Fisiologia Del Mesangio

8/13/2019 Fisiologia Del Mesangio

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J o urn a l o f th e A m e rica n S o c ie ty o f N e p h ro lo g y S 6 5

n pp roach to th e S tru c tu re and Func tion o f th eG lom eru la r M esang iumH arrison La tta2

H . L a tta , D e p artm e n t o f P a th o lo g y a n d L a b o ra to ryM e d ic in e , U n iv e rs ity o f C a lifo rn ia M e d ica l C en te r,L o s A n g e le s , C A(J . A m . S o c . N e p h ro l. 1 9 9 2 ; 2 :S 65 -S 7 3 )

A B S T R A C TT he m esa ng ium o f the g lom e ru lus is a c onne ctivetiss ue tre e a ris in g a t the v as cu la r p o le o f the g lo m er-u lu s a n d s u p p o rtin g th e g lo m e ru la r ca p illa r ie s . It isp a rtly c o ve re d b y a b a se m e n t m e m b ra n e th a t fo l-lo w s the e p ith eh ia l ce lls from the pe riph e ra l g lom er-u la r c ap illa ry w a ll o ve r the su ppo rting tiss ue . T hec a p illa ry e n d o th e h iu m do e s n o t n o rm a lly h a ve a s e p -a ra te bas em en t m em bran e . T he e ndo the liu m ha sfene s tra tion s tha t o pen d irec tly in to th e m esa ng iuma nd a llo w b lood p la sm a an d tra ce rs to flo w in to th em esa ng ium . T he fe nes tra t ions pa rtia lly res tr ic t (o rs ie ve ) pa rtic les ov e r 405 A in m ean le ng th from en try .T race rs m ove in in te rc e llu la r ch ann e ls a nd a re fil-te red and con ce n tra te d by the bas em en t m em -b ra ne a t the s ide s o fthe m es an g ium o r by m esa ng ia lm a trix filam e n ts in the c han ne ls be tw e en ce lls . T h eirre gu la r d is tr ib u tions o f flow , m a trix , and co nc en tra -l io n s o f tra c e rs m a y a c co u n t fo r ir re g u la r lo bu la rrea c tions in g lom e ru la r d is ea se . T w o m a in pa th w ayso f flow s eem to be ( 1) th ro ugh the b as em e n t m em -b ra ne an d be tw e en the e p ith e lia l foo t p roc es ses tofo rm pa rt o f th e g lo m eru la r filt ra te an d (2 ) in to th ee ffe re n t ca p il la r ie s th ro u g h th e ir m e sa n g ia l fe n e s tra -tions . In tr in s ic m e sa ng ia l ce lls c an now b e reg a rde da s m yo fib rob las ts ass oc ia te d w ith th e p rod uc tion o fth e c onn ect ive tis su e m a trix . T hes e c e lls ho ld th eba sem en t m e m bra ne to m a in ta in the s hap e o f th eg lom eru la r c ap illa r ies , th ey sw e ll rea d ily , an d th eyc an c ons tr ic t like s m oo th m usc le ce lls w ith app rop ri-a te s tim u la tio n . T he se re ac t ion s m ay e nab le th em toc on tro l the flo w o f b loo d th rou gh the cap illa ry ne t-w o rk in g lom eru la r d is eas e . M es an g ia l ce lls c an takeT hi s ar ti cl e w as p re pa re d f or a l ec tu re p re se nt ed a t t he T hi rd P or no N ep hr ol og y

c on fe re nc e i n Fiu gg i. It al y. on S ep te rn be r 2 7. 992coffe pondence to Dr. H. Lafla, Departrnent of Pathology and LaboratoryM ed ic ine , U n iv e rs ity o f ca lifo rn ia M ed ic a l cen te r. Los An ge les, C A 9002 4-1732 .1046-6673/02 O-0S65$03 .00 /0J ou rn al o f t h e A rn er ic an S oc ie ty o f N e ph ro lo gycopyright 1992 by the A rn e rican S ocie ty o f N ephro logy

u p la rg e am o un ts o f fo re ig n m a te ria l w ith in 24 h .In tr in s ic m e san g ia l ce lls an d m o noc y te s ca n in -c rea se in n um b ers in d is eas e . C e lls in the po la r cus h -ion (P o lk is sen ) rea c t d iffe re n tly than do m e san g ia lcel ls.K ey W o rd s: M e sa ng ia l filtra tio n , flo w , fe n estra tio ns , b as em en tm em bra n e, e nd o cy to s is , m es an g ia l ce lls , m yofib ro b la s t

h is d isc u ss io n w ill re v ie w th e lig h t an d e le c tro nm ic ro sc o p y s tud ie s th a t d e sc r ib e th e s truc tu re

o f th e m e sa n g ia l re g io n , its ce llu la r a n d e x tra ce llu la rco m p o n e n ts , its re la tio n sh ip s to a d ja ce n t s tru c tu re s ,so m e o f its fu n c tio n s u n d e r p h ys io lo g ic co n d itio n s ,an d so m e o f its re a c tio n s in d ise a s e . F ig u re 1 is ad ia g ra m o f th e m a in fe a tu re s o f th e m e sa n g ia l re g io n .O th e rs h a v e re v ie w e d m o re re ce n t s tu d ie s o f th em es a n g iu m th a t e lu c id a te b io s yn th e tic a c tiv itie s a n dre a c tio n s to v a rio u s s u b s ta n ce s in c lu d in g e n zy m e s ,h o r m o n es , c y to k in e s , im m u n e co m p lex e s , a n d m e -d ia to n s o f in fla m m a tio n (1 ,2 ) .

T h e m esan g i u m w a s co n s ide re d b y Z im m e rm a n n(3 ,4 ) to b e a co n n e c tive tiss u e tre e th a t a r ise s fro mth e va sc u la r p o le o f th e g lo m e ru lu s , e x te n d s in to th elo b u le s , an d su p p o rts th e g lo m e ru la r ca p il la rie s . H ed e scr ib e d a n d illus tra te d it in 1 9 2 9 (3 ), b u t h e d id n o tu se th e te rm m e sa n g iu m u n til 1 9 3 3 (4 ). Z im m e n -m an n s o b s e rva tio n s w e re d e ta ile d a n d re m a rka b le .H o w e ve r, th ey w e re n o t acc ep ted by s om e in ves tig a -to n s w h o u se d lig h t m ic ro sco p y a n d e a r ly e le c tro nm ic ro sco p y te ch n iq u e s . In th is p e r io d , th e te rm s a p -p lied to th is reg ion in c lu ded in te rc ap illa ry , ax ia l, a ndce n tro lo b u la r . T h e d e ve lo p m e n t o f im p ro ve d e le c tro nm ic ro sco p y te c h n iq u e s e n a b le d co n firm a tio n o f Z im -m en m a n n s o b se rva tio n s (5 ). A n um b e r o f s tu d ie sfro m th is la b o ra to ry h av e de a lt w ith th e m e sa n g iu m(5 -1 5 ), a n d w e h a ve re v ie w e d it b r ie fly in 1 9 7 3 (1 1 )a n d 1 9 8 5 (1 5 ). O the r s tu d ie s a n d re v ie w s h a ve p re -se n te d fu rth e r in fo rm a tio n w ith e le c tro n m ic ro sco p ya n d o th e r te ch n iq u e s (1 ,1 6 -2 1 ).

B A S E M E N T M E M B R A N ET h e b asem en t m e m b r a n e (b asa l lam ina ) o f th e

g lom e ru lu s a p p e a rs e a r ly in th e e m b ry o lo g ic d e ve l-o p m e n t o f th e g lo m e ru lu s in a s so c ia tio n w ith th ee p ith e lia l c e lls th a t fo rm th e re n a l ve s ic le . It re ta in sth is a sso c ia tio n w ith e p ith e lia l ce lls as th e g lo m e ru la rca p il la r ie s a n d th e m e s a n g iu m d e ve lo p . In th e m a tu rea n im a l, th e b a se m e n t m e m b ra n e c om e s to lie o ve r


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S truc tu re an d F un ctio n o f M e sa ng iu m

s6 6 V o lu m e 2 - S u p p lem en t 2 1 9 92

F ig u re 1 . D ia g ra m o f th e m e sa n g ia h re g io n . T h e m e sa n g iu m is s h o w n a t th e ce n te r o f ca p illa r ie s fo rm in g a g lo m e ruh a r lo b u le .P o rtio n s o f th e m es an g iu m a re co ve red by the lam in a de ns a (L D ) a nd la m ina rara e x te rna (IR E ), w h ich fo llow th e fo o tp ro ces se s o f th e e p ith e h iu m (E p ) fro m th e p e rip h e ra l g lo m e ru la r ca p il la ry w a ll o ve r th e m e sa n g iu m . T h e c a p illa ry b a se m e n tm em b rane (B M ) (bas a l ha m ina ) is com pos ed o f the IR E , the ID , a nd th e la m ina ra ra in te rn a (L R I). W h e re it jo in s th em e sa n g ium , th e IR I is co n tin u o u s w ith th e m e sa n g ia l m a tr ix (M M ). T h e M M va rie s in d e n s ity a nd is ir re gu la rly d is tr ib u te d inth e m e sa n g iu m . It is o fte n m o re d e n se w he re it a n ch o rs p ro c e sse s o f m e sa n g ia h c e lls (M ) to th e ID o f th e in fo hd e d B M . T h eM M is u su a lly le ss d e n se b e n e a th ce n tra l po rtio n s o f e n d o th e lia l c e lls (E n ) ly in g o v e r th e m e sa n g iu m . E n d o th e lia l c e lls d on o t n o rm a lly h a ve a s e p a ra te b a se m e n t m e m b ra n e . T h e c en tra l p o rtio n s o f e n d o th e h ia l c e lls o ften h a ve fe ne s tra tio n s (F )th a t a re s im ila r in s iz e to b u t fe w e r in n u m b e r th a n fe n e s tra tio n s in th e p e r ip h e ra l c a p illa ry w a ll. T h e fe n e s tra tio ns a llo w b lo o dp la s m a an d p a rticu la te tra c e rs to d ire c tly e n te r in to th e m e sa n g iu m a n d m o ve in in te rce llu la r ch a n n e ls (IC ) w h e re th e re islitt le o r n o m a trix . O n e p a th w a y o f flo w o u t o f th e m e sa n g iu m se e m s to b e th ro u g h th e L D a n d b e tw e e n fo o t p ro ce ss e s ov e rth e m e s a n g iu m , co n tr ib u ting to th e g lo m e ru la r fi ltra te (a rro w to th e r ig h t) . A se c o n d p a th w a y o f flo w o u t o f th e m e sa n g iu ms e e m s to b e th ro u g h th e in te rc e llu la r c h a nn e ls a n d e n d o th e lia l fe n e s tra tio n s o f e ffe re n t c ap illa rie s in to th e ir lu m e n s (a rro wto th e le ft) . A th ird b u t s m a ll pa th w a y o f flo w se e m s to b e th ro u g h th e h ilu s in to th e p o la r c u sh io n (P o lk is se n ) o f th e JG A .A d ja ce n t foo t p ro c e sse s co m e fro m d iffe re n t ce lls , h e n ce th e n um b e r co ve re d b y e p ith e h ia l cy to p la sm is a lw a y s o d d .M o d ifie d fro m L a tta e t a . (5 ) w ith p erm is sio n.

th e g lo m e ru la r ca p illa ry n e tw o rk a n d the m e sa n g iu m g lo m e ru li in th e re n a l c o rte x o f h u m a n fe tu se s u n d e rlik e a fo ld e d s h e e t (1 1 ). D iffe re n t s ta g e s o f th is p ro c - 3 5 w k o f g e s ta tio n . T h e re is n o se p a ra te b as e m e n te ss ca n b e se e n b y lig h t m ic ro s co p y in d e ve lo p in g m e m b ra n e a sso c ia te d w ith g lo m e ru la r e n d o th e lia l


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Lat ta

Jou rn a l o f the A m erica n S o c ie ty o f N e ph ro lo gy 67

ce lls e ith e r in th e p e r ip h e ra l c a p illa ry w a ll o r o v erthe m esang iu m in no rm a l an im als (5 , 1 1) , bu t o nem ay d ev e lop in g lo m eru lar d is ea se a s in hum an m es -a n g io ca p illa ry (m e m b ra n o pro life ra tive ) g lo m e ru lo -n ep hn itis (2 0 ,22 ) . A lth oug h th e te rm , basem en t m em -b rane , seem s w e ll estab lished in the litera tu re ong lom e ru la r c ap illa rie s an d refe rs to th e la m in a ra raex te rna , lam ina densa , an d lam ina ra ra in te rn a, h is -to lo g is ts n ow p re fe r th e te rm b a s a l la m in a (2 3 ).

M E S A N G IA L M A T R IXT h e m esang ia l m a tr ix w as d escr ibed b y Z im m er-

m ann (4 ) as conn ec tive tissue w ith a f ib rous n e tw o rkth at is denser an d stain s m ore strong ly w ith A zanthan th e c onn ect ive t iss ue ou ts id e the g lom eru lus .O the r sta in s ind ica te th a t it h a s a la rg e po lysa c ch a -r ide o r p ro teo g lycan con ten t ( 1 1 , 24 ). E lec tro n m ic ro s-cop y stud ies sho w ed a la rg e co m po nen t o f filam en ts1 2 to 25 A w ide (24 ) and a few banded co llagen fib ers(7 ). B and ed co llag en m ay becom e m uch m ore p rom i-nen t in g lo m e ru la r d ise a se (6 ). F ib ro n e c tin an d lam -m m have b een desc rib ed (1 ). R u then iu m red sta in ingin d icate s a nega tive (p o lyan io n ic ) cha rg e on the m es -ang ial fibn ils (24 ) , w h ich a re m uch m ore clo se lypacked than th e re lativ ely large , nega tive ly cha rg edla ttic e- like ne tw ork desc rib ed by K anw ar an d F a r-q uha r (25 ). D ep osits in th e m esan g ium rep re sen tingabn orm a l m ate r ials o r inc reased am o un ts o f n o rm a lcom pon en ts are recog n ized in d iabe tic g lo m eru losc le -rosis , o the r ty pes o f g lom eru lo scle rosis , am y lo ido sis ,foca l and d iffu se g lom eru lon ep hn itis , im m u ne c o m -plex d isea se , e tc . (2 2 ).

M esang ia l ce lls and fibe rs seem to ho ld th e g lom er-u lar basem en t m em bran e aga ins t the b lood pres su rein the cap illa r ies (1 1 , 1 5). T h is has been stud ied inso m e de ta il b y K riz et a t. (26 ). L o ss o f th is ho ld ingfo rce w ou ld a llow th e b asem en t m em b rane to p opo u t an d fo rm m ic roaneu rysm s, w h ich appea r in m e s -ang io lys is w ith n ec rosis o f m esan g ia l ce lls , d iabe tes ,and o the r g lom eru la r d isea se s (1 1 ,20 ) .

M E S A N G IA L P L A S M A F L O WT he con cep t o f p lasm a flow in the m esang iu m

seem s to be a key to un de rstan d ing the stru c tu re andfunc tion s o f the m esang iu m .

E n try in to M es ang iumT he rap id ent ry of sm a ll trace rs in to the m es an -

g ium within a few m inu te s af te r i.v . in jec tion ind i-ca tes a cons iderab le f low o f b loo d p la sm a in to th isreg ion (5 ). E n try in to the m esang ium seem s to occu rth rou gh fen estra tions o f the sam e size an d shape asth ose in the pe rip he ra l g lo m eru lar cap illa ry w all (15 ).T he m ean w id th is 3 7 6 A in th e ra t. A n a lys is o f th em easu rem en ts o f the fenestra tio ns and asy m m etr icth o riu m diox ide (T hO 2) pa rtic le s used as tracers in -

d ica ted tha t pa rtic les w ith a m ean len g th o f 4 05 A o rm ore w ere p artia lly re stric ted from en try . T h is con -stitu te s siev in g , w h ich pa rtially e x c lu d e s la rg e r s u b -stances . H o w ev er , the p re sence o f so m e la rg e fen es -tra tion s allo w ed the en try o f a few thorium dio x ideo r ca rbon pa rticle s ov er 60 0 A in size . T he en try o ftracers in to th e m esang ium is favo red by th e ab sen ceo f a b asem en t m em b rane u nde r th e endo theh ium ov e rthe m esang ium . I t is a lso fa vo re d b y th e le sse r d e n s ityof the m esang ia l m a trix ly ing und er the end o theh ium(15) .

S low er en try in to the m esang iu m of agg rega te s o ftracers cou ld occu r in hours o r day s w ith enve lop-m e n t b y th e end o the lium . E n ve lopm en t w as sug-g e s te d b y c lu m p s o f T h 0 2 p a rtic le s in ca p il la ry lu -m ens th at a p p e a r to b e inco rpo ra ted in to the m es-an g ium b y th in lay ers o f endo the lium m o ving o ve rthem (8) . T h is w o u ld b e a n a lo g o u s to th e m o v em en to f th e endo the lium o ve r th e su rface o f a m u ra l th ro m -bus . T h is m ech an ism co u ld a lso ex p la in in co rp o ra-tion in to the m esan g ium of m asse s o f ca rbon (2 7),p o s s ib ly fib r in , c a p illa ry th ro m b i, la rg e r a g g re g a te so f p ro te in o r im m une com plexes, e tc .

M e sa n g ia l ce lls ca n p ro je c t in to th e cap illa ry lum en(4 ,9 , 1 0, 1 3, 1 6 ). Z im m erm an n (4 ) sug gested tha t theym i g h t d o th is fo r nou rish m en t. N o ev idence has b eenfo und b y e lec tron m icrosco py tha t the se p rocesse sta ke u p tra c e rs , a n d o u r im p re s s io n is th a t th e sesw o lle n p ro ce ss e s a re a re sp o n s e to isch e m ia o r d is -ease con d ition s (9 , 1 0 , 1 3 ) .

S u b s ta n c e s m a y b e ca rrie d in to th e m es a n g iu m byce lls m ig ra tin g fro m th e c a p illa rie s . A fte r the in je c -tio n o f fo reig n o rg an ism s, w h ich ad he re to the gb -meru la r en do th eb ium , m ono cy te s and n eu tro ph ilslodged in th e g lo m e ru li a n d b eg an p hagocy to sis in 10m m (2 8 ,2 9 ). M o n oc y te s c o n ta in in g fe rritin b e g a n toin filtra te th e m e sa n g iu m in 4 h (3 0 ). S u c h in fla m -m a to ry ce lls m ay con tr ibu te to the gb om eru la r h ype r-ce llu la r ity appa ren t b y ligh t m ic rosco py .

O the r m ech an ism s o f inco rpo ra tion have been sug -gested (s uc h a s b y p a s sa g e a lo n g th e p e rip h e ra l g b -m er u l a r ca p illa ry w a ll, b y transport across en do th e-h a l cy to p la sm , o r b y m e sa n g ia l c e lls s w e e p in g th ep e riph e ra l ca p il la ry w a ll) , bu t there is litt le e vid en cefo r th em (1 5,1 9,2 0).

F a c to rs fa vo r in g m e sa n g ia l lo ca liza tio n ha v e b e e nd iscussed b y M ich a e l e t a t. (19 ) , S terzeb e t a t. (20 ) ,a n d M en {2 3 2 }t a t. (1 ) a n d in c lu d e h ig h concen trat ionsin the b lood , d e cre as e d a c tiv ity o f th e sy stem ic ph ag-o cy tic sy s te m , co rtico s te ro id s , b a rg e size, posi t ivech a rge , and h ig h a v id ity o f im m un e co m plexes(31 ,32) .

P a thw ay s o f F lo w an d F iltra tion in th eM es ang i um

If p la sm a f l o w s into th e m es ang ium rap id ly , flu idm us t f low o u t ra p id ly (5 ,1 1 ,15 ). P a thw a ys o f flow


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S truc tu re a n d F u n c tio n o f M esa n g iu m

$6 8 V o lu m e 2 S u pp le m e n t 2 1 9 9 2

h a ve b ee n su g g e s te d b y th e a p p e a ra n c e a n d a ccu -m ubat i on of t r acers an d im m u ne com plexes. T race rse n te rin g in a few m inutes m ov e in channe ls b etw eenm e sa n g ia l ce lls w h e re th e m a trix is le ss co n c e n -tra te d . W ith tim e , tra ce rs a cc u m u la te in tw o p la ce sin th e m esang iu m . O ne is un de r th e dense lay er o fthe basem en t m em bran e, w h ic h fo llo w s th e e p ithe -hu m o ve r th e m e sa n g iu m . T ra ce rs (h em o g lo b in , fer-rit in , d e x tra n s , p la s m a pro te in s ) and im m un e com -p lexes can concen trate in th is pa ram esang iab a rea( se e r efe re n ce s 1 5, 3 3 , a n d 3 4 ). T h is co n c e n tra tio nsug gests th at th ese sub stances a re be ing filte red o u tb y th e ba s e m e n t m e m b ra n e a n d th a t th e flu id w iththem flow s on th rou gh th e b asem en t m em brane ,b e t w een fo o t p ro ce s se s , a n d co n tr ib u te s to th e g b -m eru la r filtra te (3 4 ) . T h is fo rm s on e pa thw ay of f lowth ro u g h th e m e sa n g iu m . T h e b e h a v io r o f th e s etra ce rs sug gests tha t th e pe rm eab ility o f th e base -m e n t m e m b ra n e a n d fo o t p ro ce s se s o ve r th e m e sa n -g iu m is sim ila r to tha t ove r th e p e riph era l g lom eru la rcap illary w a ll (3 4 ).A se c o n d p a th w a y o f flow th roug h the m esang iumw as su g g e s te d b y th e co n ce n tra tio n o f tra c e rs o npo rtion s o f th e m e sa n g ia b m a trix in in te rc ellu la rchannels (8 ). T h is p a th w a y w o u l d co n d u c t flo w f romth e a ffe re n t ve s se ls in th e g b o m e ru la r c a p illa ry n e t-w o rk to th e e fferen t cap illa rie s . A hy drody nam icana logy is s u g g e s te d b y th e d iffe re n t d ire c tio n s a n dra te s o f flo w a rive r can tak e p assing th ro ugh a d e ltareg io n . A no the r co nside ratio n fa v o rin g flo w th ro u g hth e m esa ng ium from a ffe ren t to e ffe ren t c ap illa r iesis th a t, w ith o u t su c h flo w , p la s m a p ro te in s filte re do u t a t the basem en t m em brane ov er the m esang iumw o u l d b eco m e un du ly c onc en tra ted . T he y w ou ld hav eto be ca rrie d b a c k into th e cap illa ry c ircu la tion fo rth e m esang ium to m a in ta in its no rm a l sta te . T h eaccum u latio n o f trace rs on p ortions o f the m esang iabmatr ix re p re se n ts a n o th e r ty p e o f fi ltra tio n in a d d i-tio n to f iltra tion a t the basem en t m em b rane m en -tio ned abov e. C oncen tratio n o n th e m a trix w ou ld g ivetrace rs m ore tim e to be ta ke n u p b y ce lls in th em e sa n g iu m . T h e irre g u la r d is trib u tio n o f th e m e s-a n g ia l m a trix and va ria tion s in flo w a cco u n t fo r th ed iffe re n t n u m b e rs o f tra ce rs fo u n d in d iffe re n t g b -m e r u b i an d in d iffe re n t lo bu le s o f the sam e g lom eru -b u s . It m a y a lso e xp la in th e m o re p ro m in e n t c h a n g e sin s o m e lob u le s in foca l gb om erubo neph ritis an d o th ergbomeru lar d is e a se s . T h e flo w o f b lood p lasm ath ro ug h th e m e sa n g iu m w o u ld a lso enab le the m e s -ang iab cel ls to re a c t to su bstances ca rr ied in th ep la s m a , su c h a s h o rm o n e s , cy to k in e s , im m u n e c o m -p lexes , etc .

A th ird p a th w a y o f flo w to th e h ilu s o f th e g lo m e r-u lu s a n d th e ju x ta g b o m e ru la r a p p a ra tu s (J G A ) h a sb e e n s ug g e s te d (8 ), b u t th e s m a ll n u m b e rs o f tra ce rsfo u n d in th e JG A in 2 4 h (8 ) a n d th e de la ye d tim e so f co n ce n tra tio n s in th e JG A (seve ral h o u rs fo r iro ndex t ran 135 1 a nd fe rr it in [3 6 1 a n d 4 w k fo r ca rb o n

[27 ] ) ind ica te th at f low in th is p ath w ay w o u ld haveto be qu ite sm a ll (1 5 ) . M ost o f th e h ilu s o f a g bo me r-u lus is occup ied by the tw o arte rio le s , w h ich leavesth e re ma in in g area o f c o n ta c t b e tw e e n the m e sa n -g ium and the JG A so sm a ll tha t it m u st act as abo ttlen eck lim iting th e passage o f tra ce rs , w h e the re x tra ce b lu b a r o r in tra ce llu la r. M o re o v e r, th e ce lls o fth e JG A are pack ed c lose ly t oge ther , and w here the rei s i n te r st it ia l matr ix b e tw e e n th e m , it is q u ite d e n se ,a s if to p artia lly sea l o ff the JG A from ex tran eo usin f luences. T h is e n a b le s th e co m p o n e n ts o f the J G Ato re s p o n d b e tte r to phy sio lo g ic stim u li. A po ssib leal ternat ive m eans b y w h ich tra c e rs c o u ld e n te r th eJG A is from th e ad jacen t in te rstitia l tissue and yes-se ls , b u t th e e v id e n ce fo r th is is le ss im p re ss ive th a nthat fo r slow passage from th e m esang ium .

O th er fate s fo r tra c e rs in th e m e s a n g iu m h a ve b e e nsug gested (1 5 , 1 9 ) . T hese in c lude in tracellu lar an dex tracel lu lar d ig es tio n, re gu rg ita tio n into the b lo o d ,t ranspor ta t i on by ce ll m ov em en t o r c e ll- to -c e ll pas-sa g e , p a ssa g e th ro u g h th e b a se m e n t m e m bra n e b yliqu efactio n o f its th ixo trop ic g el struc tu re, o r d isso -lu tio n o f im m u n e co m p le xe s by ex cess an tig en . In -d igest ib le tra ce rs m a y re m a in fo r m o n th s .

C E LL T Y P E S IN T H E M E S A N G IU MIt is g en er ally ag reed th at th e n o rm a l m e sa n g iu m

conta ins at b east tw o c e ll typ e s , th e in tr in s ic m e sa n -g ial cell an d the m o nocy te /m ac ro phage . E ach o fth e se ce ll ty p e s p e rfo rm s m u ltip le fu n c tio n s .

T he In tr ins ic M es ang ia l C e llT he F ib ro b la s tic N a tu re of In trin s ic M esan g ia l

C ells . Z im m e rm an n (4 ) con side red m esang ia l cells tob e fib ro b b a s ts b e c a us e th ey b a y in a fib ro u s m a trixth a t s ta in e d like c o n n e c tiv e tiss u e . E le c tro n m ic ro s -co p y s u p po rt fo r the con nectiv e tissue na tu re o f th em e s a n g i u m w as ob tain ed in th is la b o ra to ry w h e nb a n d e d co lla g en fib e rs w e re o bse rved in ex pe rim en -ta b (6 ) a n d h u m a n (3 7 ) g b o m e ru la r d is e as e . O c ca s io n a lsm a l l b u n d le s o f b a n d e d co lla g e n fib e rs w e re a lsofound in the norm a l ra t m esang iu m (7 ). Inc rea seddeposi t ion o f th e m e sa n g ia b m a tr ix (and som etim esco lla g e n ) ca n o cc u r in d iab e te s a n d d iffe re n t types o fg b o m e ru lo n e p h ritis a n d g b o m e ru lo s c le ro s is . A m y lo iddepo sits o ccu r in v a riou s conn ec tiv e tissue site s inth e b o d y , in c lu d in g th e m esan g i u m (22) .

T h e S m o o th M u sc le N a tu re of M es a n g ia l C e lls .O u r e a r ly e le c tro n m ic ro sc o p y s tu d ies sh o w e d b u n -d le s o f m ic ro fib a m e n ts a n d a tta c hm e n t b o d ie s inm e sa n g ia b c e lls lik e th o se in arte r ia l sm o o th m u sc le(8 ). O th e rs d e m o ns tra te d a c to m yo s in a c tiv ity in m e s-ang iab cel ls b y im m u n o flu o re sc e n ce (3 8 ,3 9 ). M esan -g ia b ce lls loca lize ang io ten sin II in situ (40 ) andco n tra c t in tis su e c u ltu re w h e n s tim u la te d w ith an -


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g io ten sin (41 ). M esang ia l ce lls sw ell eas ily and lif tthe ov erly ing e n d o th e b iu m o r p ro je c t th ro u g h it in toth e ca p illa ry lu m e n (9 , 1 0 , 1 3 ). Z im m erm a n n d e -sc r i bed and illu stra ted th is p ro cess by b igh t m icros -co p y in 1 9 3 3 (4 ). Similar c h a n g e s h a ve b ee n o b se rve din th e sm o o th m u sc le o f th e ao rtic w a ll (42 ) . C o n trac -tion and sw e lling cou ld co n tro l b loo d flo w th rou ghthe gbo m eru lar cap illa ry ne tw ork . E n do th eb ial sw e ll-in g m ay a id in th is p ro c e ss . C o n s id e ra b le e v id e n cesugges ts a c o nt ri bu ti on o f m e s a ng ia l ce lls to th e re g -u la tion o f g lom erub ar filtratio n (2 1 ,43 ) . S w e lling ise sp e c ia lly p ro m in e n t af te r the cessa tion o f b loo d flow(9 ) o r af ter isch e m ia fo r 1 5 to 6 0 m m (1 3 ). S u chsw e llin g co u ld acco un t fo r the loss o f gb om eru la rp e rfu s io n a n d f iltra tion in sh o ck , to xe m ia o f p re g-n a n c y , o r g l om e r u lo n e ph r it is .

T h e co n c e p t of the m yo fib ro b la s t dev e lope d fromstu d ie s on fib ro bbasts in w ou nd hea ling (4 4 ). D a rb ye t a t. (4 5 ) h av e d escr ibed the d ev elo pm en t and reg res -s io n o f sm o o th m u sc le a c tin in g ran u la tion tis suef ib ro b b a s ts . T h is is a n e xa m p le o f the p la stic ity o fp h e n o typ e in the e xpre ssion o f d iffe re n t fe a tu re s incon nectiv e tis sue ce lls u nde r va rio us stim u li (46 ) . F o rexam p le, sm oo th m u sc le ce lls can acqu ire f ib ro -b la stic fea tu res ( 1 ) in th e u terus (and p o ss ib ly a c -co u n t fo r th e d e ve lo p m en t o f u te r in e fib ro m y o m a s)o r (2 ) w h e n m ig ra tin g fro m th e m e d ia to th e in tim ain a th e ro s cle ro s is . It ha s ev en b een sug gested th a tthe m ac rop hage can expres s m usc le p ro te in s (4 6 ).T h e fib rou s h is tioc y to m a m ay be d e riv ed from a m e s-enchym ab ce ll capab le o f m ub tid ire c tio n a l d iffe re n tia -tion to expre ss f ib rou s an d h is tiocy tic fea tu re s (47 ).A co n tra c tile s ys te m w o u l d h e lp m e s a n g ia l ce lls h o ldth e in fo ld ed basem en t m em bran e a g a in s t th e b lo o dp re ss u re in the c a p illa rie s (8 ,2 6 ).M esang iab ce lls have been con side red to be p en -cy te s b y se ve ra l in ve s tig a to rs . H o w e v e r, p er ic y te s a reu su a lly d e sc ribe d a s h a v in g b o n g b ra n c h in g p ro c -esse s tha t ex tend a rou nd cap illary en do th eliu m (23 ).Z im m erm an n (4 ) , hav in g ea rlie r stud ied pe ricy tesa rou nd cap illa r ies in o the r t i ssues , w as part icular lyin te re s te d in se a rc h in g fo r th e m in th e k id n e y . In o n ep re p a ra tio n o f a ca t k idn e y , h e fo u n d fiv e c e lls w ithsm a ll p ro ce s se s , a p p a re n tly g ra sp in g g b o m eru la r ca p -i l lar ies, and con clu ded th at th ey w ere p e rh a p s tru ep e ricy te s . N o o n e u s in g e le c tro n m ic ro sco p y s e e m sto h a v e d e s cr ib e d a p p ro p ria te p e r ic y te p ro ce ss e s o u t-s id e o f the e n d o th e h iu m o f the p e r ip h e ra l gb o m e ru la rca p il la ry w a ll in th e n o rm a l a n im a l. T h e re fo re , itd o e s n ot s e e m that n o rm a l m e sa n g ia l c e lls o rd in a rilyfulfi l l th e h is to log ic c rite ria fo r p er icy te s . M esang ialp ro c e sse s m a y a p p e a r in the ca p illa ry w a lls o f m e s-a n g io ca p illa ry g b o m eru b o n e p h ritis , bu t t hese wallsar e g rea tly a lte re d .

E nd ocy tic F un ctio n o f M esang ia l C ells . In 1 96 0 ,w e (5 ) desc ribed the spec ia l featu re s o f th e m esan g iabreg ion a n d its cel ls with n ew er e lec tron m icroscopytechn iques. In 1 9 6 1 , b e fo re th e co n c e p t o f th e m e s-

ang ia l reg ion w as gen era lly accep ted , F arqu ha r e t a t.(4 8 ) re p o rte d th a t in jec te d fe rritin a cc u m u la te d o nth e l u m i n a l s id e o f th e g b o m e ru la r b a se m e n t m e m -b ra n e , e s p e c ia lly in a x ia l re g io n s , a n d w a s ta ke n upb y th e d e ep c e lls , w h ich w e re c o n s id e re d to be e n d o -thel ial . In 1 962 , w e (8 ) dem on strated th a t la rg ea m o u n ts o f th o riu m d io x id e p a rtic le s w ere e n g u lfedb y ce n tro b o b u la r m e sa n g ia l ce lls w ith in 2 4 h . A d ja -cen t cap illa ry en do th elia l c e lls sh o w e d little o r n ou p ta ke . L a te r, in 1 9 6 2, F a rq u h a r a n d P a la d e (1 6 )w ro te a n a rtic le a g re e in g th a t th e a x ia l re g io n h a ds pe cia l c ha ra cte ris tic s an d sh o w in g th a t th e d e e pce lls a cc u m u la te d m ore o f th e tra c e rs th a n th e s u -pe rf ic ia l end o th eb ium . T hey c onc lud ed tha t the de epce lls co u ld b e c o n s id e re d a d is tin c tive th ird ce llt ype .

A n u m b e r o f fo re ig n su b s ta nc e s h a ve b e e n fo u n din ce lls in th e m esa ng iu m ( 1 , 1 9,20 ), bu t th e e vid en ceneeds to be re e va lu a te d in lig h t o f tw o q u e s tio n s :w e re th e ce lls th a t w e re in vo lv e d in tr in s ic m e sa n g ia lce lls o r m a cro p h a g e s , a n d w h a t ty p e o f e n d o cy to s isw as stim u la ted b y each su bstance? T h e u p ta ke o fm a c ro m o le c u la r su b s ta n ce s in to a m e m b ran e -h im -ite d o rg an elle in a liv ing ce ll is no w ca lled end ocy-to s is an d is d iv ided in to th ree typ es : ( 1 ) phagocy tos iso f la rg e p a rtic le s , (2 ) m a cro p in o cy to s is , a n d (3 )co a te d p it-m e d ia te d e n d o cy to s is , w h ich a cco u n ts fo rthe m ajo rity o f u p ta ke o f flu id -p h a se an d recep to r -b o u n d m a te r ia ls b y m o s t ce lls , w ith th e fo rm a tio n o fre ce p to s o m e s (o r e n d o so m e s ) (4 9 ). T h e s e m a tte rs w illb e co n s id e re d a g a in b e low w h e n th e g b o m e ru la r m o n -oc y te /m ac roph age is d isc uss ed .

T he M ultipo ten tial N a tu re o f M esang ial andO th e r C onn ec tive T issue C e lls . W hile the co ncep tso f d ifferen t fun ctio ns fo r th e m e s a n g ia l ce lls h a veb e e n d e v e lo p in g , e v id e n ce h a s b e e n a ccu m u la tin gth a t o th e r co n n e c tive c e ll typ e s m a y sh o w m o re th a no n e k in d o f a c tiv ity . M yo fib ro b la s ts in w o u n d h ea lin gan d in u te r in e m y o fib ro m a s a n d fib ro u s h is tio cy to -m a s h a ve b e e n m e n tio n e d a b o ve . S m o o th m u sc lece lls h a ve b e e n a sso c ia te d w ith th e p ro d u c tio n o fco lla ge n a nd e la stin in norm a l a r ter ie s (50 ) . S m o o thm u s c le c e lls fro m a rte rie s ca n in g e s t ye a s t c e lls a n dla te x sp h e re s (5 1 ). T h e y m a y a cq u ire F c a n d C 3 re ce p -to rs a n d th e ab ility to in g e s t im m u n og b o b u lin G -co a te d re d b lo o d ce lls (5 2 ). In a th e ro s c le ro s is , th e ymigrate in to th e in tim a a nd p ro d uc e co lla g e n (5 3 ).C o n s id e ra b le e v id e n c e h a s led to th e c o nc e p t o f th ea rte r ia l sm o o th m u s c le c e ll as a m ultifun ctio na l m es-en c h ym a l c e ll (5 4 ). A n o the r p o te n tia l is sh o w n b yco n n e c tiv e tis su e ce lls in m u sc le . W h en s tim u la te db y tra um a (a n d b o n e m o rp h o g e n e tic p ro te in ) , th e yca n p ro d uc e c a rti la g e a n d b o n e in a p ro c e ss ca b le dh e te ro tro p ic b o n e fo rm a tio n (fo rm e rly m y o s itis o ss i-fica n s ) (5 5 ). H e n c e , m e s a n g ia l c e lls se e m to b e p lu r i-po te n tia l a n d a re b ike o th e r co n n e c tiv e tis su e c e lls inbe in g a b le to e xh ib it d iffe re n t fu n c tio n s u p o n a p p ro-p ria te s tim ula tio n.


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$7 0 V olum e 2 S u pp le m e n t 2 19 92

T he M o noc y te /M a crop hag e in theM es ang i um

Stud ies h av e sh ow n tha t no rm a l ra t m esang ia con-ta m ph ag ocy tic ce lls d ifferen t from in trin sic m esan -g ia l ce lls and d erived from the b one m arrow (56) .Ph agocy to sis w as con side red as the up take o f la texbead s, b ac te ria , ag g reg ated gam m a g lobu lin , o r o th erla rge p artic les . T he re w ere 8 to 1 8 m esang ia l p hago-cy tes pe r g lom eru lus, and all w e re fo und to exp re ssth e leu kocy te com m on an tig en . A bo u t ha lf o f th esebear Ia d ete rm inan ts . W ith an av erage o f 28 1 m es-an g ia l ce lls in a ra t g lom eru lus (57 ) , th e ph ag ocy te swould rep re sen t b etw een 3 and 7 % (o r 1 in 35 to 1 In1 5) o f the norm a l m esang ia l p opu latio n . T h e k ine tic so f a slo w tra ffic o f m ono cy te s from the b one m arro wand th e b lood th ro ugh th e m esan g ium w ere co nsid -ered (56 ) .

A cco rd in g to the abo ve m easu rem en ts , 93 to 97 %of the m esan g ia l p opu latio n is com p osed of in trin sicm esang ia l ce lls . T he am ou n t o f u p take o f v ariou sfo re ign trace rs in the m esang ium w ith in a few m m -u te s or hou rs o f in jec tion m akes it seem like ly th atthe in tr in sic m esang ia l ce lls are inv o lved (8 ,19 ,2 0 );how eve r, w h ich ty pe o f end ocy to sis they use n eedsto be d ete rm ined . T h e typ e prob ab ly d ep en ds on th etracer .

Mo n o c y te s can loca lize in g lo m eru li w ith in m inu tes(2 9 ) o r h ours (28 ) o f an in jec tion o f p ath ogen ic o rg a-n ism s and can con trib u te to the h ype rce llu la r ity o fthe d ev elo p ing fo ca l gb om eru lon ep hritis . W ith thestim u lus o f fo reig n trace rs , m on ocy te s seem to m i-g rate in to the m esang ium (30 ,3 6 ). A fte r po ly v iny la lcoho l in jec tio ns, Ia -pos itiv e m esang ia l m on ocy te s-m ac ro phag es show ed n o up take a t 2 4 h , w h e rea sth ere w as som e in s tella te m esang ia l ce lls (58 ) . C on -sid e rab le am oun ts w ere foun d in the m on ocy te s-m ac ro phag es a fte r 3 d ay s. T he num ber o f m on o-cy te s-m ac rop hages a lso in creased be tw een 1 and 3d ay s (36 ) .

H ence , it seem s th at the in tr in sic m esang ial cellsaccoun t fo r m uch o f the end ocy tos is in the m esan -g ium w ith in the f irs t 2 4 h , an d afte r tha t, en do cy tosisby m ono cy tes -m ac ro ph ag es b eco m es p rom inen t. I tm ay be tha t af te r en coun ter ing som e substances, th ein tr in sic m esang ial ce lls s tim u late the rec ru itm en to f m o nocy tes in to th e m esan g ium from th e circu la t-ing b lood . M acrop hages can be prom in en t in g lom er-u lar d isease and m ay serve as th e p rinc ip al effec to rce ll in som e types o f g lom eru lon ep hritis (2 ) .

O T H E R F U N C T IO N S A N D R E A C T IO N S IN T H EM E S A N G I U M

Th e prol i ferat ion of m esang ia l ce lls h as been m eas-u red in d iabe tic g lo m eru lo sc leros is (59 ), com pensa -to ry h ype rtro phy (57 ), and im m uno log ica lly m ed ia tedg lo m eru lo neph ritis (2 ). L ob u la r o r d iffu se p ro life ra-

tion s o f m esang ial ce lls h av e been ob served in o th ertyp es o f g lom eru la r d isea se invo lv ing g lo m eru lo neph -r itis o r g lom eru lo sc lerosis (22 ,60 ). Inc rea sed m esan -g ia l m atr ix is ev iden t in d iffe ren t ty pes o f g lom eru -lo scle rosis . D eposits o f am y lo id , im m u ne com p lex es ,and o the r su bstances m ay o ccu r. T h ere is ev idencefo r the m ed ia tion o f g lom eru la r d isea se b y n eu tro -p h ils , m o nocy tes and m ac ro phages, ly m ph ocy te s,a nd p la te le ts (2 ) .

In som e typ es o f g lo m eru loneph ritis , pa rticu la r lym em bran opro lifera tive (o r m esang iocap illa ry ) gb -m eru lon ephritis , end o the liab ce lls m ay be lifted aw ayfro m th e cap illa ry b asem en t m em brane and the m es -ang iab ce lls m ay ex tend ou t in th e cap illa ry w all in ap rocess cab led m esang ia l in te rp ositio n (22 ,60 ). A sec-o nd basem en t m em brane fo rm s benea th the d is-p laced en do th eliu m , p ro duc ing the dou b le -con tou re ffect seen b y ligh t m icroscop y .

T H E R E LA T IO N S H IP O F T H E M E S A N G IU M T OT H E J G AG ranu la r ep itheb io id ce lls h ad been fo und in the

w a lls o f a fferen t a r ter io le s b y R uy ter (6 1 ) and O ber-ling (62 ) w hen G oorm agh tigh (63 ) and Z im m erm an n(4 ) desc rib ed in m ore de tail jux tag lo m eru lar struc -tu res con ta in in g m o d ified sm oo th m usc le ce lls . Z im -m erm ann cab led a g roup of cells a ris in g from th eaffe ren t a rte rio le o u tsid e o f the v ascu la r po le th ePotkissen w hich m ean s po la r cu sh ion in E ng lish .T he cells in it m ade c lose con tac t w ith the m acubadensa o f th e d ista l tu bu le . T he cells in the po la rcu sh ion w ere c lose ly packed an d w ere sepa ra ted o n lyb y a th in fib rou s n e tw o rk , w h ich w as m uch le ssp ro m inen t than the m ore ab und an t and d arke r sta in -ing co nnec tive tissu e f ibe rs in the ad jacen t m esan -g lum , w hich a lso con tain s few er cells . T he nuc le i inthe po la r cu sh io n m ay b e e long a ted an d p laced p ar-albel to e a ch o th e r. S tr ik in g d iffe rences a t the tran -sition fro m th e po la r cush ion to th e m esang ium w erew ell illu stra te d in sev era l fig u res (4 ) . E lec tro n m l-croscop y s tud ie s by u s (8 , 1 1 ,64 -68 ) an d o the rs(69 ,70 ) h av e con firm ed an d ex tended th e ligh t m i-croscop y o bse rv atio ns.

A lthou gh the stru ctu re s o f the po lar cush ion andth e m esan g ium ap pear q u ite d iffe ren t, th e ce lls o fth e po lar cush io n and the m esang ia l ce lls s eem to bem o d if ied sm oo th m usc le ce lls and fu nc tiona l sim ilar-itie s have lo ng been p ostu lated (8 ,69 ) . H ow eve r, anum ber o f stud ies have sho w n fun ctio na l d iffe r-en ces. A fter ad rena lecto m y , rat jux tag bom eru la r cellshad a str ik ing inc rea se in g ranu lar ity , bu t no su chgran u la rity w as foun d in m esang ia l cells (67 ). A fte rth e in jectio n o f trace rs , pene tra tion an d accum u la-tio n in the m esang ial reg io n w as rap id , bu t it w asde lay ed an d sm alle r in am o un t in th e po la r cu sh io n(8 ,27 ,35 ,3 6 ) . T he de layed app ea ran ce in the po la r


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S72 V o lu m e 2- S up p le m e nt 2 1 99 2

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