Endothelial Glycocalyx of Peritubular Capillaries in Experimental Diabetic Nephropathy: A Target of ACE Inhibitor-Induced Kidney Microvascular Protection.

Peritubular capillary rarefaction is a recurrent aspect of progressive nephropathies. We previously found that peritubular capillary density was reduced in BTBR / mice with type 2 diabetic nephropathy. In this model, we searched for abnormalities in the ultrastructure of peritubular capillaries, with a specific focus on the endothelial glycocalyx, and evaluated the impact of treatment with an angiotensin-converting enzyme inhibitor (ACEi).

Add-On Cyclic Angiotensin-(1-7) with Cyclophosphamide Arrests Progressive Kidney Disease in Rats with ANCA Associated Glomerulonephritis.

Rapidly progressive crescentic glomerulonephritis associated with anti-neutrophil cytoplasmic antibodies (ANCA-GN) is a major cause of renal failure. Current immunosuppressive therapies are associated with severe side effects, intensifying the need for new therapeutic strategies. The activation of Mas receptor/Angiotensin-(1-7) axis exerted renoprotection in chronic kidney disease.

Shiga Toxin 2 Triggers C3a-Dependent Glomerular and Tubular Injury through Mitochondrial Dysfunction in Hemolytic Uremic Syndrome.

Shiga toxin (Stx)-producing is the predominant offending agent of post-diarrheal hemolytic uremic syndrome (HUS), a rare disorder of microvascular thrombosis and acute kidney injury possibly leading to long-term renal sequelae. We previously showed that C3a has a critical role in the development of glomerular damage in experimental HUS. Based on the evidence that activation of C3a/C3a receptor (C3aR) signaling induces mitochondrial dysregulation and cell injury, here we investigated whether C3a caused podocyte and tubular injury through induction of mitochondrial dysfunction in a mouse model of HUS.

Characterization of a Rat Model of Myeloperoxidase-Anti-Neutrophil Cytoplasmic Antibody-Associated Crescentic Glomerulonephritis.

Background/aim: Necrotizing crescentic glomerulonephritis (GN) associated with anti-neutrophil cytoplasmic antibodies (ANCA) against myeloperoxidase (MPO) is a devastating disease that quickly progresses to kidney failure. Current therapies are broadly immunosuppressive and associated with adverse effects. We wanted to set up a model that could be suitable for testing narrowly targeted therapies.

Morphofunctional Effects of C5 Convertase Blockade in Immune Complex-Mediated Membranoproliferative Glomerulonephritis: Report of Two Cases with Evidence of Terminal Complement Activation.

A membranoproliferative pattern of glomerular injury is frequently observed in patients with complement-mediated disorders, such as C3 glomerulopathies (C3G) and primary immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN). The outcomes of C3G and -IC-MPGN are poor, independently of immunosuppressive therapy. However, two 48-week treatment periods with the anti-C5 monoclonal antibody eculizumab, divided by a -12-week washout period, achieved remission of proteinuria and stabilization/improvement of the glomerular filtration rate (GFR), measured through iohexol plasma clearance, in 3 of 10 patients with biopsy-proven MPGN, nephrotic syndrome and terminal complement complex sC5b-9 plasma levels >1,000 mg/mL, at inclusion.

Histological Examination of the Diabetic Kidney.

The increasing prevalence of diabetes worldwide has led to a concomitant rise in diabetic kidney disease (DKD) as a major cause of end-stage renal disease. Glomerular lesions constitute the most striking and consistent features identified in biopsies from patients with DKD, although tubulointerstitial injury has an important and often under-recognized role in the progression to overt nephropathy. In advanced stages of the disease, podocyte detachment is a pivotal event in the loss of glomerular filtration barrier integrity and may explain, at least in part, the inability of current therapies to halt renal function decline.

Addition of cyclic angiotensin-(1-7) to angiotensin-converting enzyme inhibitor therapy has a positive add-on effect in experimental diabetic nephropathy.

The Renin-Angiotensin System (RAS) possesses a counter-regulatory axis composed of angiotensin converting enzyme (ACE)2, angiotensin-(1-7) [Ang-(1-7)] and the Mas receptor, which opposes many AT1-receptor-mediated effects of ligand angiotensin II. Ang-(1-7), as a ligand of the Mas receptor, has inhibitory effects on renal inflammation and fibrosis in experimental diabetes. However, Ang-(1-7) has a short half-life in plasma, which may render it unsuitable for use in clinics.

Fenofibrate attenuates cardiac and renal alterations in young salt-loaded spontaneously hypertensive stroke-prone rats through mitochondrial protection.

Objectives: The simultaneous presence of cardiac and renal diseases is a pathological condition that leads to increased morbidity and mortality. Several lines of evidence have suggested that lipid dysmetabolism and mitochondrial dysfunction are pathways involved in the pathological processes affecting the heart and kidney. In the salt-loaded spontaneously hypertensive stroke-prone rat (SHRSP), a model of cardiac hypertrophy and nephropathy that shows mitochondrial alterations in the myocardium, we evaluated the cardiorenal effects of fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARα) agonist that acts by modulating mitochondrial and peroxisomal fatty acid oxidation.

Acute Kidney Injury and Hemolytic Anemia Secondary to Mycoplasma pneumoniae Infection.

Glomerulonephritis as well as kidney injury secondary to fulminant intravascular hemolysis are rare extrapulmonary manifestations of Mycoplasma pneumoniae infection. We describe a 50-year-old female diagnosed with M. pneumoniae infection-associated hemolytic anemia, characterized by negative cold agglutinin tests but with laboratory evidence of complement alternative pathway activation.

A previously unrecognized role of C3a in proteinuric progressive nephropathy.

Podocyte loss is the initial event in the development of glomerulosclerosis, the structural hallmark of progressive proteinuric nephropathies. Understanding mechanisms underlying glomerular injury is the key challenge for identifying novel therapeutic targets. In mice with protein-overload induced by bovine serum albumin (BSA), we evaluated whether the alternative pathway (AP) of complement mediated podocyte depletion and podocyte-dependent parietal epithelial cell (PEC) activation causing glomerulosclerosis.

Lipoprotein X Causes Renal Disease in LCAT Deficiency.

Human familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) is characterized by low HDL, accumulation of an abnormal cholesterol-rich multilamellar particle called lipoprotein-X (LpX) in plasma, and renal disease. The aim of our study was to determine if LpX is nephrotoxic and to gain insight into the pathogenesis of FLD renal disease. We administered a synthetic LpX, nearly identical to endogenous LpX in its physical, chemical and biologic characteristics, to wild-type and Lcat-/- mice.

Therapy with a Selective Cannabinoid Receptor Type 2 Agonist Limits Albuminuria and Renal Injury in Mice with Type 2 Diabetic Nephropathy.

Background/aims: A critical involvement of the endocannabinoid/cannabinoid receptor system in diabetes and its complications has been recognized. Experimental evidence suggested that activation of the cannabinoid receptor type 2 (CB2), which is expressed in the kidney by podocytes and inflammatory cells, had a protective role in early streptozotocin-induced type 1 diabetes in mice. No experimental evidence is so far available on the effects of CB2 agonists in type 2 diabetes.

Functional Human Podocytes Generated in Organoids from Amniotic Fluid Stem Cells.

Generating kidney organoids using human stem cells could offer promising prospects for research and therapeutic purposes. However, no cell-based strategy has generated nephrons displaying an intact three-dimensional epithelial filtering barrier. Here, we generated organoids using murine embryonic kidney cells, and documented that these tissues recapitulated the complex three-dimensional filtering structure of glomerular slits in vivo and accomplished selective glomerular filtration and tubular reabsorption.

Mitochondrial-dependent Autoimmunity in Membranous Nephropathy of IgG4-related Disease.

The pathophysiology of glomerular lesions of membranous nephropathy (MN), including seldom-reported IgG4-related disease, is still elusive. Unlike in idiopathic MN where IgG4 prevails, in this patient IgG3 was predominant in glomerular deposits in the absence of circulating anti-phospholipase A2 receptor antibodies, suggesting a distinct pathologic process. Here we documented that IgG4 retrieved from the serum of our propositus reacted against carbonic anhydrase II (CAII) at the podocyte surface.

Renal primordia activate kidney regenerative events in a rat model of progressive renal disease.

New intervention tools for severely damaged kidneys are in great demand to provide patients with a valid alternative to whole organ replacement. For repairing or replacing injured tissues, emerging approaches focus on using stem and progenitor cells. Embryonic kidneys represent an interesting option because, when transplanted to sites such as the renal capsule of healthy animals, they originate new renal structures.

Progression of renal injury toward interstitial inflammation and glomerular sclerosis is dependent on abnormal protein filtration.

Chronic proteinuric renal diseases, independent from the type of the initial insult, have in common a loss of selectivity of the glomerular barrier to protein filtration. Glomerular sclerosis is the progressive lesion affecting the glomerular capillary wall, the primary site at which the protein filtration is abnormally enhanced by disease. Dysfunction of podocytes, that serve to maintain the intact barrier, is a central event in lesion development.

Analogs of bardoxolone methyl worsen diabetic nephropathy in rats with additional adverse effects.

Bardoxolone methyl is an antioxidant inflammation modulator acting through induction of Keap1-Nrf2 pathway. Results from a recent phase IIb clinical trial reported that bardoxolone methyl was associated with improvement in the estimated glomerular filtration rate in patients with advanced chronic kidney disease and Type 2 diabetes. However, increases in albuminuria, serum transaminase, and frequency of adverse events were noted.

In vivo maturation of functional renal organoids formed from embryonic cell suspensions.

The shortage of transplantable organs provides an impetus to develop tissue-engineered alternatives. Producing tissues similar to immature kidneys from simple suspensions of fully dissociated embryonic renal cells is possible in vitro, but glomeruli do not form in the avascular environment. Here, we constructed renal organoids from single-cell suspensions derived from E11.

MicroRNA-324-3p promotes renal fibrosis and is a target of ACE inhibition.

The contribution of microRNA (miRNA) to the pathogenesis of renal fibrosis is not well understood. Here, we investigated whether miRNA modulates the fibrotic process in Munich Wistar Fromter (MWF) rats, which develop spontaneous progressive nephropathy. We analyzed the expression profile of miRNA in microdissected glomeruli and found that miR-324-3p was the most upregulated.

Erythropoietin, but not the correction of anemia alone, protects from chronic kidney allograft injury.

Anemia can contribute to chronic allograft injury by limiting oxygen delivery to tissues, particularly in the tubulointerstitium. To determine mechanisms by which erythropoietin (EPO) prevents chronic allograft injury we utilized a rat model of full MHC-mismatched kidney transplantation (Wistar Furth donor and Lewis recipients) with removal of the native kidneys. EPO treatment entirely corrected post-transplant anemia.

Prolonged cold ischemia accelerates cellular and humoral chronic rejection in a rat model of kidney allotransplantation.

One of the leading causes of long-term kidney graft loss is chronic allograft injury (CAI), a pathological process triggered by alloantigen-dependent and alloantigen-independent factors. Alloantigen-independent factors, such as cold ischemia (CI) may amplify the recipient immune response against the graft. We investigated the impact of prolonged cold ischemia and the subsequent delayed graft function on CAI in a fully MHC-mismatched rat model of kidney allotransplantation.

Multipotent mesenchymal stromal cell therapy and risk of malignancies.

Cell therapy with Multipotent Mesenchymal Stromal Cells (MSC) holds enormous promise for the treatment of a large number of degenerative and immune/inflammatory diseases. Their multilineage differentiation potential, immunoprivilege and capacity of promoting recovery of damaged tissues coupled with anti-inflammatory and immunosuppressive properties are the focus of a multitude of clinical studies currently underway. The recognized clinical potential of MSC repairing/immunomodulatory effects now encompasses graft-versus-host disease, hematologic malignancies, cardiovascular diseases, neurologic and inherited diseases, autoimmune diseases, organ transplantation, refractory wounds, and bone/cartilage defects among others.

Human amniotic fluid stem cell preconditioning improves their regenerative potential.

Human amniotic fluid stem (hAFS) cells, a novel class of broadly multipotent stem cells that share characteristics of both embryonic and adult stem cells, have been regarded as promising candidate for cell therapy. Taking advantage by the well-established murine model of acute kidney injury (AKI), we studied the proregenerative effect of hAFS cells in immunodeficient mice injected with the nephrotoxic drug cisplatin. Infusion of hAFS cells in cisplatin mice improved renal function and limited tubular damage, although not to control level, and prolonged animal survival.

Is the SHRSP [corrected] strain a suitable model of spontaneous CADASIL?

A number of features of the pathology occurring in spontaneously hypertensive stroke prone rats (SHRSPs), such as MRI brain signal abnormalities, the presence of high protein content in cerebrospinal fluid and vessel wall thickening, seem to indicate that this strain is a suitable model for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). To explore this hypothesis, we sought the human diagnostic hallmarks of the disease [the accumulation of granular osmiophilic material (GOM) deposits in vessel walls and NOTCH3 gene mutations] in SHRSPs. Male SHRSPs fed a permissive diet were sacrificed 3 days after the first MRI visualisation of brain abnormalities.