Podocyte injury and its consequences

Podocytes maintain the glomerular filtration barrier, and the stability of this barrier depends on their highly differentiated postmitotic phenotype, which also defines the particular vulnerability of the glomerulus. Recent podocyte biology and gene disruption studies in vivo indicate a causal relationship between abnormalities of single podocyte molecules and proteinuria and glomerulosclerosis. Podocytes live under various stresses and pathological stimuli. They adapt to maintain homeostasis, but excessive stress leads to maladaptation with complex biological changes including loss of integrity and dysregulation of cellular metabolism. Podocyte injury causes proteinuria and detachment from the glomerular basement membrane. In addition to “sick” podocytes and their detachment, our understanding of glomerular responses following podocyte loss needs to address the pathways from podocyte injury to sclerosis. Studies have found a variety of glomerular responses to podocyte dysfunction in vivo, such as disruption of podocyte-endothelial cross talk and activation of podocyte–parietal cell interactions, all of which help us to understand the complex scenario of podocyte injury and its consequences. This review focuses on the cellular aspects of podocyte dysfunction and the adaptive or maladaptive glomerular responses to podocyte injury that lead to its major consequence, glomerulosclerosis. Podocytes maintain the glomerular filtration barrier, and the stability of this barrier depends on their highly differentiated postmitotic phenotype, which also defines the particular vulnerability of the glomerulus. Recent podocyte biology and gene disruption studies in vivo indicate a causal relationship between abnormalities of single podocyte molecules and proteinuria and glomerulosclerosis. Podocytes live under various stresses and pathological stimuli. They adapt to maintain homeostasis, but excessive stress leads to maladaptation with complex biological changes including loss of integrity and dysregulation of cellular metabolism. Podocyte injury causes proteinuria and detachment from the glomerular basement membrane. In addition to “sick” podocytes and their detachment, our understanding of glomerular responses following podocyte loss needs to address the pathways from podocyte injury to sclerosis. Studies have found a variety of glomerular responses to podocyte dysfunction in vivo, such as disruption of podocyte-endothelial cross talk and activation of podocyte–parietal cell interactions, all of which help us to understand the complex scenario of podocyte injury and its consequences. This review focuses on the cellular aspects of podocyte dysfunction and the adaptive or maladaptive glomerular responses to podocyte injury that lead to its major consequence, glomerulosclerosis. Cells normally maintain homeostasis under health. When they encounter physiological stresses or pathological stimuli, they adapt to preserve function.1Frey N. Olson E.N. Cardiac hypertrophy: the good, the bad, and the ugly.Annu Rev Physiol. 2003; 65: 45-79Crossref PubMed Scopus (794) Google Scholar Podocytes maintain the glomerular filtration barrier by synthesis of glomerular basement membrane (GBM) components,2Pavenstadt H. Kriz W. Kretzler M. Cell biology of the glomerular podocyte.Physiol Rev. 2003; 83: 253-307Crossref PubMed Google Scholar formation of the slit membrane,3Saleem M.A. O'Hare M.J. Reiser J. et al.A conditionally immortalized human podocyte cell line demonstrating nephrin and podocin expression.J Am Soc Nephrol. 2002; 13: 630-638Crossref PubMed Google Scholar and interactions securing endothelial cell viability,4Scott R.P. Quaggin S.E. Review series: the cell biology of renal filtration.J Cell Biol. 2015; 209: 199-210Crossref PubMed Scopus (12) Google Scholar all of which may be affected under stress. The localization of podocytes, which enables their function in filtration, also puts these cells under stress. Transcapillary pressure is a prerequisite for filtration but becomes a stress on podocytes when it rises beyond physiological levels. Glomerular hypertension/hyperfiltration leads to expansion of the subpodocyte space that lifts the podocyte cell body up.5Neal C.R. Muston P.R. Njegovan D. et al.Glomerular filtration into the subpodocyte space is highly restricted under physiological perfusion conditions.Am J Physiol Renal Physiol. 2007; 293: F1787-F1798Crossref PubMed Scopus (30) Google Scholar Capillary growth during glomerular hypertrophy elongates podocyte processes.6Nagata M. Kriz W. Glomerular damage after uninephrectomy in young rats. II. Mechanical stress on podocyte as a pathway to sclerosis.Kidney Int. 1992; 42: 148-160Abstract Full Text PDF PubMed Google Scholar These mechanical stresses on podocytes were noted earlier by ultrastructural study in remnant kidney models6Nagata M. Kriz W. Glomerular damage after uninephrectomy in young rats. II. Mechanical stress on podocyte as a pathway to sclerosis.Kidney Int. 1992; 42: 148-160Abstract Full Text PDF PubMed Google Scholar and were nicely illustrated by a recent serial multiphoton microscopy study.7Peti-Peterdi J. Kidokoro K. Riquier-Brison A. Novel in vivo techniques to visualize kidney anatomy and function.Kidney Int. 2015; 88: 44-51Abstract Full Text Full Text PDF PubMed Google Scholar Although podocytes may adapt to such stresses by cell hypertrophy, excessive stress may cause cytoskeletal dysregulation and promote podocyte intrinsic stress as described herein. Reactive oxygen species (ROS) are oxygen-derived free radicals, which are unstable chemicals and attack cellular proteins and lipids, leading to dysfunction.8Kummer V. Abbas A.K. Aster J.C. Robbins Basic Pathology. Elsevier Saunders, Philadelphia, PA2013Google Scholar Podocytes synthesize ROS as a general response to injurious stimuli such as ischemia-reperfusion, chemical/toxic substances from the primary urine, and inflammatory cells.9Chen S. Meng X.F. Zhang C. Role of NADPH oxidase-mediated reactive oxygen species in podocyte injury.Biomed Res Int. 2013; 2013: 839761PubMed Google Scholar Typical ROS-driven podocyte stress is seen in puromycin aminonucleoside (PAN) nephrosis, a model of minimal-change disease.10Diamond J.R. Bonventre J.V. Karnovsky M.J. A role for oxygen free radicals in aminonucleoside nephrosis.Kidney Int. 1986; 29: 478-483Abstract Full Text PDF PubMed Google Scholar Receptor-mediated ROS generation is known in podocytes. Aldosterone, a ligand of mineralocorticoid receptor, induces ROS in podocytes via Rac1 activation.11Shibata S. Nagase M. Yoshida S. et al.Podocyte as the target for aldosterone: roles of oxidative stress and Sgk1.Hypertension. 2007; 49: 355-364Crossref PubMed Scopus (202) Google Scholar, 12Shibata S. Nagase M. Yoshida S. et al.Modification of mineralocorticoid receptor function by Rac1 GTPase: implication in proteinuric kidney disease.Nat Med. 2008; 14: 1370-1376Crossref PubMed Scopus (216) Google Scholar, 13Liu Y. Hitomi H. Diah S. et al.Roles of Na+/H+ exchanger type 1 and intracellular pH in angiotensin II-induced reactive oxygen species generation and podocyte apoptosis.J Pharmacol Sci. 2013; 122: 176-183Crossref Google Scholar Angiotensin II also activates the Rac1–induced nicotinamide adenine dinucleotide phosphate oxidase-ROS cascade via type I angiotensin II receptor and impairs podocyte function, particularly by dysregulation of cytoskeletal organization.13Liu Y. Hitomi H. Diah S. et al.Roles of Na+/H+ exchanger type 1 and intracellular pH in angiotensin II-induced reactive oxygen species generation and podocyte apoptosis.J Pharmacol Sci. 2013; 122: 176-183Crossref Google Scholar Aldosterone/angiotensin II–Rac1-mediated podocyte oxidative stress is seen in various kidney diseases, including hypertensive nephropathy and diabetic nephropathy.14Nagase M. Fujita T. Role of Rac1-mineralocorticoid-receptor signaling in renal and cardiac disease.Nat Rev Nephrol. 2013; 9: 86-98Crossref PubMed Scopus (11) Google Scholar Another intrinsic stress is endoplasmic reticulum stress. The endoplasmic reticulum regulates protein homeostasis via the unfolded protein response pathway.15Inagi R. Nangaku M. Onogi H. et al.Involvement of endoplasmic reticulum (ER) stress in podocyte injury induced by excessive protein accumulation.Kidney Int. 2005; 68: 2639-2650Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar Podocytes internalize plasma protein by free fatty acid receptor-mediated micropinocytosis, and protein accumulation in the endoplasmic reticulum results in dysregulation of the unfolded protein response pathway, causing mitochondrial damage.16Inagi R. Ishimoto Y. Nangaku M. Proteostasis in endoplasmic reticulum—new mechanisms in kidney disease.Nat Rev Nephrol. 2014; 10: 369-378Crossref PubMed Scopus (14) Google Scholar Endoplasmic reticulum stress is induced by ROS, and mitochondrial damage causes ROS generation, suggesting a vicious cycle of oxidative stress in podocytes. Podocytes express various cytokine receptors, such as the transforming growth factor β receptor and chemokine receptors.17Lee E.Y. Chung C.H. Khoury C.C. et al.The monocyte chemoattractant protein-1/CCR2 loop, inducible by TGF-beta, increases podocyte motility and albumin permeability.Am J Physiol Renal Physiol. 2009; 297: F85-F94Crossref PubMed Scopus (46) Google Scholar In glomerulonephritis, inflammatory cells and glomerular intrinsic cells synthesize various cytokines in situ. CC chemokine receptor 2, a receptor for monocyte chemotactic protein 1, potentially activates intracellular signaling pathways that modulate podocyte function.18Tarabra E. Giunti S. Barutta F. et al.Effect of the monocyte chemoattractant protein-1/CC chemokine receptor 2 system on nephrin expression in streptozotocin-treated mice and human cultured podocytes.Diabetes. 2009; 58: 2109-2118Crossref PubMed Scopus (63) Google Scholar In addition, tumor necrosis factor receptor, receptor activator of NF-kappa-B ligand (RANKL), its receptor (RANK), and NF-kappa-B are expressed in podocytes, suggesting cytokine mediated intracellular stress in podocytes in glomerulonephritis.19Bruggeman L.A. Drawz P.E. Kahoud N. et al.TNFR2 interposes the proliferative and NF-κB-mediated inflammatory response by podocytes to TNF-α.Lab Invest. 2011; 91: 413-425Crossref PubMed Scopus (32) Google Scholar Complement also damages podocytes. Sublytic C5b-9 activates a variety of downstream pathways in podocytes, including protein kinases, lipid metabolism, cytokine production, ROS generation, growth factor signal transduction, endoplasmic reticulum stress, and the ubiquitin-proteasome system.20Nangaku M. Shankland S.J. Couser W.G. Cellular response to injury in membranous nephropathy.J Am Soc Nephrol. 2005; 16: 1195-1204Crossref PubMed Scopus (100) Google Scholar In addition, complement targets podocyte in hemolytic uremic syndrome.21Locatelli M. Buelli S. Pezzotta A. et al.Shiga toxin promotes podocyte injury in experimental hemolytic uremic syndrome via activation of the alternative pathway of complement.J Am Soc Nephrol. 2014; 25: 1786-1798Crossref PubMed Scopus (7) Google Scholar Those actions impact the integrity of the cytoskeleton and slit diaphragm proteins and occasionally promote cell detachment via integrin-linked kinase–dependent podocyte dysfunction.21Locatelli M. Buelli S. Pezzotta A. et al.Shiga toxin promotes podocyte injury in experimental hemolytic uremic syndrome via activation of the alternative pathway of complement.J Am Soc Nephrol. 2014; 25: 1786-1798Crossref PubMed Scopus (7) Google Scholar Not all stress causes cell injury. Podocytes seem to have an intrinsic system for withstanding stresses, and they may undergo injury when the stresses exceed their compensatory capacity. The term “podocyte injury” is ambiguous because it has been characterized by electron microscopy–based morphology, such as foot process effacement (FPE), cytoplasmic vacuoles, blebs, and irregularities in organelles and the cell membrane.22Grishman E. Churg J. Focal glomerular sclerosis in nephrotic patients: an electron microscopic study of glomerular podocytes.Kidney Int. 1975; 7: 111-122Abstract Full Text PDF PubMed Google Scholar, 23Kriz W. Gretz N. Lemley K.V. Progression of glomerular diseases: is the podocyte the culprit?.Kidney Int. 1998; 54: 687-697Abstract Full Text Full Text PDF PubMed Scopus (399) Google Scholar, 24Kriz W. Shirato I. Nagata M. et al.The podocyte's response to stress: the enigma of foot process effacement.Am J Physiol Renal Physiol. 2013; 304: F333-F347Crossref PubMed Scopus (65) Google Scholar Although these changes reflect impaired cell metabolism, as is commonly seen in injured cells, a molecular signature to define podocyte injury is needed. In support of this possibility, altered expression of podocyte molecules in podocyte injury models and proteinuria and sclerosis in mice with podocyte-specific gene deletions make us understand podocyte injury as molecular dysfunction.25Fogo A.B. Causes and pathogenesis of focal segmental glomerulosclerosis.Nat Rev Nephrol. 2015; 11: 76-87Crossref Scopus (1) Google Scholar, 26Otaki Y. Miyauchi N. 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Adaptation and distortion of podocytes in rat remnant kidney.Pathol Int. 1998; 48: 368-383Crossref PubMed Google Scholar Under high glucose in vitro, podocytes up-regulate vascular endothelial growth factor (VEGF) and undergo cell hypertrophy.29Hoshi S. Shu Y. Yoshida F. et al.Podocyte injury promotes progressive nephropathy in Zucker diabetic fatty rats.Lab Invest. 2002; 82: 25-35Crossref PubMed Google Scholar Podocytes synthesize antioxidant to protect against ROS. Sirtuin1, is a nicotinamide adenine dinucleotide–positive (NAD+)–dependent deacetylase that protects against ROS.30Nihalani D. Susztak K. Sirt1-Claudin-1 crosstalk regulates renal function.Nat Med. 2013; 19: 1371-1372Crossref Scopus (3) Google Scholar Podocyte Sirt1 deficiency worsened anti-GBM nephritis, and Sirt1 activation in podocytes ameliorated H2O2-induced podocyte injury by deacetylation of the actin-binding protein cortactin.31Motonishi S. Nangaku M. 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Podocyte foot processes are maintained by the cytoskeletal actin system, and abnormalities of the podocyte actin system lead to FPE. As is typically seen in minimal change disease, FPE is closely associated with proteinuria. For this reason, studies have addressed the specific mechanisms of proteinuria by modulating the interaction of the actin cytoskeleton and slit molecules in vitro and by using podocyte-specific gene disruption models.27Mundel P. Shankland S.J. Podocyte biology and response to injury.J Am Soc Nephrol. 2002; 13: 3005-3015Crossref PubMed Scopus (428) Google Scholar, 50Yanagida-Asanuma E. Asanuma K. Kim K. et al.Synaptopodin protects against proteinuria by disrupting Cdc42:IRSp53:Mena signaling complexes in kidney podocytes.Am J Pathol. 2007; 171: 415-427Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 51Blattner S.M. Hodgin J.B. 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A potential role for mechanical forces in the detachment of podocytes and the progression of CKD.J Am Soc Nephrol. 2015; 26: 258-269Crossref PubMed Scopus (0) Google Scholar As podocytes are the main producers of GBM, their dysfunction may cause proteinuria via GBM alterations.24Kriz W. Shirato I. Nagata M. et al.The podocyte's response to stress: the enigma of foot process effacement.Am J Physiol Renal Physiol. 2013; 304: F333-F347Crossref PubMed Scopus (65) Google Scholar WT1 is a critical transcription factor for podocyte differentiation and function. The WT1+/R394W mouse with heterozygous for a hot-spot missense mutation, and Denys-Drash syndrome caused by WT1 mutations show GBM abnormalities.63Gao F. Maiti S. Sun G. et al.The Wt1+/R394W mouse displays glomerulosclerosis and early-onset renal failure characteristic of human Denys-Drash syndrome.Mol Cell Biol. 2004; 24: 9899-9910Crossref Scopus (40) Google Scholar, 64Ito S. Hataya H. Ikeda M. et al.Alport syndrome-like basement membrane changes in Frasier syndrome: an electron microscopy study.Am J Kidney Dis. 2003; 41: 1110-1115Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar However, whether GBM irregularities often seen in human biopsy samples are caused by podocyte injury in general is unknown. Endothelial cells are also the component of the filtration barrier, and podocytes help to maintain endothelial cell functions.65Garsen M. Rops A.L. Rabelink T.J. et al.The role of heparanase and the endothelial glycocalyx in the development of proteinuria.Nephrol Dial Transplant. 2014; 29: 49-55Crossref PubMed Scopus (20) Google Scholar However, the possible