Podocyte loss is the fundamental basis of glomerulosclerosis. Focal segmental glomerulosclerosis (FSGS) is a progressive glomerular disease, and its glomerular features are a prototype of podocyte loss-driven glomerulosclerosis. The glomerular pathology of FSGS is characterized by a focal and segmental location of the sclerotic lesions in human FSGS; segmental sclerosis often shows simultaneous intra- and extra-capillary changes, including parietal cell migration, capillary collapse, hyaline deposition, and intra-capillary thrombi and occasional hypercellularity. This suggests that local cellular events, initiated by podocyte loss, are the basis of the segmental lesions in FSGS. Using podocyte-specific injury by toxin administration, a series of recent works has identified the cellular basis of the glomerular response to podocyte loss. This review discusses the molecular pathway of the local response to podocyte loss and its progression to sclerosis. Recent results suggest that segmental sclerosis is a physiological tissue response aimed at halting protein leakage from a disrupted filtration barrier.
This is a preview of subscription content, log in to check access.
The author celebrates the 80th birthday of Professor W. Kriz and congratulates him for his life work of unique and thought-provoking morphology studies interpreting kidney function and diseases. The content of the present manuscript is based on the recent works from our laboratory supported by the Grants-in-Aid for Scientific Research program of the Japan Society for the Promotion of Science (KAKEN; research project no. 17 K09685 and 26461210) and the Progressive Renal Disease Research program of the Ministry of Health, Labor. The author thanks Professor W. Kriz for understanding and continuous encouragement for my podocyte research since 1989 started at Heidelberg.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Churg J, Habib R, White RH (1970) Pathology of the nephrotic syndrome in children: a report for the international study of kidney disease in children. Lancet 760:1299–1302CrossRefPubMedGoogle Scholar
Churg, Sorbin (1982) Focal segmental glomerulosclerosis. In: Renal disease. Classification and atlas of glomerular diseases, IGAKU-SHOIN, Tokyo/New York, pp 37–39Google Scholar
D'Agati VD, Fogo AB, Bruijn JA et al (2004) Pathologic classification of focal segmental glomerulosclerosis: a working proposal. Am J Kidney Dis 43:368–382CrossRefPubMedGoogle Scholar
Dijkman H, Smeets B, van der Laak J et al (2005) The parietal epithelial cell is crucially involved in human idiopathic focal segmental glomerulosclerosis. Kidney Int 68:1562–1572CrossRefPubMedGoogle Scholar
Fries JW, Sandstrom DJ, Meyer TW et al (1989) Glomerular hypertrophy and epithelial cell injury modulate progressive glomerulosclerosis in the rat. Lab Investig 60(2):205–218PubMedGoogle Scholar
Grishman E, Churg J (1975) Focal glomerular sclerosis in nephrotic patients: an electron microscopic study of glomerular podocytes. Kidney Int 7:111–122CrossRefPubMedGoogle Scholar
Hara S, Kobayashi N, Sakamoto K et al (2015) Podocyte injury-driven lipid peroxidation accelerates the infiltration of glomerular foam cells in focal segmental glomerulosclerosis. Am J Pathol 185:2118–2131CrossRefPubMedPubMedCentralGoogle Scholar
Hoshi S, Shu Y, Yoshida F et al (2002) Podocyte injury promotes progressive nephropathy in Zucker diabetic fatty rats. Lab Investig 82:25–35CrossRefPubMedGoogle Scholar
Kobayashi N, Ueno T, Ohashi K et al (2015) Podocyte injury-driven intracapillary plasminogen activator inhibitor type 1 accelerates podocyte loss via uPAR-mediated β1-integrin endocytosis. Am J Physiol Renal Physiol 308:F614–F626CrossRefPubMedPubMedCentralGoogle Scholar
Kriz W, Gretz N, Lemley KV (1998) Progression of glomerular diseases: is the podocyte the culprit? Kidney Int 54:687–697CrossRefPubMedGoogle Scholar
Kriz W, Hartmann I, Hosser H et al (2001) Tracer studies in the rat demonstrate misdirected filtration and peritubular filtrate spreading in nephrons with segmental glomerulosclerosis. J Am Soc Nephrol 12:496–506PubMedGoogle Scholar
Kriz W, Hosser H, Hähnel B et al (1998) Development of vascular pole-associated glomerulosclerosis in the Fawn-hooded rat. J Am Soc Nephrol 9:381–396PubMedGoogle Scholar
Kriz W, Hähnel B, Hosser H et al (2014) Structural analysis of how podocytes detach from the glomerular basement membrane under hypertrophic stress. Front Endocrinol (Lausanne) 5:207Google Scholar
Kriz W, Shirato I, Nagata M et al (2013) The podocyte’s response to stress: the enigma of foot process effacement. Am J Physiol Renal Physiol 304:F333–F347CrossRefPubMedGoogle Scholar
Kriz W, Lemley KV (2015) A potential role for mechanical forces in the detachment of podocytes and the progression of CKD. J Am Soc Nephrol 26:258–269CrossRefPubMedGoogle Scholar
Miyazaki K, Isbel NM, Lan HY et al (1997) Up-regulation of macrophage colony-stimulating factor (M-CSF) and migration inhibitory factor (MIF) expression and monocyte recruitment during lipid-induced glomerular injury in the exogenous hypercholesterolaemic (ExHC) rat. Clin Exp Immunol 108:318–323CrossRefPubMedPubMedCentralGoogle Scholar
Nagata M, Hattori M, Hamano Y et al (1998) Origin and phenotypic features of hyperplastic epithelial cells in collapsing glomerulopathy. Am J Kidney Dis 32:962–969CrossRefPubMedGoogle Scholar
Nagata M, Horita S, Shu Y (2000) Phenotypic characteristics and cyclin-dependent kinase inhibitors repression in hyperplastic epithelial pathology in idiopathic focal segmental glomerulosclerosis. Lab Investig 80:869–880CrossRefPubMedGoogle Scholar
Nagata M, Kriz W (1992) Glomerular damage after uninephrectomy in young rats. II. Mechanical stress on podocyte as a pathway to sclerosis. Kidney Int 42:148–161CrossRefPubMedGoogle Scholar
Okamoto T, Sasaki S, Yamazaki T et al (2013) Prevalence of CD44-positive glomerular parietal epithelial cells reflects podocyte injury in adriamycin nephropathy. Nephron Exp Nephro 124:11–18CrossRefGoogle Scholar
Orian-Rousseau V (2015) CD44 acts as a signaling platform controlling tumor progression and metastasis. Front Immunol 8;6:154Google Scholar
Shih NY, Li J, Karpitskii V, Nguyen A (1999) Congenital nephrotic syndrome in mice lacking CD2-associated protein. Science 286:312–315CrossRefPubMedGoogle Scholar
Smeets B, Stucker F, Wetzels J et al (2014) Detection of activated parietal epithelial cells on the glomerular tuft distinguishes early focal segmental glomerulosclerosis from minimal change disease. Am J Pathol 184:3239–3248CrossRefPubMedGoogle Scholar
Su H, Chen S, He FF, Wang YM et al (2015) New insights into glomerular parietal epithelial cell activation and its signaling pathways in glomerular diseases. Biomed Res Int 318935Google Scholar
Suzuki T, Matsusaka T, Nakayama M et al (2009) Genetic podocyte lineage reveals progressive podocytopenia with parietal cell hyperplasia in a murine model of focal segmental glomerulosclerosis. Am J Pathol 174:1675–1682CrossRefPubMedPubMedCentralGoogle Scholar
Ueno T, Kobayashi N, Nakayama M et al (2013) Aberrant Notch1-dependent effects on glomerular parietal epithelial cells promotes collapsing focal segmental glomerulosclerosis with progressive podocyte loss. Kidney Int 83:1065–1075CrossRefPubMedGoogle Scholar
Yoshioka T, Shiraga H, Yoshida Y et al (1988) “Intact nephrons” as the primary origin of proteinuria in chronic renal disease. Study in the rat model of subtotal nephrectomy. J Clin Invest 82:1614–1623CrossRefPubMedPubMedCentralGoogle Scholar