Progression of glomerular diseases: Is the podocyte the culprit?
1998; Elsevier BV; Volume: 54; Issue: 3 Linguagem: Inglês
10.1046/j.1523-1755.1998.00044.x
ISSN1523-1755
AutoresWilhelm Kriz, Norbert Gretz, Kevin V. Lemley,
Tópico(s)Genetic and Kidney Cyst Diseases
ResumoProgression of glomerular diseases: Is the podocyte the culprit? The stereotyped development of the glomerular lesions in many animal models and human forms of progressive renal disease suggests that there are common mechanisms of disease progression. We propose the outline of such a mechanism based on following aspects: (1) The glomerulus is a complex structure, the stability of which depends on the cooperative function of the basement membrane, mesangial cells and podocytes, counteracting the distending forces originating from the high glomerular hydrostatic pressures. Failure of this system leads to quite uniform architectural lesions. (2) There is strong evidence that the podocyte is incapable of regenerative replication post-natally; when podocytes are lost for any reason they cannot be replaced by new cells. Loss of podocytes may therefore lead to areas of “bare” GBM, which represent potential starting points for irreversible glomerular injury. (3) Attachment of parietal epithelial cells to bare GBM invariably occurs when bare GBM coexists with architechtural lesions, leading to the formation of a tuft adhesion to Bowman's capsule, the first “committed” lesion progressing to segmental sclerosis. (4) Within an adhesion the tuft merges with the interstitium, allowing filtration from perfused capillaries inside the adhesion towards the interstitium. The relevance of such filtration is as yet unclear but may play a considerable role in progression to global sclerosis and interstitial fibrosis. Progression of glomerular diseases: Is the podocyte the culprit? The stereotyped development of the glomerular lesions in many animal models and human forms of progressive renal disease suggests that there are common mechanisms of disease progression. We propose the outline of such a mechanism based on following aspects: (1) The glomerulus is a complex structure, the stability of which depends on the cooperative function of the basement membrane, mesangial cells and podocytes, counteracting the distending forces originating from the high glomerular hydrostatic pressures. Failure of this system leads to quite uniform architectural lesions. (2) There is strong evidence that the podocyte is incapable of regenerative replication post-natally; when podocytes are lost for any reason they cannot be replaced by new cells. Loss of podocytes may therefore lead to areas of “bare” GBM, which represent potential starting points for irreversible glomerular injury. (3) Attachment of parietal epithelial cells to bare GBM invariably occurs when bare GBM coexists with architechtural lesions, leading to the formation of a tuft adhesion to Bowman's capsule, the first “committed” lesion progressing to segmental sclerosis. (4) Within an adhesion the tuft merges with the interstitium, allowing filtration from perfused capillaries inside the adhesion towards the interstitium. The relevance of such filtration is as yet unclear but may play a considerable role in progression to global sclerosis and interstitial fibrosis. The progression of chronic renal disease tends to follow a stereotypical course in many cases. Regardless of the nature of the initial insult, once a substantial portion of the renal tissue has been destroyed, there is a steady decline in the glomerular filtration rate with time associated with a progressive loss of viable nephrons. A common histologic finding in these cases is focal segmental glomerulosclerosis (FSGS) with tubulointerstitial fibrosis1.Ichikawa I. Fogo A. Focal segmental glomerulosclerosis.Pediatr Nephrol. 1996; 10: 374-391Crossref PubMed Scopus (99) Google Scholar, 2.Rennke H.G. Anderson S. Brenner B.M. 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As defined by Rennke, the glomerular lesion in FSGS consists of “global or segmental collapse of the capillaries with disappearance of the cellular elements and microvascular lumina, entrapment of foamy macrophages, cellular debris, and hyaline material, also known as hyalinosis, and adhesion of the tuft to Bowman's capsule by synechiae”4.Rennke H.G. How does glomerular epithelial cell injury contribute to progressive glomerular damage?.Kidney Int. 1994; 45: S58-S63PubMed Google Scholar. We have studied the development of FSGS in several experimental models including subtotal renal ablation27.Nagata M. Schärer K. Kriz W. Glomerular damage after uninephrectomy in young rats. I. Hypertrophy and distortion of capillary architecture.Kidney Int. 1992; 42: 136-147Abstract Full Text PDF PubMed Scopus (129) Google Scholar, 28.Nagata M. Kriz W. Glomerular damage after uninephrectomy in young rats. II. 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Long-term treatment of rats with FGF-2 results in focal segmental glomerulosclerosis.Kidney Int. 1995; 48: 1435-1450Abstract Full Text PDF PubMed Scopus (169) Google Scholar. These studies have led us to propose a framework mechanism that explains glomerular tuft destruction in FSGS as the result of a progressive loss of structural stability within a tuft segment to a point at which repair of the complex tuft architecture is no longer possible. The same basic considerations apply regardless of the nature of the initiating injury (toxic, hemodynamic, inflammatory, immune-mediated) and, we believe, explain the remarkable uniformity of the lesions seen in several types of progressive injury of the glomerular tuft. It is our contention that—due to its inability to replicate effectively postnatally and its unique susceptibility to specific injury—the podocyte is the most vulnerable component of the glomerular tuft and that, in most cases of FSGS, it is injury to the podocyte that initiates the definitive pathologic sequence. The glomerulus is a complex structure. It consists of an intricately folded basement membrane (GBM), which separates two compartments: an endocapillary compartment containing the capillaries and the mesangium, and an extracapillary compartment containing the podocytes in Bowman's space36.Elger M. Kaissling B. Le Hir M. Kriz W. Microanatomy of the kidney: Vessels, interstitium, and glomerulus,.in: Neilson E.G. Couser W.G. Immunologic Renal Diseases. Lippincott-Raven, Philadelphia1997: 15Google Scholar. A large hydrostatic pressure difference (40 mm Hg in the rat) exists across the capillary wall of the glomerulus. Counteracting the expansile forces that arise from this pressure gradient is not a function of any single glomerular structure or cell type, but rather is achieved in concert by two glomerular cell types (mesangial cells and podocytes) together with the GBM. Mesangial cells interconnect the turning points of the GBM from the inside and podocytes from the outside, thereby stabilizing the folding pattern of the GBM. This pattern establishes the basic architectural pattern of the glomerulus. In addition, podocyte foot processes, like cell processes of pericytes elsewhere, counteract (together with the GBM) the elastic distension of the capillary wall37.Kriz W. Elger M. Mundel P. Lemley K.V. Structure-stabilizing forces in the glomerular tuft.J Am Soc Nephrol. 1995; 5: 1731-1739PubMed Google Scholar, 38.Mundel P. Kriz W. Structure and function of podocytes: An update.Anat Embryol. 1995; 192: 385-397Crossref PubMed Scopus (261) Google Scholar, 39.Kriz W. Hackenthal E. Nobiling R. Sakai T. Elger M. A role for podocytes to counteract capillary wall distension.Kidney Int. 1994; 45: 369-376Abstract Full Text PDF PubMed Scopus (151) Google Scholar. It is the failure of the mechanical integrity of this system that leads to the characteristic lesions in tuft architecture seen in those experimental and human glomerulopathies that manifest FSGS40.Kriz W. Kretzler M. Nagata M. Provoost A.P. Shirato I. Uiker S. Sakai T. Lemley K.V. A frequent pathway to glomerulosclerosis: Deterioration of tuft architecture – podocyte damage – segmental sclerosis.Kidney Blood Press Res. 1996; 19: 245-253Crossref PubMed Scopus (66) Google Scholar. Such architectural lesions essentially are local expansions of the tuft that have a tendency to develop into more widespread structural lesions. These may present in two ways: (i) expansion of a compartment (mesangial expansion, capillary ballooning) and (ii) loss of the folding pattern of the GBM (capillary unfolding). In our view, the stereotypical character of these lesions derives from the mutual interdependence of the supporting systems: whether the mesangium fails primarily or the podocytes are the focus of the initial injury, the capacity of the integrated biomechanical system to counteract the high intraglomerular pressures will be compromised. In addition, whether the system fails due to primary mesangial cell or podocyte injury in the setting of normal capillary pressures, or an intact cell-GBM system fails to withstand elevated capillary pressures, the end result will be the same40.Kriz W. Kretzler M. Nagata M. Provoost A.P. Shirato I. Uiker S. Sakai T. Lemley K.V. A frequent pathway to glomerulosclerosis: Deterioration of tuft architecture – podocyte damage – segmental sclerosis.Kidney Blood Press Res. 1996; 19: 245-253Crossref PubMed Scopus (66) Google Scholar. Repair of architectural lesions, that is, restoration of the complex glomerular structure, has to occur in the face of the large transmural distending forces present in the glomerulus. The glomerulus is not capable of shutting down for repair. In the case of extensive injury disrupting either the endocapillary compartment or the epithelial cell layer, repair would probably have to recapitulate glomerular ontogeny in part in order to arrive at a proper structure. Even in a “simpler” system like the S3 segment of the proximal tubule—composed of a single cell type—repair of ischemic injury involves a process of dedifferentiation and redifferentiation, duplicating essential aspects of normal development41.Witzgall R. Brown D. Schwarz C. Bonventre J.V. Localization of proliferating cell nuclear antigen, vimentin, c-Fos, and clustrin in the post-ischemic kidney.J Clin Invest. 1994; 93: 2175-2188Crossref PubMed Scopus (496) Google Scholar. 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Areas of solidified mesangial expansion (what is often called “mesangial sclerosis”) in our view may still represent a kind of successful healing by scarring, that is, successful in the sense that the supporting function of the mesangium has been reestablished with reconnection of the GBM to the mesangium. These areas appear fairly stable, and progression to segmental sclerosis has not been demonstrated to occur in experimental settings. These areas may, of course, represent loci of increased vulnerability to any further structural challenges, thereby increasing the probability of exocapillary injuries at this site (see below). More severe endocapillary damage may result in a glomerular microaneurysm, characterized by the loss of any separation between the capillary and the mesangial compartments2.Rennke H.G. Anderson S. Brenner B.M. The progression of renal disease: Structural and functional correlations,.in: Tisher C.C. Brenner B.M. Renal Pathology. J.B. 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Cell culture data strongly support the view that differentiated podocytes are unable to proliferate (although they may develop into multinucleated giant cells), whereas undifferentiated or dedifferentiated podocytes that grow out from isolated glomeruli can proliferate53.Mundel P. Kriz W. Cell culture of podocytes.Exp Nephrol. 1996; 4: 263-266PubMed Google Scholar, 54.Mundel P. Reiser J. Kriz W. Induction of differentiation in cultured rat and human podocytes.J Am Soc Nephrol. 1997; 8: 697-705PubMed Google Scholar, 55.Mundel P. Reiser J. Zuniga Boree A. Davidson G. Pavenstädt H. Kriz W. Zeller R. Rearrangements of cytoskeleton and cell contacts induce process formation and postmitotic differentiation of conditionally immortalized mouse podocyte cell lines.Exp Cell Res. 1997; 236: 248-258Crossref PubMed Scopus (723) Google Scholar. In rats, podocytes subjected to sustained mitogenic stimulation by FGF-235.Kriz W. Hähnel B. Rosener S. Elger M. 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Nangaku M. Hugo C. Pippin J. Henne K. Hockenberry D.M. Johnson R.J. Couser W.G. Cyclin kinase inhibitors are increased during experimental membranous nephropathy: Potential role in limiting glomerular epithelial cell proliferation in vivo.Kidney Int. 1997; 52: 404-413Abstract Full Text PDF PubMed Scopus (108) Google Scholar. Reports in the human pathology literature describe glomerular epithelial cell hyperplasia as well as mitotic figures in podocytes. However, in the absence of a quantitative morphometric assessment of actual podocyte number, phenomena such as the crowding of exocapillary glomerular cells on a shrinking tuft—as commonly seen in collapsing FSGS6.Detwiler R.K. Falk R.J. Hogan S.L. Jennette J.C. Collapsing glomerulopathy: A clinically and pathologically distinct variant of focal segmental glomerulosclerosis.Kidney Int. 1994; 45: 1416-1424Abstract Full Text PDF PubMed Scopus (246) Google Scholar,7.Valeri A. Barisoni L. Appel G.B. Seigle R. D’Agati V. Idiopathic collapsing focal segmental glomerulosclerosis: A clinicopathologic study.Kidney Int. 1996; 50: 1734-1746Abstract Full Text PDF PubMed Scopus (219) Google Scholar—cannot be said to demonstrate effective podocyte proliferation. Moreover, a recent study of various types of glomerulopathies in humans shows that extracapillary cells (that is, the presumed podocytes) in collapsing FSGS do not represent simply another podocyte phenotype, since these cells, in addition to not expressing the usual “differentiated” podocyte markers (GLEPP1, synaptopodin, the C3b-receptor), do not even express the transcription factor WT-161.Barisoni L. Kriz W. Wiggins R.C. Mundel P. D’agati V. Podocyte (P) dedifferentiation predicts glomerulosclerosis (GS) in nephrotic syndrome. (abstract).J Am Soc Nephrol. 1997; 8: 532AGoogle Scholar, a factor that is present from the very beginning of podocyte ontogeny. It is therefore difficult even to assign these cells the status of “dedifferentiated” podocytes. If in fact podocytes are incapable of replication post-natally, then when podocytes are lost for any reason, they cannot be replaced by new cells. Thus, the only way to compensate for podocyte loss is by cell hypertrophy. Moreover, the ability of remaining podocytes to take over the function of the lost podocytes is likely to be decreased by the fact that in many cases they have been subjected to sublethal injury of the same type that destroyed the podocytes which actually were lost. As a whole, the evidence suggests that the glomerulus has a rather limited ability to compensate for podocyte loss. Any significant damage to the podocyte must therefore be viewed as a potential starting point for irreversible glomerular injury. Following a variety of challenges62.Kerjaschki D. Dysfunction of cell biological mechanisms of visceral epithelial cell (podocytes) in glomerular diseases.Kidney Int. 1994; 45: 300-313Abstract Full Text PDF PubMed Scopus (100) Google Scholar,63.Ronco P.M. 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