NEFROLOGIA. Vol. XVI. Suplemento 3. 1996 Physiology and pathophysiology of the mesangial cell P. Menè Cattedra di Nefrologia, Università degli Studi. «La Sapienza» di Roma The intercapillary area of the kidney glomerulus w a s first described and named «mesangium» by Zimmermann in 1933 1. The advent of electron microscopy enabled Marinozzi in Italy 2 a n d Latta in the U.S. 3 to conclusively demonstrate that a separate cell type exists in the kidney glomerulus, in add i t i o n to epithelial and endothelial cells lining a r o u n d the basement membrane. The functions of t h e s e «mesangial» cells have been subsequently elucidated, based on recognition of their contractil e phenotype and involvement in a variety of glomerular diseases (table I) 4-7. Mechanical / structural functions M e s a n g i a l cells are relatively rare in a normal g l o m e r u l u s , not exceeding 2-3 nuclei in a typical l i g h t microscopy section of a mesangial space. T h e i r total number is approximately 250-300 in a r a t glomerulus 8 . Scarce extracellular matrix surrounds mesangial cells and bridges the space betw e e n neighbouring podocytes and endothelial cells. A direct relationship exists with the glomerul a r basement membrane at specialized structures t e r m e d «mesangial angles» by Kriz and Sakai 9 . These links may serve a mechanical function, exert i n g traction on the basement membrane so to c o u n t e r b a l a n c e the hydraulic force driving ultrafiltration 10. T h e smooth muscle phenotype in vivo, and the ability of cultured mesangial cells to undergo contraction when exposed to vasonstrictors, and relax i n response to vasodilators, has attracted interest around the possibility that these cells may regulate the caliber of glomerular capillaries, and thus bloo d pressure and flow, with obvious implications o n ultrafiltration 4 - 7 , 1 1 . While conclusive in vivo evidence is difficult to achieve, many ex vivo or in vitro findings suggest that this may well be the case. First, the volume of glomeruli varies in response to contractile agents, indicating that responsive s m o o t h muscle elements reside within the capil l a r y tuft 4 - 1 0 . As mesangial cells are abundantly endowed with actin and myosin bundles, they are m a j o r candidates for this mechanical function. A d d i t i o n a l l y , contractility in culture, regulated by a variety of vasoactive agents 5 , is consistent with such model. Second, the single nephron glomerular filtration rate is a function of two determinants: t h e mean net ultrafiltration pressure, resulting f r o m the balance between hydraulic and oncotic p r e s s u r e s across the filtering unit, and the ultrafiltration coefficient, Kf. This parameter has been ex- Table I. Recognized functions of glomerular mesangial cells 1. Mechanical - structural -- Perivascular, intercapillary cell (pericyte) -- GBM tensioning, countering Puf -- Contraction / regulation of filtration surface area -- Matrix elaboration, processing -- Reparative proliferation following immune injury 2. Ultrafiltration -- GBM-like filtration of plasma -- Sieving of macromolecules, immune complexes 3. Immune-effector cell -- Antigen presenting -- Phagocytosis -- Reactive oxygen species production / scavenging -- Leukocyte chemoattraction 4. Biosynthesis -- Bioactive lipids -- Enzymes -- Matrix components -- Cytokines -- Growth factors -- Adhesion molecules Correspondence to: Paolo Menè, M.D. Cattedra di Nefrologia 2.ª Clinica Medica Policlinico Umberto I Viale del Policlinico 00161 Roma Italy 8 MESANGIAL CELL PATHOPHYSIOLOGY perimentally found to vary in several pathophysiol o g i c settings. Interestingly, both its determinants, the surface area (A) of capillaries and the effective h y d r a u l i c permeability of the glomerular capillary w a l l (k), are likely to change as the result of mes a n g i a l contraction 1 2 . Third, selective experiment a l mesangial injury by specific antisera often res u l t s in impairment of glomerular flow and f i l t r a t i o n , that would be difficult to explain if mesangial cells had no role in glomerular hemodynamics 5, 6, 11. Contraction is not the only mechanical function subserved by mesangial cells. Deposition of extracellular matrix is another prominent feature with likely implications for glomerular function. Not only does matrix contribute to the normal architecture of the mesangial space, but it also constitutes a tridimensional meshwork that allows filtration of blood, s i m i l a r to the glomerular basement membrane (GBM) 4-7. As a matter of fact, the biochemical comp o s i t i o n of the mesangial matrix resembles that of the GBM, while its spatial organization seems bett e r suited to trapping of macromolecules and imm u n e complexes, which are then disposed of thr o u g h phagocytosis and subsequent progression across the mesangial space 13. U p r e g u l a t i o n of mesangial matrix is an interest i n g feature of several glomerular diseases. This event may result from increased deposition of matrix, reduced catabolism, or possibly the combination of both 14. A number of growth factors and cyt o k i n e s , both released by glomerular cells and infiltrating leukocytes, appear well suited to stimul a t e matrix accumulation. This event seems to underlie glomerular lesions in slow-progressing, noninflammatory conditions, such as diabetes or focal g l o m e r u l o s c l e r o s i s . The occurrence of mesangial h y p e r p l a s i a , or proliferation of the cells, whose number is actually increased, is often encountered i n more rapidly evolving diseases, with extensive l e u k o c y t e infiltration, necrotizinglesions, and the signs of acute or subacute inflammation. These are features of mesangiocapillary nephritis, lupus nephritis, rapidly progressive glomerulonephritis, or vasculitis. Clearly, the pathophysiologic mechanism of m e s a n g i a l involvement is different, although the common denominator seems represented by in situ cell «activation» with phenotypic changes. This has brought interest into the functional connotations of m e s a n g i a l cells, which appear rather poorly differ e n t i a t e d under resting conditions in the normal kidney. Latta coined the expression «myofibroblast» to describe this wide potential of mesangial cells to express a contractile or secretory / reparative phen o t y p e , according to the functional needs and the presence of appropriate stimuli 4, 11. Indeed, recent evidence that smooth muscle actin isoforms are exp r e s s e d by mesangial cells upon induction of immune-mediated damage points to the availability of «markers» of mesangial activation in vivo 11 . Immunologic functions T h e presence of specialized phagocytes within the glomerular mesangium has long been a matter of controversy. The mesangial population is mostly a c c o u n t e d for by a smooth muscle / fibroblastic p h e n o t y p e that seems only marginally suited for i m m u n e functions as either antigen-presenting c e l l s or «professional» phagocytes 4 - 7 . Only 2 to 5 % of the cells confined in mesangial areas display o b v i o u s markers of bone marrow origin, such as the leukocyte common antigen or the Ia marker of p h a g o c y t i c differentiation 1 5 , 16 . Interestingly, bone marrow suppressive treatment rapidly depletes the glomerulus of these cells, clearly showing that they Fig. 1.--Binding of undifferentiated human myelomonocytes of the U-937 cell line to cultured human mesangial cells. Note tight a d h e s i o n of monocytes to underlying mesangial cells via cytoplasmic processes. Scanning electron microscopy, original magnification 1000 ×. 9 P. MENE migrate into the mesangium from the blood stream a n d differentiate in situ, most likely to serve phagocytic functions 16. Culture of glomerular explants g i v e s rise to a homogeneous cell population devoid of such markers, that should be considered as «intrinsic» mesangial cells. Nevertheless, evidence h a s been gathered showing that these cultures indeed internalize and process opsonized gold partic l e s , latex-coated microbeads, and immune comp l e x e s 1 7 . The process appears to involve Fc r e c e p t o r s , whose cross-linking appears to elicit specific biochemical events such as phosphoinosit i d e breakdown, changes of free cytosolic Ca 2 + ( [ C a2 + ] i ) , and prostaglandin (PG) biosynthesis 1 8 , 19. The release and scavenging of reactive oxygen spec i e s , not only as a byproduct of normal cellular metabolism, but also in response to specific immunologic challenge, further points to an active partic i p a t i o n in the immune response 2 0 . This may acc o u n t for the accumulation of immune complexes in mesangial areas occurring in various experiment a l and human nephritides, as a result of trapping through the reticular structure of the mesangial mat r i x , and delayed or insufficient clearance of the deposits 21. Failure of the mesangium to rapidly disp o s e of the material accumulated during filtration or formed in situ may explain this common finding, probably responsible for triggering subsequent glomerular inflammation and leukocyte chemoattraction 21. R e c e n t work has elucidated the mechanisms by which mesangial cells represent a target for neutrophils or monocytes / macrophages that infiltrate the glomerulus 22, 23. Mesangial cells express a variety of integrins and adhesion molecules that promote leuk o c y t e chemoattraction and adhesion (figure 1). W h i l e devoid of endothelial integrins such as ELAM-1, mesangial cells express intercellular adhes i o n molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), RANTES and monocyte chemoattractant protein-1 (MCP-1), all of which app e a r upregulated by several cytokines and ligands r e l e a s e d at the site of inflammation 2 3 - 2 8 . Together with matrix components that bind leukocyte counterreceptors, this sets the stage for further leukocyte i n f i l t r a t i o n and local activation, thus perpetuating glomerular inflammation 22. The role of vasoactive agents such as constrictor prostaglandins (PG), leuk o t r i e n e s (LT), platelet activating factor (PAF) and e v e n the endothelial products endothelin-1 (ET-1) and angiotensin II (ANG II) remains to be elucidat e d . As discussed earlier, these compounds may m o d i f y the mesangial phenotype and promote expression of surface determinants that trigger homing of leukocytes and amplify local damage. Local hem o d y n a m i c s itself, controlled by such vasoactive 10 a g e n t s , may indeed be relevant to glomerular inflammation. Biosynthetic functions M e s a n g i a l cells have secretory features beyond b i o s y n t h e s i s and layering of extracellular matrix. Both in vitro and in vivo, there is extensive evidence that bioactive lipids, such as arachidonate metab o l i t e s or PAF, enzymes, vasoactive peptides, and c y t o k i n e s are locally produced and released. I n t e r e s t i n g l y , mesangial cells generally express receptors for all of these compounds, pointing to autocrine effects or paracrine interactions with contig u o u s mesangial cells, glomerular epithelial and endothelial cells, and possibly infiltrating leukocyt e s during glomerular inflammation. Table II lists t h e major products of mesangial cells presently identified. Bioactive lipids are generally labile derivatives of p l a s m a membrane turnover, released as means of i n t e r c e l l u l a r communication upon stimulation of m e m b r a n e - a s s o c i a t e d phospholipases. Endowed with powerful vasomotor activity, PG, LT and PAF h a v e other cellular actions that include regulation o f proliferation and protein synthesis, leukocyte chemoattraction, and probably vascular permeability 29. Table II. M a j o r products of glomerular mesangial cells Growth factors Platelet-derived growth factor Transforming growth factor - ß1 Insulinlike growth factor 1 Cytokines Interleukins 1, 6, 8 Tumor necrosis factor GM - colony stimulating factor Adhesion molecules, chemokines ICAM-1 VCAM-l MCP-1 RANTES Bioactive lipids Prostaglandins, leukotrienes, lipoxins Platelet activating factor Vasoactive agents Endothelin-1 Nitric oxide (EDRF) Enzymes Renin Neutral proteinases MESANGIAL CELL PATHOPHYSIOLOGY Renin has been one of the first enzymes identif i e d in mesangial cultures 3 0 , 31 . The patterns of ren i n regulation match those described for juxtaglom e r u l a r cells, suggesting structural similarities b e t w e e n cell populations that may be electromec h a n i c a l l y coupled via a syncytial organization 3 2 . I n t e r e s t i n g l y , cultured cells retain this ability to f o r m syncytial structures, that have been recently e x p l o i t e d by means of diffusible tracers and microinjection 33. T h e significance of renin biosynthesis may be better appreciated if one realizes that components of the renin-angiotensin system, including convert i n g enzyme activity in glomerular endothelial cells, may locally function to generate active ANG I I in situ, within the glomerular microcirculation. Since abundant receptors exist for this peptide both i n mesangial cells, afferent and efferent arterioles, a s well as glomerular epi- thelial cells, ANG II is well suited for autocrine or paracrine regulation of l o c a l hemodynamics, along with cell growth and matrix formation 5, 6, 12, 34. Another peptide relevant to the control of vascular tone, ET-1, has been recently identified as a product of mesangial cells 35, 36. Similar to the renin-angiotensin system, it is likely that local loops link the b i o s y n t h e s i s of ET-1 by mesangial and neighbour i n g endothelial cells to mesangial receptors, with implications for a wide range of pathophysiological e v e n t s . Both populations also exhibit nitric oxide synthetase activity 37, 38. As the constitutive and inducible isoforms of this enzyme release the potent vasodilator, nitric oxide, or endothelial-derived relaxing factor (EDRF), an endothelial - smooth muscle feedback has been proposed, with two opposite branches regulating the vascular tone of the glomerular capillary microcirculation. C y t o k i n e s are another relevant product of mesangial cells. Several interleukins, notably IL-1 and IL-6, are produced by «activated» cells, and act on r e c e p t o r s expressed by the same cells 3 9 - 4 2 . Interferon, GM-CSF, tumor necrosis factor, MCP-1, R A N T E S 2 6 , 27, 43, 44 a r e other examples of the wide host of mesangial peptides acting on bone marrowderived cells that also appear to mediate paracrine i n t e r a c t i o n s within the inflammed glomerulus. A d h e s i o n molecules belonging to the integrin superfamily regulate adhesion and cell-to-cell immun e reactions 2 2 . Platelet-derived growth factor (PDGF) isoform AA is the predominant growth factor produced by mesangial cells 45, 46 , although relevant levels of transforming growth factor-1 (TGFß) 47, insulinlike growth factor 1 (IGF-l) 48, fibroblast growth factor (FGF), epidermal growth factor (EGF) 46 h a v e been reported. Interestingly, PDGF gene expression appears an early step in the response of mesangial cells to several mitogens, such as thrombin, ET-1, etc. 49. The biological significance of this r e p o n s e is unclear, as mesangial cells express mostly ß isoforms of the receptor for PDGF, which are known to bind the homodimer BB or the heter o d i m e r AB, but not the endogenous form AA 4 9 . The endogenous peptide is thus likely to act at sites o t h e r than the intrinsic mesangial cells, since its r o l e in the early phase of mesangial proliferative g l o m e r u l o n e p h r i t i d e s has been convincingly s h o w n 5 0 . A vast body of studies employing blocking anti-TGF-ß1 antibodies or binding glycans imp l i c a t e s also this growth factor in a variety of glom e r u l a r diseases with predominant mesangial expression 51-53. A unifying view combines the two growth factors as sequential activators and regulat o r s of mesangial proliferation and matrix deposition 11. Conclusions T h e vast number of publications focusing on mesangial cells testifies to the extreme interest rais e d in recent years by this apparently amorphous a n d inert structure of the glomerulus. The search f o r a key player in the reshaping of the filtering u n i t that occurs following immunologic or metabolic insult, has placed high hopes on the possibil i t y of understanding and manipulating mesangial c e l l function. 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