lymphatic flow via mechanisms involving intestinally generated IsoLG. The data identify a new pathway in the kidney gut-heart axis and present a new target for kidney disease-induced intestinal disruptions that may lessen the major adverse consequence of kidney impairment, namely cardiovascular disease.


Assuntos
Doenças Cardiovasculares , Hipertensão , Vasos Linfáticos , Insuficiência Renal Crônica , Animais , Apolipoproteína A-I/metabolismo , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Citocinas , Células Endoteliais/metabolismo , Humanos , Hipertensão/metabolismo , Inflamação/metabolismo , Vasos Linfáticos/metabolismo , Peroxidase/metabolismo , Insuficiência Renal Crônica/metabolismo
7.
Int J Mol Sci ; 23(11)2022 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-35682697

RESUMO

We previously found that short-term treatment (week 8 to 12 after injury) with high-dose angiotensin receptor blocker (ARB) induced the regression of existing glomerulosclerosis in 5/6 nephrectomy rats. We therefore assessed the effects of long-term intervention with ARB vs. nonspecific antihypertensives in this study. Adult rats underwent 5/6 nephrectomy and renal biopsy 8 weeks later. The rats were then divided into three groups with equivalent renal function and glomerular sclerosis and treated with high-dose losartan (ARB), nonspecific antihypertensive triple-therapy (TRX), or left untreated (Control) until week 30. We found that blood pressure, serum creatinine levels, and glomerulosclerosis were lower at sacrifice in ARB and TRX vs. Control. Only ARB reduced proteinuria and maintained the density of WT-1-positive podocytes. Glomerular tufts showed more double-positive cells for CD44, a marker of activated parietal epithelial cells, and synaptopodin after ARB vs. TRX or Control. ARB treatment reduced aldosterone levels. ARB-treated rats had significantly improved survival when compared with TRX or Control. We conclude that both long-term ARB and triple-therapy ameliorate progression, but do not sustain the regression of glomerulosclerosis. ARB resulted in the superior preservation of podocyte integrity and decreased proteinuria and aldosterone, linked to increased survival in the uremic environment.


Assuntos
Nefropatias , Podócitos , Aldosterona/farmacologia , Antagonistas de Receptores de Angiotensina/farmacologia , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Pressão Sanguínea , Nefropatias/patologia , Podócitos/patologia , Proteinúria/tratamento farmacológico , Proteinúria/patologia , Ratos
8.
Int J Mol Sci ; 23(3)2022 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-35163352

RESUMO

Lymphatic vessels are highly responsive to changes in the interstitial environment. Previously, we showed renal lymphatics express the Na-K-2Cl cotransporter. Since interstitial sodium retention is a hallmark of proteinuric injury, we examined whether renal sodium affects NKCC1 expression and the dynamic pumping function of renal lymphatic vessels. Puromycin aminonucleoside (PAN)-injected rats served as a model of proteinuric kidney injury. Sodium 23Na/1H-MRI was used to measure renal sodium and water content in live animals. Renal lymph, which reflects the interstitial composition, was collected, and the sodium analyzed. The contractile dynamics of isolated renal lymphatic vessels were studied in a perfusion chamber. Cultured lymphatic endothelial cells (LECs) were used to assess direct sodium effects on NKCC1. MRI showed elevation in renal sodium and water in PAN. In addition, renal lymph contained higher sodium, although the plasma sodium showed no difference between PAN and controls. High sodium decreased contractility of renal collecting lymphatic vessels. In LECs, high sodium reduced phosphorylated NKCC1 and SPAK, an upstream activating kinase of NKCC1, and eNOS, a downstream effector of lymphatic contractility. The NKCC1 inhibitor furosemide showed a weaker effect on ejection fraction in isolated renal lymphatics of PAN vs controls. High sodium within the renal interstitium following proteinuric injury is associated with impaired renal lymphatic pumping that may, in part, involve the SPAK-NKCC1-eNOS pathway, which may contribute to sodium retention and reduce lymphatic responsiveness to furosemide. We propose that this lymphatic vessel dysfunction is a novel mechanism of impaired interstitial clearance and edema in proteinuric kidney disease.


Assuntos
Injúria Renal Aguda/metabolismo , Endotélio Linfático/citologia , Rim/química , Óxido Nítrico Sintase Tipo III/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Puromicina Aminonucleosídeo/efeitos adversos , Sódio/análise , Membro 2 da Família 12 de Carreador de Soluto/metabolismo , Injúria Renal Aguda/induzido quimicamente , Animais , Células Cultivadas , Endotélio Linfático/efeitos dos fármacos , Endotélio Linfático/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Imageamento por Ressonância Magnética , Masculino , Fosforilação/efeitos dos fármacos , Ratos , Água/análise
9.
Kidney Int ; 99(3): 620-631, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33137336

RESUMO

Previously, we found that mild tubulointerstitial injury sensitizes glomeruli to subsequent injury. Here, we evaluated whether stabilization of hypoxia-inducible factor-α (HIF-α), a key regulator of tissue response to hypoxia, ameliorates tubulointerstitial injury and impact on subsequent glomerular injury. Nep25 mice, which express the human CD25 receptor on podocytes under control of the nephrin promotor and develop glomerulosclerosis when a specific toxin is administered were used. Tubulointerstitial injury, evident by week two, was induced by folic acid, and mice were treated with an HIF stabilizer, dimethyloxalylglycine or vehicle from week three to six. Uninephrectomy at week six assessed tubulointerstitial fibrosis. Glomerular injury was induced by podocyte toxin at week seven, and mice were sacrificed ten days later. At week six tubular injury markers normalized but with patchy collagen I and interstitial fibrosis. Pimonidazole staining, a hypoxia marker, was increased by folic acid treatment compared to vehicle while dimethyloxalylglycine stimulated HIF-2α expression and attenuated tubulointerstitial hypoxia. The hematocrit was increased by dimethyloxalylglycine along with downstream effectors of HIF. Tubular epithelial cell injury, inflammation and interstitial fibrosis were improved after dimethyloxalylglycine, with further reduced mortality, interstitial fibrosis, and glomerulosclerosis induced by specific podocyte injury. Thus, our findings indicate that hypoxia contributes to tubular injury and consequent sensitization of glomeruli to injury. Hence, restoring HIFs may blunt this adverse crosstalk of tubules to glomeruli.


Assuntos
Nefropatias , Podócitos , Animais , Fibrose , Hipóxia , Subunidade alfa do Fator 1 Induzível por Hipóxia , Nefropatias/patologia , Glomérulos Renais/patologia , Camundongos
10.
Kidney Int ; 100(3): 585-596, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34102217

RESUMO

Kidney disease affects intestinal structure and function. Although intestinal lymphatics are central in absorption and remodeling of dietary and synthesized lipids/lipoproteins, little is known about how kidney injury impacts the intestinal lymphatic network, or lipoproteins transported therein. To study this, we used puromycin aminoglycoside-treated rats and NEP25 transgenic mice to show that proteinuric injury expanded the intestinal lymphatic network, activated lymphatic endothelial cells and increased mesenteric lymph flow. The lymph was found to contain increased levels of cytokines, immune cells, and isolevuglandin (a highly reactive dicarbonyl) and to have a greater output of apolipoprotein AI. Plasma levels of cytokines and isolevuglandin were not changed. However, isolevuglandin was also increased in the ileum of proteinuric animals, and intestinal epithelial cells exposed to myeloperoxidase produced more isolevuglandin. Apolipoprotein AI modified by isolevuglandin directly increased lymphatic vessel contractions, activated lymphatic endothelial cells, and enhanced the secretion of the lymphangiogenic promoter vascular endothelial growth factor-C by macrophages. Inhibition of isolevuglandin synthesis by a carbonyl scavenger reduced intestinal isolevuglandin adduct level and lymphangiogenesis. Thus, our data reveal a novel mediator, isolevuglandin modified apolipoprotein AI, and uncover intestinal lymphatic network structure and activity as a new pathway in the crosstalk between kidney and intestine that may contribute to the adverse impact of kidney disease on other organs.


Assuntos
Vasos Linfáticos , Fator C de Crescimento do Endotélio Vascular , Animais , Apolipoproteína A-I , Células Endoteliais , Rim , Linfangiogênese , Camundongos , Ratos
11.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360965

RESUMO

Decades of epidemiological studies have established the strong inverse relationship between high-density lipoprotein (HDL)-cholesterol concentration and cardiovascular disease. Recent evidence suggests that HDL particle functions, including anti-inflammatory and antioxidant functions, and cholesterol efflux capacity may be more strongly associated with cardiovascular disease protection than HDL cholesterol concentration. These HDL functions are also relevant in non-cardiovascular diseases, including acute and chronic kidney disease. This review examines our current understanding of the kidneys' role in HDL metabolism and homeostasis, and the effect of kidney disease on HDL composition and functionality. Additionally, the roles of HDL particles, proteins, and small RNA cargo on kidney cell function and on the development and progression of both acute and chronic kidney disease are examined. The effect of HDL protein modification by reactive dicarbonyls, including malondialdehyde and isolevuglandin, which form adducts with apolipoprotein A-I and impair proper HDL function in kidney disease, is also explored. Finally, the potential to develop targeted therapies that increase HDL concentration or functionality to improve acute or chronic kidney disease outcomes is discussed.


Assuntos
Nefropatias/metabolismo , Lipoproteínas HDL/metabolismo , Animais , Humanos , Lipoproteínas HDL/genética
12.
Am J Physiol Renal Physiol ; 319(6): F1027-F1036, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33103446

RESUMO

Similar to other organs, renal lymphatics remove excess fluid, solutes, and macromolecules from the renal interstitium. Given the kidney's unique role in maintaining body fluid homeostasis, renal lymphatics may be critical in this process. However, little is known regarding the pathways involved in renal lymphatic vessel function, and there are no studies on the effects of drugs targeting impaired interstitial clearance, such as diuretics. Using pressure myography, we showed that renal lymphatic collecting vessels are sensitive to changes in transmural pressure and have an optimal range of effective pumping. In addition, they are responsive to vasoactive factors known to regulate tone in other lymphatic vessels including prostaglandin E2 and nitric oxide, and their spontaneous contractility requires Ca2+ and Cl-. We also demonstrated that Na+-K+-2Cl- cotransporter Nkcc1, but not Nkcc2, is expressed in extrarenal lymphatic vessels. Furosemide, a loop diuretic that inhibits Na+-K+-2Cl- cotransporters, induced a dose-dependent dilation in lymphatic vessels and decreased the magnitude and frequency of spontaneous contractions, thereby reducing the ability of these vessels to propel lymph. Ethacrynic acid, another loop diuretic, had no effect on vessel tone. These data represent a significant step forward in our understanding of the mechanisms underlying renal lymphatic vessel function and highlight potential off-target effects of furosemide that may exacerbate fluid accumulation in edema-forming conditions.


Assuntos
Rim/anatomia & histologia , Rim/fisiologia , Vasos Linfáticos/fisiologia , Animais , Cálcio/metabolismo , Cloretos/metabolismo , Furosemida/farmacologia , Vasos Linfáticos/efeitos dos fármacos , Masculino , NG-Nitroarginina Metil Éster , Óxido Nítrico/metabolismo , Pressão , Ratos , Ratos Sprague-Dawley , Inibidores de Simportadores de Cloreto de Sódio e Potássio/farmacologia
13.
Kidney Int ; 98(1): 219-227, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32327202

RESUMO

Although the respiratory and immune systems are the major targets of Coronavirus Disease 2019 (COVID-19), acute kidney injury and proteinuria have also been observed. Currently, detailed pathologic examination of kidney damage in critically ill patients with COVID-19 has been lacking. To help define this we analyzed kidney abnormalities in 26 autopsies of patients with COVID-19 by light microscopy, ultrastructural observation and immunostaining. Patients were on average 69 years (19 male and 7 female) with respiratory failure associated with multiple organ dysfunction syndrome as the cause of death. Nine of the 26 showed clinical signs of kidney injury that included increased serum creatinine and/or new-onset proteinuria. By light microscopy, diffuse proximal tubule injury with the loss of brush border, non-isometric vacuolar degeneration, and even frank necrosis was observed. Occasional hemosiderin granules and pigmented casts were identified. There were prominent erythrocyte aggregates obstructing the lumen of capillaries without platelet or fibrinoid material. Evidence of vasculitis, interstitial inflammation or hemorrhage was absent. Electron microscopic examination showed clusters of coronavirus-like particles with distinctive spikes in the tubular epithelium and podocytes. Furthermore, the receptor of SARS-CoV-2, ACE2 was found to be upregulated in patients with COVID-19, and immunostaining with SARS-CoV nucleoprotein antibody was positive in tubules. In addition to the direct virulence of SARS-CoV-2, factors contributing to acute kidney injury included systemic hypoxia, abnormal coagulation, and possible drug or hyperventilation-relevant rhabdomyolysis. Thus, our studies provide direct evidence of the invasion of SARSCoV-2 into kidney tissue. These findings will greatly add to the current understanding of SARS-CoV-2 infection.


Assuntos
Infecções por Coronavirus/patologia , Rim/ultraestrutura , Pneumonia Viral/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19 , China , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias
14.
Nephrol Dial Transplant ; 34(12): 2042-2050, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31071225

RESUMO

BACKGROUND: Plasminogen activator inhibitor-1 (PAI-1) expression increases extracellular matrix deposition and contributes to interstitial fibrosis in the kidney after injury. While PAI-1 is ubiquitously expressed in the kidney, we hypothesized that interstitial fibrosis is strongly dependent on fibroblast-specific PAI-1 (fbPAI-1). METHODS: Tenascin C Cre (TNC Cre) and fbPAI-1 knockdown (KD) mice with green fluorescent protein (GFP) expressed within the TNC construct underwent unilateral ureteral obstruction and were sacrificed 10 days later. RESULTS: GFP+ cells in fbPAI-1 KD mice showed significantly reduced PAI-1 expression. Interstitial fibrosis, measured by Sirius red staining and collagen I western blot, was significantly decreased in fbPAI-1 KD compared with TNC Cre mice. There was no significant difference in transforming growth factor ß (TGF-ß) expression or its activation between the two groups. However, GFP+ cells from fbPAI-1 KD mice had lower TGF ß and connective tissue growth factor (CTGF) expression. The number of fibroblasts was decreased in fbPAI-1 KD compared with TNC Cre mice, correlating with decreased alpha smooth muscle actin (α-SMA) expression and less fibroblast cell proliferation. TNC Cre mice had decreased E-cadherin, a marker of differentiated tubular epithelium, in contrast to preserved expression in fbPAI-1 KD. F4/80-expressing cells, mostly CD11c+/F4/80+ cells, were increased while M1 macrophage markers were decreased in fbPAI-1 KD compared with TNC Cre mice. CONCLUSION: These findings indicate that fbPAI-1 depletion ameliorates interstitial fibrosis by decreasing fibroblast proliferation in the renal interstitium, with resulting decreased collagen I. This is linked to decreased M1 macrophages and preserved tubular epithelium.


Assuntos
Fibroblastos/metabolismo , Fibrose/prevenção & controle , Nefropatias/prevenção & controle , Serpina E2/fisiologia , Obstrução Ureteral/complicações , Actinas/metabolismo , Animais , Colágeno Tipo I/metabolismo , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Fibrose/etiologia , Fibrose/metabolismo , Nefropatias/etiologia , Nefropatias/metabolismo , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Obstrução Ureteral/metabolismo
15.
Toxicol Pathol ; 46(8): 944-948, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30157700

RESUMO

Tubular injury sensitizes glomeruli to injury. We review potential mechanisms of this tubuloglomerular cross talk. In the same nephron, tubular injury can cause stenosis of the glomerulotubular junction and finally result in atubular glomeruli. Tubular injury also affects glomerular filtration function through tubuloglomerular feedback. Progenitor cells, that is, parietal epithelial cells and renin positive cells, can be involved in repair of injured glomeruli and also may be modulated by tubular injury. Loss of nephrons induces additional workload and stress on remaining nephrons. Hypoxia and activation of the renin-angiotensin-aldosterone system induced by tubular injury also modulate tubuloglomerular cross talk. Therefore, effective therapies in chronic kidney disease may need to aim to interrupt this deleterious tubuloglomerular cross talk.


Assuntos
Glomérulos Renais/patologia , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Injúria Renal Aguda/complicações , Injúria Renal Aguda/fisiopatologia , Animais , Humanos , Glomérulos Renais/metabolismo , Glomérulos Renais/fisiopatologia , Túbulos Renais/fisiopatologia , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/fisiopatologia
16.
BMC Nephrol ; 19(1): 17, 2018 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-29374468

RESUMO

BACKGROUND: Our aim was to evaluate lipid trafficking and inflammatory response of macrophages exposed to lipoproteins from subjects with moderate to severe chronic kidney disease (CKD), and to investigate the potential benefits of activating cellular cholesterol transporters via liver X receptor (LXR) agonism. METHODS: LDL and HDL were isolated by sequential density gradient ultracentrifugation of plasma from patients with stage 3-4 CKD and individuals without kidney disease (HDLCKD and HDLCont, respectively). Uptake of LDL, cholesterol efflux to HDL, and cellular inflammatory responses were assessed in human THP-1 cells. HDL effects on inflammatory markers (MCP-1, TNF-α, IL-1ß), Toll-like receptors-2 (TLR-2) and - 4 (TLR-4), ATP-binding cassette class A transporter (ABCA1), NF-κB, extracellular signal regulated protein kinases 1/2 (ERK1/2) were assessed by RT-PCR and western blot before and after in vitro treatment with an LXR agonist. RESULTS: There was no difference in macrophage uptake of LDL isolated from CKD versus controls. By contrast, HDCKD was significantly less effective than HDLCont in accepting cholesterol from cholesterol-enriched macrophages (median 20.8% [IQR 16.1-23.7] vs control (26.5% [IQR 19.6-28.5]; p = 0.008). LXR agonist upregulated ABCA1 expression and increased cholesterol efflux to HDL of both normal and CKD subjects, although the latter continued to show lower efflux capacity. HDLCKD increased macrophage cytokine response (TNF-α, MCP-1, IL-1ß, and NF-κB) versus HDLCont. The heightened cytokine response to HDLCKD was further amplified in cells treated with LXR agonist. The LXR-augmentation of inflammation was associated with increased TLR-2 and TLR-4 and ERK1/2. CONCLUSIONS: Moderate to severe impairment in kidney function promotes foam cell formation that reflects impairment in cholesterol acceptor function of HDLCKD. Activation of cellular cholesterol transporters by LXR agonism improves but does not normalize efflux to HDLCKD. However, LXR agonism actually increases the pro-inflammatory effects of HDLCKD through activation of TLRs and ERK1/2 pathways.


Assuntos
Mediadores da Inflamação/sangue , Lipoproteínas HDL/sangue , Lipoproteínas LDL/sangue , Receptores X do Fígado/agonistas , Macrófagos/metabolismo , Insuficiência Renal Crônica/sangue , Adulto , Idoso , Transporte Biológico/efeitos dos fármacos , Transporte Biológico/fisiologia , Feminino , Humanos , Hidrocarbonetos Fluorados/farmacologia , Macrófagos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Transporte Proteico/efeitos dos fármacos , Transporte Proteico/fisiologia , Sulfonamidas/farmacologia , Células THP-1/efeitos dos fármacos , Células THP-1/metabolismo
17.
Am J Physiol Renal Physiol ; 312(3): F375-F384, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-27974318

RESUMO

Chronic kidney disease (CKD) will progress to end stage without treatment, but the decline of renal function may not be linear. Compared with glomerular filtration rate and proteinuria, new surrogate markers, such as kidney injury molecule-1, neutrophil gelatinase-associated protein, apolipoprotein A-IV, and soluble urokinase receptor, may allow potential intervention and treatment in the earlier stages of CKD, which could be useful for clinical trials. New omic-based technologies reveal potential new genomic and epigenomic mechanisms that appear different from those causing the initial disease. Various clinical studies also suggest that acute kidney injury is a major risk for progressive CKD. To ameliorate the progression of CKD, the first step is optimizing renin-angiotensin-aldosterone system blockade. New drugs targeting endothelin, transforming growth factor-ß, oxidative stress, and inflammatory- and cell-based regenerative therapy may have add-on benefit.


Assuntos
Falência Renal Crônica/prevenção & controle , Rim/efeitos dos fármacos , Insuficiência Renal Crônica/tratamento farmacológico , Agentes Urológicos/uso terapêutico , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/fisiopatologia , Injúria Renal Aguda/prevenção & controle , Animais , Progressão da Doença , Epigênese Genética , Marcadores Genéticos , Predisposição Genética para Doença , Taxa de Filtração Glomerular , Humanos , Rim/metabolismo , Rim/patologia , Rim/fisiopatologia , Falência Renal Crônica/genética , Falência Renal Crônica/metabolismo , Falência Renal Crônica/fisiopatologia , Fenótipo , Proteinúria/metabolismo , Proteinúria/fisiopatologia , Proteinúria/prevenção & controle , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/fisiopatologia , Sistema Renina-Angiotensina , Fatores de Risco , Agentes Urológicos/efeitos adversos
18.
Kidney Int ; 92(6): 1395-1403, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28709637

RESUMO

Chronic glomerular injury is associated with eventual development of tubulointerstitial fibrosis. Here we aimed to assess whether, and how, mild chronic tubulointerstitial injury affects glomeruli. For this, we generated mice expressing different toxin receptors, one on their proximal tubular epithelial cells (diphtheria toxin receptor [DTR]) and the other only on podocytes (human CD25 [IL-2R] driven by the nephrin promoter [Nep25]), allowing serial induction of tubule-specific and glomerular (podocyte)-specific injury, respectively. Six weeks after diphtheria toxin injection, mild interstitial fibrosis was found in Nep25+/DTR+, but not in Nep25+/DTR- mice. However, atubular glomeruli and neuronal nitric oxide synthase, a mediator of tubuloglomerular feedback, were higher in Nep25+/DTR+ than in DTR- mice and these atubular glomeruli had less podocyte density as assessed by WT-1 biomarker expression. Peritubular capillary density, hypoxia-inducible factor-1 and -2, and cyclooxygenase 2 expression were similar at week six in the two groups. At week seven, all mice were given the immunotoxin LMB-2, which binds to CD25 to induce podocyte injury. Ten days later, proteinuria, podocyte injury, and glomerulosclerosis were more severe in Nep25+/DTR+ than Nep25+/DTR- mice with more severe sclerosis in the tubule-connected glomeruli. This supports the concept that even mild preexisting tubulointerstitial injury sensitizes glomeruli to subsequent podocyte-specific injury. Thus, increased atubular glomeruli and abnormal tubuloglomerular feedback significantly contribute to the crosstalk between the tubulointerstitium and glomeruli.


Assuntos
Nefropatias/patologia , Glomérulos Renais/patologia , Túbulos Renais/patologia , Animais , Anticorpos Monoclonais/toxicidade , Toxina Diftérica/toxicidade , Modelos Animais de Doenças , Exotoxinas/toxicidade , Fibrose , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/genética , Humanos , Subunidade alfa de Receptor de Interleucina-2/genética , Nefropatias/induzido quimicamente , Nefropatias/urina , Glomérulos Renais/citologia , Glomérulos Renais/efeitos dos fármacos , Túbulos Renais/irrigação sanguínea , Túbulos Renais/efeitos dos fármacos , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Podócitos/efeitos dos fármacos , Podócitos/metabolismo , Regiões Promotoras Genéticas/genética , Proteinúria/induzido quimicamente , Proteinúria/patologia , Proteinúria/urina , Esclerose
19.
Lab Invest ; 96(6): 602-9, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26999660

RESUMO

We previously observed that high-dose angiotensin receptor blocker (ARB) can induce regression of existing glomerulosclerosis. We also found that proliferator-activated recepto-γ (PPARγ) agonist can attenuate glomerulosclerosis in a nondiabetic model of kidney disease, with specific protection of podocytes. We now assessed effects of combination therapy with ARB and pioglitazone on established glomerulosclerosis. Sprague-Dawley male rats underwent 5/6 nephrectomy (5/6 Nx) at week 0 and renal biopsy at week 8. Rats were randomized to groups with equal starting moderate glomerulosclerosis, and treated with ARB, PPARγ agonist (pioglitazone), combination or vehicle from weeks 8 to 12. Body weight, systolic blood pressure (SBP), and urinary protein (UP) were measured at intervals. In rats with established sclerosis, SBP, UP, and GS were equal in all groups at week 8 before treatment by study design. Untreated control rats had hypertension, decreased GFR, and progressive proteinuria and glomerulosclerosis at week 12. Only combination therapy significantly ameliorated hypertension and proteinuria. ARB alone or pioglitazone alone had only numerically lower SBP and UP than vehicle at week 12. Both pioglitazone alone and combination had significantly less decline in GFR than vehicle. Combination-induced regression of glomerulosclerosis in more rats from weeks 8 to 12 than ARB or pioglitazone alone. In parallel, combination treatment reduced plasminogen activator inhibitor-1 expression and macrophage infiltration, and preserved podocytes compared with vehicle. These results were linked to increased AT2 receptor and Mas1 mRNA in the combination group. PPARγ agonists in combination with ARB augment regression of glomerulosclerosis, with downregulation of injurious RAAS components vs PPARγ alone, with increased anti-fibrotic/healing RAAS components, enhanced podocyte preservation, and decreased inflammation and profibrotic mechanisms.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Glomerulosclerose Segmentar e Focal/tratamento farmacológico , PPAR gama/agonistas , Tiazolidinedionas/administração & dosagem , Animais , Benzimidazóis/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Creatinina/sangue , Progressão da Doença , Quimioterapia Combinada , Glomerulosclerose Segmentar e Focal/patologia , Glomerulosclerose Segmentar e Focal/fisiopatologia , Rim/efeitos dos fármacos , Rim/patologia , Rim/fisiopatologia , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Masculino , Oxidiazóis/administração & dosagem , Pioglitazona , Podócitos/efeitos dos fármacos , Podócitos/patologia , Proteinúria/tratamento farmacológico , Proto-Oncogene Mas , Ratos , Ratos Sprague-Dawley , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia
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