scholarly journals Mitochondrial Dysfunction in Podocytes Caused by CRIF1 Deficiency Leads to Progressive Albuminuria and Glomerular Sclerosis in Mice

2021 ◽  
Vol 22 (9) ◽  
pp. 4827
Author(s):  
Ki Ryang Na ◽  
Jin Young Jeong ◽  
Jin Ah Shin ◽  
Yoon-Kyung Chang ◽  
Kwang-Sun Suh ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Interstitial Fibrosis ◽  
Renal Diseases ◽  
Glomerular Sclerosis ◽  
Loss Of Function ◽  
Inner Mitochondrial Membrane ◽  
Glomerular Diseases ◽  
Glomerular Function ◽  
Tubulointerstitial Lesions ◽  
Deficient Mice

Recent studies have implicated mitochondrial disruption in podocyte dysfunction, which is a characteristic feature of primary and diabetic glomerular diseases. However, the mechanisms by which primary mitochondrial dysfunction in podocytes affects glomerular renal diseases are currently unknown. To investigate the role of mitochondrial oxidative phosphorylation (OxPhos) in podocyte dysfunction, glomerular function was examined in mice carrying a loss of function mutation of the gene encoding CR6-interacting factor-1 (CRIF1), which is essential for intramitochondrial production and the subsequent insertion of OxPhos polypeptides into the inner mitochondrial membrane. Homozygotic deficiency of CRIF1 in podocytes resulted in profound and progressive albuminuria from 3 weeks of age; the CRIF1-deficient mice also developed glomerular and tubulointerstitial lesions by 10 weeks of age. Furthermore, marked glomerular sclerosis and interstitial fibrosis were observed in homozygous CRIF1-deficient mice at 20 weeks of age. In cultured mouse podocytes, loss of CRIF1 resulted in OxPhos dysfunction and marked loss or abnormal aggregation of F-actin. These findings indicate that the OxPhos status determines the integrity of podocytes and their ability to maintain a tight barrier and control albuminuria. Analyses of the glomerular function of the podocyte-specific primary OxPhos dysfunction model mice demonstrate a link between podocyte mitochondrial dysfunction, progressive glomerular sclerosis, and tubulointerstitial diseases.

The Relevance of Periglomerular Fibrosis in the Evaluation of Routine Needle Core Renal Biopsies

2011 ◽  
Vol 135 (1) ◽  
pp. 117-122
Author(s):  
Joseph Jenkins ◽  
Sergey V. Brodsky ◽  
Anjali A. Satoskar ◽  
Gyongyi Nadasdy ◽  
Tibor Nadasdy
Keyword(s):  
Renal Function ◽  
Renal Biopsy ◽  
Renal Injury ◽  
Interstitial Fibrosis ◽  
Renal Diseases ◽  
Glomerular Sclerosis ◽  
Poor Renal Function ◽  
Renal Biopsies ◽  
Biopsy Report ◽  
Relationship Of

Abstract Context—Renal interstitial fibrosis and, to a lesser extent, sclerotic glomeruli correlate with poor renal function. However, not all nonfunctional glomeruli are sclerotic. Many or most glomeruli with periglomerular fibrosis, while retaining blood flow, probably do not filter; therefore, they may not contribute to renal function. Objective—To examine the relationship of periglomerular fibrosis and the sum of globally sclerotic glomeruli and glomeruli with periglomerular fibrosis (GSG+PF) with interstitial fibrosis and renal function. Design—Native kidney biopsies from 177 patients with chronic renal injury were assessed for interstitial fibrosis, glomerular sclerosis, and GSG+PF. Renal biopsies with active or acute lesions were not included. The percentage of globally sclerotic glomeruli and GSG+PF was correlated with the degree of interstitial fibrosis and serum creatinine levels. Results—The percentage of GSG+PF correlates better with the degree of interstitial fibrosis and renal function than does the percentage of globally sclerotic glomeruli alone. This appears particularly true in chronic renal diseases of patients without diabetes. The number of globally sclerotic glomeruli correlates better with interstitial fibrosis and renal function than does the sum of globally and segmentally sclerotic glomeruli. Conclusions—The percentage of GSG+PF in a renal biopsy specimen provides a better estimate of chronic renal injury than does the percentage of sclerotic glomeruli alone, probably because many or most glomeruli with periglomerular fibrosis are nonfunctional. Therefore, we recommend that the number of glomeruli with periglomerular fibrosis also be provided in the renal biopsy report.

scholarly journals P0470IS GLYCOSURIA A MARKER OF TUBULO-INTERSTITITAL FIBROSIS AND PROGNOSIS IN PRIMARY GLOMERULOPATHIES?

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Carolina Ormonde ◽  
Ivo Laranjinha ◽  
Augusta Gaspar ◽  
Margarida Gonçalves ◽  
Célia Gil ◽  
...  
Keyword(s):  
Interstitial Fibrosis ◽  
Glomerular Sclerosis ◽  
Similar Proportion ◽  
Tubular Damage ◽  
Tubular Dysfunction ◽  
Ckd Progression ◽  
Tubular Atrophy ◽  
Glomerular Diseases ◽  
Glomerular Lesion ◽  
Ckd Stage

Abstract Background and Aims Multiple studies have shown that tubular damage is common in glomerular diseases and that it correlates better with chronic kidney disease (CKD) progression than glomerular lesion itself. The link between glomerular and tubular damage is not entirely established. Glycosuria can be found in (proximal) tubular dysfunction and may be used as a marker of tubular lesion and CKD progression. The aim of this study was to evaluate the association between glycosuria (at the diagnosis) and known histological prognostic markers (glomerular sclerosis (%GS) and interstitial fibrosis/tubular atrophy (IFTA)) and CKD progression, in patients with primary glomerulopathies (GP). Method We conducted a 36-month retrospective cohort study with 110 patients with primary GP confirmed by renal biopsy in the last 10 years in our centre – 39 (35.5%) IgA Nephropathy, 27 (24.5%) Membranous Nephropathy, 26 (23.6%) Focal Segmental Glomerulosclerosis and 18 (16.4%) Minimal Change Disease. Patients were divided in two groups according to their glycosuric status at the time of the diagnosis. Data was collected from patients’ charts. Exclusion criteria: patients with diabetes or glucose intolerance, use of SGLT2 inhibitors, secondary GP and transplant kidney patients. Results The global prevalence of glycosuria was 9.1% (n=10). Glycosuric patients had, at baseline, higher serum creatinine (3.9±5.1 vs 1.7±1.3mg/dL, p=0.001), higher baseline albuminuria (7.1±6.3 vs 3.2±3.4 g/g, p=0.002) and lower serum albumin (2.3±0.7 vs 3.2±1.1 g/dL, p=0.022). Both groups had similar proportion of patients that underwent immunosuppressive therapy. At the end of the follow-up, in glycosuric patients, only albuminuria was higher (3.3±0.6 vs 0.7±0.8 g/g, p<0.0001); the eGFR decline rate (ml/min/year), 3-year eGFR and 3-year CKD stage 5D incidence were not statistically different. Glomerular sclerosis (%GS) and interstitial fibrosis and tubular atrophy (IFTA) were not different between groups. These results were confirmed by multivariate analysis. Conclusion Patients with primary GP with glycosuria at diagnosis had higher baseline creatinine and albuminuria. Even though a worse clinical presentation, glycosuria was not associated with well-known prognostic factors (%GS and IFTA) or CKD progression. We can hypothesize that patients with primary GP with glycosuria have severe diseases at diagnosis, but the lesions may have greater reversibility. Prospective and longer studies are needed to confirm these results.

scholarly journals Impacts of Indoxyl Sulfate and p-Cresol Sulfate on Chronic Kidney Disease and Mitigating Effects of AST-120

Toxins ◽  
2018 ◽  
Vol 10 (9) ◽  
pp. 367 ◽  
Author(s):  
Wen-Chih Liu ◽  
Yasuhiko Tomino ◽  
Kuo-Cheng Lu
Keyword(s):  
Oxidative Stress ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Large Scale ◽  
Interstitial Fibrosis ◽  
Uremic Toxins ◽  
Indoxyl Sulfate ◽  
Renal Diseases ◽  
Glomerular Sclerosis ◽  
Inflammatory Reactions

Uremic toxins, such as indoxyl sulfate (IS) and p-cresol, or p-cresyl sulfate (PCS), are markedly accumulated in the organs of chronic kidney disease (CKD) patients. These toxins can induce inflammatory reactions and enhance oxidative stress, prompting glomerular sclerosis and interstitial fibrosis, to aggravate the decline of renal function. Consequently, uremic toxins play an important role in the worsening of renal and cardiovascular functions. Furthermore, they destroy the quantity and quality of bone. Oral sorbent AST-120 reduces serum levels of uremic toxins in CKD patients by adsorbing the precursors of IS and PCS generated by amino acid metabolism in the intestine. Accordingly, AST-120 decreases the serum IS levels and reduces the production of reactive oxygen species by endothelial cells, to impede the subsequent oxidative stress. This slows the progression of cardiovascular and renal diseases and improves bone metabolism in CKD patients. Although large-scale studies showed no obvious benefits from adding AST-120 to the standard therapy for CKD patients, subsequent sporadic studies may support its use. This article summarizes the mechanisms of the uremic toxins, IS, and PCS, and discusses the multiple effects of AST-120 in CKD patients.

scholarly journals The role of interstitial cells in the progression of renal diseases.

1992 ◽  
Vol 2 (10) ◽  
pp. S198 ◽  
Author(s):  
G A Müller ◽  
J Markovic-Lipkovski ◽  
J Frank ◽  
H P Rodemann
Keyword(s):  
Epithelial Cells ◽  
Interstitial Fibrosis ◽  
Interstitial Cells ◽  
Intercellular Adhesion Molecule ◽  
Renal Diseases ◽  
Intercellular Adhesion Molecule 1 ◽  
Glomerular Diseases ◽  
Aberrant Expression ◽  
Hla Dq ◽  
Renal Biopsies

Renal interstitial fibrosis (RIF) is frequently associated with distinct inflammatory and noninflammatory glomerular diseases. RIF is mainly responsible for a decline of excretory renal function and therefore influences the prognosis of several renal diseases. The resident interstitial cells of the kidney, which play a major role in causing RIF, are different renal fibroblasts, which respond to a variety of cytokines released by various cell types. Immunohistochemical analysis of human renal biopsies with different glomerulopathies revealed that CD2+ T lymphocytes are the major cells infiltrating the renal interstitium. In most forms of glomerulonephritis accompanied by interstitial inflammation, an abnormal expression of HLA-DQ/HLA-DP antigens, often associated with an aberrant expression of the intercellular adhesion molecule 1, was observed on proximal tubular epithelial cells, indicating that these cells may play an important role in local immune responses and probably function as antigen-presenting cells. Furthermore, it has been shown by Northern blot analysis that renal epithelial cells in culture express interleukin 6, platelet-derived growth factor and granulocyte-macrophage colony stimulating factor. Cell cultures established from renal biopsies revealed the presence of the three mitotic fibroblast types (MF I through MF III) and the three postmitotic types (PMF IV through PMF VI). The frequencies of the various progenitor fibroblasts MF I, MF II, and MF III differed significantly in cultures established from kidneys with (FKIF cells) and without RIF (NKF cells). In comparison to NKF cells, FKIF cells are characterized by the expression of a "new" protein, called "FIBROSIN," which seems to be specific for FKIF cells.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Podocytes and Proteinuric Kidney Disease

2015 ◽  
Vol 12 (1) ◽  
pp. 16-19
Author(s):  
Alketa Koroshi ◽  
Alma Idrizi
Keyword(s):  
Treatment Strategies ◽  
Glomerular Disease ◽  
Glomerular Sclerosis ◽  
Endstage Renal Disease ◽  
Glomerular Diseases ◽  
Podocyte Injury ◽  
Glomerular Function ◽  
Podocyte Loss ◽  
Insight Into

Abstract Glomerular disease is the most common cause of endstage renal disease (ESRD), accounting for almost two thirds of cases. In glomerular disease, alterations of po-docytes are of particular importance. Podocyte loss represents a central mediator of glomerular sclerosis. Toxic, genetic, immune, infectious, oxidant, metabolic, hemody-namic, and other mechanisms can all target the podo-cytes. These mechanisms provide new insight into the unique dynamic microenvironment that each individual podocyte inhabits and how it can turn hostile to survival. At the same time, they raise new therapeutic challenges to preserve glomerular function by containing podocyte injury and limiting its spread, both in podo-cytopathies and in other progressive glomerular diseases. Treatment strategies should aim at enhancing podocyte survival. The renin-angiotensin axis blockade, apart from its antifibrotic and intraglomerular hemodynamic effects, has an important role in preventing podocyte loss. However, only long-term observational studies can clarify if many patients will benefit from podocyte-targeted treatment such as abatacept or similar agents.

scholarly journals Chronic Renal Changes After a Single Ischemic Event in an Experimental Model of Feline Chronic Kidney Disease

2019 ◽  
Vol 56 (4) ◽  
pp. 536-543 ◽  
Author(s):  
Cathy A. Brown ◽  
Daniel R. Rissi ◽  
Vanna M. Dickerson ◽  
Anastacia M. Davis ◽  
Scott A. Brown ◽  
...  
Keyword(s):  
Renal Function ◽  
Structural Changes ◽  
Interstitial Fibrosis ◽  
Renal Ischemia ◽  
Loss Of Function ◽  
Tubular Atrophy ◽  
Ischemic Event ◽  
Tubulointerstitial Lesions ◽  
Atubular Glomeruli

Previous work demonstrated renal fibrosis 70 days after a single unilateral in vivo renal ischemic event, but changes associated with a single episode of renal ischemia past this time are unknown. In this study, we evaluated renal function and structural changes 6 months after a 90-minute in vivo unilateral renal ischemic event. Six adult female cats underwent unilateral renal ischemia and renal function was followed for 6 months, at which time the kidneys were evaluated by histology and histomorphometry. Over time, there was a significant reduction in the glomerular filtration rate and an elevation of serum creatinine of 31% and 42%, respectively. All cats had tubulointerstitial lesions characterized by segmental interstitial inflammation, tubular atrophy, and interstitial fibrosis. Unlike short-term studies, ischemic kidneys had variable numbers of obsolescent glomeruli, consistent with the development of atubular glomeruli and subsequent ischemic glomerulosclerosis. Chronic changes associated with acute renal ischemia may include loss of function and glomerulosclerosis.

P0445PREVALENCE AND PREDICTORS OF GLYCOSURIA IN PRIMARY GLOMERULOPATHIES

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Carolina Ormonde ◽  
Ivo Laranjinha ◽  
Augusta Gaspar ◽  
Margarida Gonçalves ◽  
Célia Gil ◽  
...  
Keyword(s):  
Serum Creatinine ◽  
Serum Albumin ◽  
Clinical Laboratory ◽  
Interstitial Fibrosis ◽  
Glomerular Sclerosis ◽  
Tubular Damage ◽  
Tubular Dysfunction ◽  
Lower Serum ◽  
Glomerular Diseases ◽  
Glomerular Lesion

Abstract Background and Aims Albuminuria is a marker of glomerular lesion, however some studies have suggested that proximal tubule (endocytosis of albumin) is also essential to determine the amount of albumin excreted in the urine. It has been hypothesized that patients with glomerulopathies and concomitant tubular damage might present higher levels of albuminuria. Glycosuria is a marker of proximal tubular dysfunction and may be used as an easy and useful marker of tubular lesion in glomerular diseases. The aim of this transversal study was to evaluate the prevalence of glycosuria in primary glomerulopathies (GP) and identify its predictors. Method We included all patients diagnosed in the last 10 years in our centre with primary GP confirmed by renal biopsy. Clinical, laboratory and biopsy results were collected from patients’ charts. Patients were divided in two groups according to their glycosuric status at the diagnosis. Exclusion criteria: patients with diabetes and glucose intolerance, use of SGLT2 inhibitors, transplant kidney patients and secondary GP. Results We studied 110 patients – 39 (35.5%) IgA Nephropathy (IgAN), 27 (24.5%) Membranous Nephropathy (MN), 26 (23.6%) Focal Segmental Glomerulosclerosis (FSGS) and 18 (16.4%) Minimal Change Disease (MCD). Demographic data were not different between patients with and without glycosuria. Global prevalence of glycosuria was 9.1% (n=10) – patients with MN had higher prevalence of glycosuria (n=4, 17.4%), followed by FSGS (n=3, 15.5%), MCD (n=1, 5.9%) and IgAN (n=2, 5.4%). We found that patients with glycosuria had higher serum creatinine (3.9±5.1 vs 1.7±1.3 mg/dL, p=0.001), higher albuminuria (7.1±6.3 vs 3.2±3.4 g/g, p=0.002), lower serum albumin (2.3±0.7 vs 3.2±1.1 g/dL, p=0.022) and lower hemoglobin (12.0±2.5 vs 13.4±2.0 g/dL, p=0.050). Nevertheless, we did not find differences between glycosuric and non-glycosuric patients in percentage of glomerular sclerosis (%GS) or interstitial fibrosis and tubular atrophy (IFTA). In a multivariate analysis, glycosuria was positively associated with MN diagnosis, serum creatinine and albuminuria, but not with hematuria, %GS and IFTA. Conclusion Glycosuria is not frequent in primary GP. MN is the primary GP that most frequently presents glycosuria. Glycosuria is associated with higher albuminuria and lower serum albumin levels, corroborating the hypothesis that albuminuria as an offender to the tubules will affect the amount of albumin excreted in the urine. We also found that patients with glycosuria presented a more severe renal dysfunction (higher creatinine) at the GP diagnosis.

scholarly journals Mpv17 in mitochondria protects podocytes against mitochondrial dysfunction and apoptosis in vivo and in vitro

2014 ◽  
Vol 306 (11) ◽  
pp. F1372-F1380 ◽  
Author(s):  
Gabriela Casalena ◽  
Stefanie Krick ◽  
Ilse Daehn ◽  
Liping Yu ◽  
Wenjun Ju ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Oxidative Dna Damage ◽  
Ros Generation ◽  
Glomerular Injury ◽  
Inner Mitochondrial Membrane ◽  
Glomerular Diseases ◽  
Mtdna Mutations ◽  
Mitochondrial Ros

Mitochondrial dysfunction is increasingly recognized as contributing to glomerular diseases, including those secondary to mitochondrial DNA (mtDNA) mutations and deletions. Mitochondria maintain cellular redox and energy homeostasis and are a major source of intracellular reactive oxygen species (ROS) production. Mitochondrial ROS accumulation may contribute to stress-induced mitochondrial dysfunction and apoptosis and thereby to glomerulosclerosis. In mice, deletion of the gene encoding Mpv17 is associated with glomerulosclerosis, but the underlying mechanism remains poorly defined. Here we report that Mpv17 localizes to mitochondria of podocytes and its expression is reduced in several glomerular injury models and in human focal segmental glomerulosclerosis (FSGS) but not in minimal change disease. Using models of mild or severe nephrotoxic serum nephritis (NTSN) in Mpv17+/+ wild-type (WT) and Mpv17−/− knockout mice, we found that Mpv17 deficiency resulted in increased proteinuria (mild NTSN) and renal insufficiency (severe NTSN) compared with WT. These lesions were associated with increased mitochondrial ROS generation and mitochondrial injury such as oxidative DNA damage. In vitro, podocytes with loss of Mpv17 function were characterized by increased susceptibility to apoptosis and ROS injury including decreased mitochondrial function, loss of mtDNA content, and change in mitochondrial configuration. In summary, the inner mitochondrial membrane protein Mpv17 in podocytes is essential for the maintenance of mitochondrial homeostasis and protects podocytes against oxidative stress-induced injury both in vitro and in vivo.

scholarly journals Therapeutic targeting of aldosterone: a novel approach to the treatment of glomerular disease

2015 ◽  
Vol 128 (9) ◽  
pp. 527-535 ◽  
Author(s):  
Andrew S. Brem ◽  
Rujun Gong
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Dysfunction ◽  
Mesangial Cells ◽  
Glycogen Synthase ◽  
Collecting Duct ◽  
Electrolyte Transport ◽  
Mitogen Activated Protein Kinase ◽  
Glomerular Sclerosis ◽  
Early Event ◽  
Glomerular Diseases

Numerous studies have established a role for mineralocorticoids in the development of renal fibrosis. Originally, the research focus for mineralocorticoid-induced fibrosis was on the collecting duct, where ‘classical’ mineralocorticoid receptors (MRs) involved with electrolyte transport are present. Epithelial cells in this segment can, under selected circumstances, also respond to MR activation by initiating pro-fibrotic pathways. More recently, ‘non-classical’ MRs have been described in kidney cells not associated with electrolyte transport, including mesangial cells and podocytes within the glomerulus. Activation of MRs in these cells appears to lead to glomerular sclerosis. Mechanistically, aldosterone induces excess production of reactive oxygen species (ROS) and oxidative stress in glomerular cells through activation of NADPH oxidase. In mesangial cells, aldosterone also has pro-apoptotic, mitogenic and pro-fibrogenic effects, all of which potentially promote active remodelling and expansion of the mesangium. Although mitochondrial dysfunction seems to mediate the aldosterone-induced mesangial apoptosis, the ROS dependent epithelial growth factor receptor (EGFR) transactivation is probably responsible for aldosterone-induced mesangial mitosis and proliferation. In podocytes, mitochondrial dysfunction elicited by oxidative stress is an early event associated with aldosterone-induced podocyte injury. Both the p38 MAPK (p38 mitogen-activated protein kinase) signalling and the redox-sensitive glycogen synthase kinase (GSK)3β pathways are centrally implicated in aldosterone-induced podocyte death. Aldosterone-induced GSK3β over-activity could potentially cause hyperphosphorylation and over-activation of putative GSK3β substrates, including structural components of the mitochondrial permeability transition (MPT) pore, all of which lead to cell injury and death. Clinically, proteinuria significantly decreases when aldosterone inhibitors are included in the treatment of many glomerular diseases further supporting the view that mineralocorticoids are important players in glomerular pathology.

Mitochondrial dysfunction in the pathophysiology of renal diseases

2014 ◽  
Vol 306 (4) ◽  
pp. F367-F378 ◽  
Author(s):  
Ruochen Che ◽  
Yanggang Yuan ◽  
Songming Huang ◽  
Aihua Zhang
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Dysfunction ◽  
Nuclear Dna ◽  
Kidney Diseases ◽  
Mitochondrial Dynamics ◽  
Critical Role ◽  
Kidney Injury ◽  
High Energy ◽  
Renal Diseases ◽  
Glomerular Diseases

Mitochondrial dysfunction has gained recognition as a contributing factor in many diseases. The kidney is a kind of organ with high energy demand, rich in mitochondria. As such, mitochondrial dysfunction in the kidney plays a critical role in the pathogenesis of kidney diseases. Despite the recognized importance mitochondria play in the pathogenesis of the diseases, there is limited understanding of various aspects of mitochondrial biology. This review examines the physiology and pathophysiology of mitochondria. It begins by discussing mitochondrial structure, mitochondrial DNA, mitochondrial reactive oxygen species production, mitochondrial dynamics, and mitophagy, before turning to inherited mitochondrial cytopathies in kidneys (inherited or sporadic mitochondrial DNA or nuclear DNA mutations in genes that affect mitochondrial function). Glomerular diseases, tubular defects, and other renal diseases are then discussed. Next, acquired mitochondrial dysfunction in kidney diseases is discussed, emphasizing the role of mitochondrial dysfunction in the pathogenesis of chronic kidney disease and acute kidney injury, as their prevalence is increasing. Finally, it summarizes the possible beneficial effects of mitochondrial-targeted therapeutic agents for treatment of mitochondrial dysfunction-mediated kidney injury-genetic therapies, antioxidants, thiazolidinediones, sirtuins, and resveratrol-as mitochondrial-based drugs may offer potential treatments for renal diseases.

Sign in / Sign up

Export Citation Format

Share Document