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Wei C.,University of Miami | El Hindi S.,University of Miami | Li J.,University of Miami | Fornoni A.,University of Miami | And 24 more authors.
Nature Medicine | Year: 2011

Focal segmental glomerulosclerosis (FSGS) is a cause of proteinuric kidney disease, compromising both native and transplanted kidneys. Treatment is limited because of a complex pathogenesis, including unknown serum factors. Here we report that serum soluble urokinase receptor (suPAR) is elevated in two-thirds of subjects with primary FSGS, but not in people with other glomerular diseases. We further find that a higher concentration of suPAR before transplantation underlies an increased risk for recurrence of FSGS after transplantation. Using three mouse models, we explore the effects of suPAR on kidney function and morphology. We show that circulating suPAR activates podocyte β3 integrin in both native and grafted kidneys, causing foot process effacement, proteinuria and FSGS-like glomerulopathy. Our findings suggest that the renal disease only develops when suPAR sufficiently activates podocyte β3 integrin. Thus, the disease can be abrogated by lowering serum suPAR concentrations through plasmapheresis, or by interfering with the suPAR-2 3 integrin interaction through antibodies and small molecules targeting either uPAR or β3 integrin. Our study identifies serum suPAR as a circulating factor that may cause FSGS. © 2011 Nature America, Inc. All rights reserved.


Brooks C.,Georgia Regents University | Brooks C.,Harvard University | Cho S.-G.,Georgia Regents University | Wang C.-Y.,Georgia Regents University | And 3 more authors.
American Journal of Physiology - Cell Physiology | Year: 2011

Recent studies have shown mitochondrial fragmentation during cell stress and have suggested a role for the morphological change in mitochondrial injury and ensuing apoptosis. However, the underlying mechanism remains elusive. Here we demonstrate that mitochondrial fragmentation facilitates Bax insertion and activation in mitochondria, resulting in the release of apoptogenic factors. In HeLa cells, over-expression of mitofusins attenuated mitochondrial fragmentation during cisplatin- and azide-induced cell injury, which was accompanied by less apoptosis and less cytochrome c release from mitochondria. Similar effects were shown by inhibiting the mitochondrial fission protein Drp1 with a dominant negative mutant (dn-Drp1). Mitofusins and dn-Drp1 did not seem to significantly affect Bax translocation/accumulation to mitochondria; however, they blocked Bax insertion and activation in mitochondrial membrane. Consistently, in rat kidney proximal tubular cells, small interfering RNA knockdown of Drp1 prevented mitochondrial fragmentation during azide-induced ATP depletion, which was accompanied by less Bax activation, insertion, and oligomerization in mitochondria. These cells released less cytochrome c and AIF from mitochondria and showed significantly lower apoptosis. Finally, mitofusin-null mouse embryonic fibroblasts (MEF) had fragmented mitochondria. These MEFs were more sensitive to cisplatin-induced Bax activation, release of cytochrome c, and apoptosis. Together, this study provides further support for a role of mitochondrial fragmentation in mitochondrial injury and apoptosis. Mechanistically, mitochondrial fragmentation may sensitize the cells to Bax insertion and activation in mitochondria, facilitating the release of apoptogenic factors and consequent apoptosis.


Barutta F.,University of Turin | Grimaldi S.,University of Turin | Franco I.,University of Turin | Bellini S.,University of Turin | And 9 more authors.
Kidney International | Year: 2014

A functionally active endocannabinoid system is present within the kidney. The cannabinoid receptor type 2 (CB2) is expressed by both inflammatory cells and podocytes, and its activation has beneficial effects in experimental diabetic nephropathy. To further explore the role of CB2 in diabetic nephropathy, we studied renal functional and structural abnormalities in streptozotocin-induced diabetic CB2 knockout mice. In diabetic mice, deletion of the CB2 receptor albuminuria, the downregulation of podocin and nephrin, mesangial expansion, overexpression of extracellular matrix components, monocyte infiltration, and reduced renal function were all exacerbated. To investigate the relative contributions of podocytes and monocytes to the phenotype of diabetic knockout mice, bone marrow transplantation experiments were performed. The lack of CB2 on bone marrow-derived cells was shown to be important in driving the enhanced glomerular monocyte accrual found in diabetic knockout mice. Absence of CB2 on resident glomerular cells had a major role in worsening diabetic nephropathy, both functional and structural abnormalities, likely by enhanced MCP-1 and CB1 signaling. Studies in cultured podocytes demonstrated that CB2 expression is not altered by a high glucose milieu but is downregulated by mechanical stretch, mimicking glomerular capillary hypertension. Thus, CB2 deletion worsens diabetic nephropathy, independent of bone marrow-derived cells. © 2014 International Society of Nephrology.


Barutta F.,University of Turin | Piscitelli F.,CNR Institute of Neuroscience | Pinach S.,University of Turin | Bruno G.,University of Turin | And 6 more authors.
Diabetes | Year: 2011

OBJECTIVE - The cannabinoid receptor type 2 (CB2) has protective effects in chronic degenerative diseases. Our aim was to assess the potential relevance of the CB2 receptor in both human and experimental diabetic nephropathy (DN). RESEARCH DESIGN AND METHODS - CB2 expression was studied in kidney biopsies from patients with advanced DN, in early experimental diabetes, and in cultured podocytes. Levels of endocannabinoids and related enzymes were measured in the renal cortex from diabetic mice. To assess the functional role of CB2, streptozotocin-induced diabetic mice were treated for 14 weeks with AM1241, a selective CB2 agonist. In these animals, we studied albuminuria, renal function, expression of podocyte proteins (nephrin and zonula occludens-1), and markers of both fibrosis (fibronectin and transforming growth factor-b1) and inflammation (monocyte chemoattractant protein-1 [MCP-1], CC chemokine receptor 2 [CCR2], and monocyte markers). CB2 signaling was assessed in cultured podocytes. RESULTS - Podocytes express the CB2 receptor both in vitro and in vivo. CB2 was downregulated in kidney biopsies from patients with advanced DN, and renal levels of the CB2 ligand 2-arachidonoylglycerol were reduced in diabetic mice, suggesting impaired CB2 regulation. In experimental diabetes, AM1241 ameliorated albuminuria, podocyte protein downregulation, and glomerular monocyte infiltration, without affecting early markers of fibrosis. In addition, AM1241 reduced CCR2 expression in both renal cortex and cultured podocytes, suggesting that CB2 activation may interfere with the deleterious effects of MCP-1 signaling. CONCLUSIONS - The CB2 receptor is expressed by podocytes, and in experimental diabetes, CB2 activation ameliorates both albuminuria and podocyte protein loss, suggesting a protective effect of signaling through CB2 in DN. © 2011 by the American Diabetes Association.


Peng J.,University of Georgia | Peng J.,Wuhan University | Dong Z.,University of Georgia | Dong Z.,Renal Research Laboratory
Kidney International | Year: 2012

Using conditional knockout models, Zhou et al. firmly establish a renoprotective role of Β-catenin in acute kidney injury. Although Β-catenin is protective at the injury phase, whether it helps kidney repair remains in question. In a renal cell scratch model, Β-catenin suppresses wound healing. Moreover, continuous activation of Β-catenin may lead to renal fibrosis. Further investigation should elucidate the distinct roles played by Β-catenin and related signaling in kidney injury, repair, and fibrosis. © 2012 International Society of Nephrology.


Peng J.,University of Georgia | Peng J.,Wuhan University | Ramesh G.,University of Georgia | Sun L.,Central South University | And 2 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2012

Wound and subsequent healing are frequently associated with hypoxia. Although hypoxia induces angiogenesis for tissue remodeling during wound healing, it may also affect the healing response of parenchymal cells. Whether and how wound healing is affected by hypoxia in kidney cells and tissues is currently unknown. Here, we used scratch-wound healing and transwell migration models to examine the effect of hypoxia in cultured renal proximal tubular cells (RPTC). Wound healing and migration were significantly slower in hypoxic (1% oxygen) RPTC than normoxic (21% oxygen) cells. Hypoxia-inducible factor-1α(HIF-1α) was induced during scratch-wound healing in normoxia, and the induction was more evident in hypoxia. Nevertheless, HIF-1α-null and wild-type cells healed similarly after scratch wounding. Moreover, activation of HIF-1α with dimethyloxalylglycine in normoxic cells did not suppress wound healing, negating a major role of HIF-1α in wound healing in this model. Scratch-wound healing was also associated with glycogen synthase kinase 3β (GSK3β)/β-catenin signaling, which was further enhanced by hypoxia. Pharmacological inhibition of GSK3β resulted in β-catenin expression, accompanied by the suppression of wound healing and transwell cell migration. Ectopic expression of β-catenin in normoxic cells could also suppress wound healing, mimicking the effect of hypoxia. Conversely, inhibition of β-catenin via dominant negative mutants or short hairpin RNA improved wound healing and transwell migration in hypoxic cells. The results suggest that GSK3β/β- catenin signaling may contribute to defective wound healing in hypoxic renal cells and tissues. Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics.


Haas M.,Cedars Sinai Medical Center | Rastaldi M.P.,Renal Research Laboratory | Fervenza F.C.,Rochester College
Kidney International | Year: 2014

The value of classification systems applied to the examination of renal biopsies is based on several factors: first, on the ability to provide efficient communication between pathologists and between pathologists and clinicians; second, on the possibility to implement diagnostic information with prognostic indication. Even more important, the practical value of a classification is proved by the ability of providing elements that guide therapeutic decisions and can be used in the follow-up of the patient. With these aims, new histologic classification systems have been proposed in the last decade for lupus nephritis and IgA nephropathy under the leadership of the Renal Pathology Society and the International Society of Nephrology. These classifications have gained a significant level of worldwide acceptance and have been the subject of multiple single-center and multicenter validation studies, which have underpinned their clinical benefits and limitations and served to highlight remaining questions and difficulties of interpretation of the biopsy sample. More recently, a classification system has also been proposed for ANCA-associated crescentic glomerulonephritis (ANCA-GN), although the validation process for this is still in an early stage. In this review, we examine in some detail the ISN/RPS classification for lupus nephritis and the Oxford classification for IgA nephropathy, with emphasis on clinicopathologic correlations, their value for and evolving impact on clinical studies and clinical practice, and their significant limitations in this regard as exposed by validation studies. We also suggest possible ways by which these classifications might be modified to make them more applicable to clinical practice. Finally, we more briefly discuss the newly proposed classification for ANCA-GN. © 2013 International Society of Nephrology.


Armelloni S.,Renal Research Laboratory | Li M.,Renal Research Laboratory | Messa P.,Renal Research Laboratory | Rastaldi M.P.,Renal Research Laboratory
International Journal of Biochemistry and Cell Biology | Year: 2012

In the renal glomerulus, podocytes envelop the external side of the capillary basement membrane with their intertwining ramifications, and ensure elimination of metabolic waste within the urine, while proteins and important blood components are retained into the circulation. To preserve the integrity of the glomerular filter, which is constantly exposed to a high variety of stimuli, podocytes need to communicate by rapid and precise signaling, likely similar to that used by neuronal cells. In the last years, we and others have shown that podocytes are indeed molecularly equipped for communicating in a synaptic-like way, where glutamate and its receptors seem to have a pivotal role, because altering glutamatergic communication leads to podocyte damage and increased filter permeability. Major components of glutamatergic signaling are organized at foot process junctions by adhesion molecules, chiefly by nephrin, and are connected to the actin cytoskeleton, that governs the health of podocytes. Further advances in understanding podocyte physiological behavior and signaling properties have the potential to improve the knowledge of podocyte diseases, first among them idiopathic focal segmental glomerulosclerosis that still needs more precise molecular-based diagnosis and targeted treatment. © 2012 Elsevier Ltd. All rights reserved.


Mondini A.,Renal Research Laboratory | Messa P.,Dialysis and Renal Transplant | Rastaldi M.P.,Renal Research Laboratory
Current Opinion in Nephrology and Hypertension | Year: 2014

PURPOSE OF REVIEW: Segmental glomerulosclerosis is the end-point of a series of processes with have podocyte damage as a common denominator. This review summarizes the important advances that have been made in the past 2 years leading to the comprehension of several molecular mechanisms of regulation of podocyte physiology and pathology. RECENT FINDINGS: From recent studies it has become clear that the dynamic cytoskeleton of podocyte foot processes has to be highly regulated to maintain cell shape and function. The importance of intracellular calcium in this process has started to be revealed, together with the channels and the organelles appointed to calcium entry and buffering.Novel data highlight the centrality and the complexity of the mammalian target of rapamycin pathways, which are implicated in the regulation of autophagy. Similarities between podocytes and neuronal cells have been extended to the process of dynamin-regulated endocytosis, and further data in mice and humans provide support to the idea that podocytes can be directly targeted by old and new drugs. SUMMARY: Research is bringing numerous advances regarding the role of podocytes in the development of glomerulosclerosis, which can lead to novel and specific therapeutic approaches, as well as to a more rational use of drugs already in use. Consequently, renal biopsy becomes the indispensable instrument not only for diagnosis but also to precisely detect molecular therapeutic targets and guide personalized therapy. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Rastaldi M.P.,Renal Research Laboratory
Kidney International | Year: 2011

Besides its primary function in maintaining systemic calcium homeostasis, the calcium-sensing receptor (CaSR) is expressed by many cell types, with different, sometimes opposite, regulatory functions. Novel work from Oh and collaborators shows that activation of CaSR in podocytes has prosurvival effects and protects the cell from puromycin aminonucleoside damage. Given that the cellular consequences of CaSR activation are largely context-dependent, further studies will be required to elucidate its precise role in podocyte physiology and pathophysiology. © 2011 International Society of Nephrology.

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