Upsala J Med Sci 90: 173-179, 1985 Arterial Hypertension-A Disease of the Juxtaglomerular Apparatus? A. Erik G . Person and UK Boberg Department of Urology, University Hospital, and the Department of Physiology and Medical Biophysics, University of Uppsala, Sweden ABSTRACl From a s p e c i a l s t r a i n o f g e n e t i c a l l y h y p e r t e n s i v e r a t s , t h e M i l a n h y p e r t e n - s i v e s t r a i n (MHS), a r t e r i a l h y p e r t e n s i o n can be t r a n s p l a n t e d w i t h t h e k i d n e y t o t h e M i l a n n o r m o t e n s i v e s t r a i n (MNS). D u r i n g development o f h y p e r t e n s i o n i n MHS r a t s t h e r e was an a c t i v a t i o n o f t h e t u b u l o g l o m e r u l a r feedback c o n t r o l t h a t re- duced g l o m e r u l a r f i l t r a t i o n r a t e , l e a d i n g t o r e t e n t i o n o f e l e c t r o l y t e s and f l u i d . T h i s i n c r e a s e d e x t r a c e l l u l a r f l u i d volume r e d u c e s feedback s e n s i t i v i t y , b u t i n a f a s h i o n t h a t g i v e s r i s e t o c h r o n i c e x t r a c e l l u l a r f l u i d e x p a n s i o n and can t h e r e b y r a i s e t h e b l o o d p r e s s u r e . I n a l i m i t e d sense, a r t e r i a l h y p e r t e n s i o n i n t h e s e a n i m a l s e x i s t s t o p r e v e n t t h e k i d n e y f r o m r e t a i n i n g more e x t r a c e l l u l a r f l u i d volume. The a l t e r e d f u n c t i o n i n t h e j u x t a g l o r n e r u l a r a p p a r a t u s o f t h e MHS r a t s t h u s may e x p l a i n t h e r i s e i n a r t e r i a l b l o o d p r e s s u r e . INTRODUCTION The t u b u l o g l o m e r u l a r feedback c o n t r o l (TGF) i s i m p o r t a n t f o r t h e c o n t r o l o f e x t r a c e l l u l a r f l u i d volume and a r t e r i a l b l o o d p r e s s u r e ( 1 1 , 1 9 ) , Recent e x p e r i - ments i n o u r l a b o r a t o r y (5,12,13) have i n d i c a t e d t h a t m a l f u n c t i o n i n g o f t h i s mechanism may be t h e cause o f development o f a r t e r i a l h y p e r t e n s i o n i n r a t s o f t h e M i l a n h y p e r t e n s i v e s t r a i n (MHS). Some e v i d e n c e i n s u p p o r t o f t h i s c o n c e p t i s d i s c u s s e d i n t h e p r e s e n t paper. I n r e c e n t y e a r s t h e g r e a t i m p o r t a n c e o f t h e i n t e r s t i t i a l space and i t s p r e s s u r e s f o r t h e f u n c t i o n o f t h e k i d n e y has become a p p a r e n t . I n t h e r a t , t h e r e n a l i n t e r s t i t i a l h y d r o s t a t i c p r e s s u r e (Pint) i s a b o u t 1-2 mm Hg under c o n t r o l c o n d i t i o n s , and i n c r e a s e d by a b o u t 2 mm Hg d u r i n g s a l i n e volume e x p a n s i o n b y 5 5 o f body w e i g h t (16,ZO). The i n t e r s t i t i a l o n c o t i c p r e s s u r e ( 3 . ) was f o u n d t o b e a b o u t 4-5 mm Hg and t o d e c r e a s e b y about 2 vm Hg d u r i n g s a l i n e volume ex- p a n s i o n (16). C o n s i d e r a b l e change e v i d e n t l y o c c u r r e d i n t h e n e t i n t e r s t i t i a l p r e s s u r e ( P . -$. i n t ) d u r i n g s a l i n e volume expansion, a s i t u a t i o n which we have i n t i n t 173 d e s c r i b e d a s " i n t e r s t i t i a l oedema". Under c o n d i t i o n s o f d e h y d r a t i o n , o n t h e o t h e r hand, t h e r a t s showed v e r y l o w h y d r o s t a t i c and h i g h i n t e r s t i t i a l o n c o t i c p r e s s u r e , c o l l e c t i v e l y d e s i g n a t e d " i n t e r s t i t i a l d e h y d r a t i o n " i n o u r s t u d i e s . I n t h e d i s c u s s i o n o f volume r e g u l a t i o n , t h e nephron may be c o n s i d e r e d as two u n i t s . One i s v o l u m e - r e g u l a t i n g , c o n s i s t i n g o f t h e g l o m e r u l u s , p r o x i m a l t u b u l e , and l o o p o f H e n l e t o t h e macula densa, a t w h i c h p o i n t t h e p o s s i b i l i t y o f a f e e d - back l o o p e x i s t s . The o t h e r u n i t may be c a l l e d t h e f i n e - a d j u s t i n g e l e c t r o l y t e and w a t e r e x c r e t o r y u n i t , c o n s i s t i n g o f t h e d i s t a l t u b u l e and c o l l e c t i n g d u c t s . C o n c e r n i n g t h e v o l u m e - r e g u l a t i n g u n i t , w h i c h we s h a l l d i s c u s s i n t h i s paper, a l a r g e f l u i d volume i s f i l t e r e d i n t o Bowman's space and from t h e r e f l o w s i n t o t h e p r o x i m a l t u b u l e . F l u i d r e a b s o r p t i o n i n t h i s segment u s u a l l y i s a c o n s t a n t f r a c t i o n o f t h e t o t a l f i l t r a t e , a b o u t 2 / 3 . I t would seem t h a t t h e mechanism o f t h i s f l u i d r e a b s o r p t i o n i s m u l t i f a c t o r i a l , and a l s o t h a t a change i n i n t e r s t i t - i a l p r e s s u r e i n d u c e d b y a l t e r e d c a p i l l a r y p r e s s u r e can modulate f l u i d t r a n s f e r ( 6 , 7 ) . I n a s i t u a t i o n t h a t l e a d s t o " i n t e r s t i t i a l oedema", t h e p r o x i m a l t u b u l a r f l u i d r e a b s o r p t i o n i s reduced, whereas d u r i n g " i n t e r s t i t i a l d e h y d r a t i o n " i t i s i n c r e a s e d . T h i s a l t e r a t i o n i n f l u i d a b s o r p t i o n r a t e may be due t o an e f f e c t on a d i r e c t pressure-dependent f l u i d t r a n s f e r a c r o s s t h e p r o x i m a l t u b u l a r w a l l (1, 10). The n e x t segment down t h e nephron t h r o u g h w h i c h t h e f l u i d passes i s t h e l o o p o f Henle. D u r i n g t h i s passage e l e c t r o l y t e s a r e p r e f e r e n t i a l l y r e a b s o r b e d , w h i l e w a t e r i s t r a n s p o r t e d t o a l e s s e r e x t e n t . T h i s e x p l a i n s t h e l o w sodium c o n c e n t r a t i o n i n t h e e a r l y d i s t a l t u b u l e . I f t h e f l u i d f l o w t h r o u g h t h i s seg- ment i s i n c r e a s e d , e l e c t r o l y t e r e a b s o r p t i o n w i l l a l s o be i n c r e a s e d , b u t n o t f u l l y p r o p o r t i o n a t e t o t h e i n c r e a s e i n f l o w , w i t h t h e r e s u l t t h a t t h e e a r l y d i s t a l sodium c h l o r i d e c o n c e n t r a t i o n , w h i c h n o r m a l l y i s l o w , w i l l r i s e ( 8 , 1 4 ) . The s i t e o f c o n t a c t between t h e a l t e r e d c e l l s i n t h e d i s t a l t u b u l e , t h e macula densa c e l l s and a r t e r i o l e s i n t h e v a s c u l a r p o l e o f t h e k i d n e y , and t h e renin-granule-containing c e l l s c o n s t i t u t e t h e j u x t a g l o m e r u l a r a p p a r a t u s . T h i s i s an i m p o r t a n t r e g u l a t o r y u n i t , t h a t can sense t h e c h l o r i d e c o n c e n t r a t i o n i n t h e d i s t a l t u b u l a r f l u i d . The system is a c t i v a t e d when t h e e l e c t r o l y t e concen- t r a t i o n i n c r e a s e s , l e a d i n g t o r e d u c t i o n i n g l o m e r u l a r c a p i l l a r y p r e s s u r e and g l o m e r u l a r f i l t r a t i o n r a t e (GFR) v i a a c t i v a t i o n o f t h e TGF mechanism, and t o i n c r e a s e d r e n i n r e l e a s e . The b a s i c f u n c t i o n o f a v o l u m e - r e g u l a t i n g u n i t i n t h e nephron can now be o u t l i n e d . I f GFR f o r some r e a s o n t e n d s t o i n c r e a s e a s a r e s u l t o f c o n s t a n t f r a c t i o n a l p r o x i m a 1 r e a b s o r p t i o n , t h e f l u i d d e l i v e r y t o t h e l o o p o f H e n l e w i l l be en- hanced. An i n c r e a s e d f l o w t h r o u g h t h i s nephron segment w i l l i n c r e a s e t h e e l e c - t r o l y t e c o n c e n t r a t i o n i n t h e e a r l y d i s t a l t u b u l e and t h e r e b y a c t i v a t e t h e j u x - t a g l o m e r u l a r a p p a r a t u s t o l o w e r t h e G F R and p r o d u c e r e n i n . I t has a l s o been found, however, t h a t t h e TGF mechanism i s o n l y s l i g h t l y a c t i v a t e d under c o n t r o l 174 conditions (11,151, i.e. the operational point is close to no activation at all (Fig. 1). This means that under control conditions there is very little activ- ation of the TGF system, just as there is only very low renin production. The question therefore arises: When is the feedback system activated to e f - fect appreciable reduction of GFR '? From several lines of evidence we have de- duced that changes in the extracellular fluid volume o r the blood pressure will alter the sensitivity of the TGF via changes in renal interstitial hydrostatic and oncotic pressures (11). Under conditions of saline volume expansion o r post- unilateral nephrectorny, o r in the initial period of ureteral occlusion- all situations with "interstitial oedema"- a low o r abolished TGF response was found, as shown by a shift of the response curve to the right in Fig. 1. This of course constitutes an important resetting of the sensitivity to avoid reduc- tion of GFR in a situation with demand f o r increased fluid excretion. GFR con- sequently can remain high despite increased distal delivery o f fluid. I n situat- ions such as saline volume expansion, renin release also is low. (mmHg) glomerular c a p i l l a r y p r e s s u r e 0 operation point 60 - e r s t i t i a I o edema " 5 5 50 c o n t r o l 4 5 - - - I n t e r s t i t i a I de h y dr a t ion " 4G - 20 30 40 10 Loop of Henle f l o w r a t e (nllmin) Fig. 1. Glomerular capillary pressure estimated for stop-flow pressure in re- lation to the f l o w rate in the loop o f Henlc. Comparisons under con- trol conditions or with "interstitial oedema" o r "interstitial dehyd- ration". The operation point for the mechanism is shown. 175 In states of dehydration, hypovolaemia o r hypotension, or following unilater- al ureteral occlusion - all situations with "interstitial dehydration"- we found high TGF sensitivity with a low flow threshold and a large reduction o f maximal glomerular capillary pressure in response to increased flow. This im- plies a shift of the response curve to the left compared with the control curve in Fig. 1. Further, in all of these situations with "interstitial dehydration", although the distal delivery of fluid was normal o r even subnormal, the increase in sensitivity was so large that the feedback was greatly activated to reduce glomerular capillary pressure and GFR. In dehydration, hypovolaemia and hypo- tension the renin releaseincreased, indicating that activation of the T G F mech- anism also proceeds parallel with renin release, a concept which accords with findings in earlier direct micropuncture studies ( 9 ) . The TGF thus is activated as a consequence of the extracellular fluid needs and the blood pressure level, and not solely as a result of increased delivery of fluid. This interrelationship, representing the influence of renal interstitial pressure on renal function, is illustrated in Fig. 2. G F R and tubular fluid reabsorption, the latter being influenced by interstitial pressure, determine the excretion rate. Furthermore, GFR and fluid reabsorption up to the early distal tubule determine the fluid load tothe juxtaglomerular apparatus. The response of this apparatus then depends on the degree of stimulation of the renal interstitial pressure. In situations with high-degree stimulation of the interstitial pressure receptor mechanism, such as hypotension, hypovolaemia and dehydration, the sensitivity of the TGF mechanism will be so high that even nor- mal o r reduced distal delivery of fluid will be sufficient to activate the jux- taglomerular apparatus that reduces GFR and increases renin production. These alterations will in turn change the urine excretion rate, which will lead to restoration of the fluid balance towards the control level. This feedback con- trol loop will then act to restore the disturbed extracellular fluid volume balance to the control level and to the control operation point. Such resetting of the TGF sensitivity is therefore an important determinant of body fluid vol- ume and an important factor in normalisation of different types of volume o r blood pressure disturbance. The TGF mechanism will strive to restore the fluid volume of the body so that it attains the operation point on the control curve. In this fashion the T G F can determine the total volume of body fluid. The link between extracellular fluid volume and blood pressure is not yet clear, though theories concerning the mode of control have been proposed (17). It is clear, however, that in patients without kidneys the extracellular volume influences blood pressure. Since the T G F mechanism and its resetting are im- portant for the actual volume of the extracellular fluid, we made comparisons of the T G F and its resetting between rats of the Milan hypertensive strain 176 c NS I I W - Tubular apparatus V I Angiotensinl tubular . L I I rurine excretion] V Renal lntersti t ial Extra cell. vdume pressure 4 fluid F i g . 2. B l o c k diagram i l l u s t r a t i n g t h e i n f l u e n c e o f r e n a l i n t e r s t i t i a l p r e s s u r e i n r e n a l volume r e g u l a t i o n . Reproduced by p e r m i s s i o n from t h e E d i t o r o f Kidney I n t e r n a t i o n a l ( f r o m r e f e r e n c e 11). (MHS) and t h e M i l a n normotensive s t r a i n (MNS). These s t u d i e s were o f p a r t i c u l a r i n t e r e s t because t h e h y p e r t e n s i v e disease i n MHS r a t s can be t r a n s p l a n t e d w i t h t h e kidney ( 2 ) . Because o f d i f f e r e n c e s i n r e n a l f u n c t i o n , we s t u d i e d MHS r a t s d u r i n g t h r e e phases o f l i f e , and MNS r a t s a t corresponding ages. The r a t s were f i r s t s t u d i e d i n t h e p r e h y p e r t e n s i v e phase, a f t e r weaning a t t h e age o f 4-5 weeks, when t h e i r weight was 60-100 kg. The second phase was d u r i n g development o f h y p e r t e n s i o n , which occurs a t 5-7 weeks when t h e body weight i s 90-150 g, and t h e t h i r d was an a d u l t phase, a t age about 3 months w i t h weight 250-350 9. E a r l i e r s t u d i e s by o t h e r a u t h o r s ( 3 ) showed t h a t MHS r a t s i n t h e p r e h y p e r t e n s i v e phase had h i g h GFR and low r e n i n p r o d u c t i o n compared w i t h MNS r a t s . I n r e c e n t i n v e s t i g a t i o n s ( 5 , 1 2 ) we found t h a t i n t h e p r e h y p e r t e n s i v e phase t h e MHS r a t s had no TGF re- sponse a t a l l , w h i l e MNS r a t s showed normal response. T h i s absence o f a feed- back response can e x p l a i n t h e h i g h GFR, s i n c e t h e o p e r a t i o n p o i n t u s u a l l y shows some s l i g h t a c t i v a t i o n o f t h e TGF mechanism i n response t o reduced GFR. These f i n d i n g s a r e a l s o i n l i n e w i t h t h e low r e n i n r e l e a s e t h a t was observed. D u r i n g development o f h y p e r t e n s i o n , by c o n t r a s t , t h e MHS r a t s d i s p l a y e d a TGF mechanism w i t h very h i g h s e n s i t i v i t y , w i t h a low f l o w t h r e s h o l d l e a d i n g t o 177 activation o f the TGF to reduce GFR. In this phase there is relative reduction in GFR and relative increase in renin production and sodium retention. These observations can readily be explained by the high feedback sensitivity, which will reduce GFR and retain electrolytes. The process thus will lead to fluid retention in the MHS animals that will tend to normalize TGF sensitivity but also increase arterial blood pressure. Indeed, in the adult MHS rats we found a normal TGF response. However, both in the adult MHS rats and during the de- velopment of hypertension, the resetting of TGF sensitivity was impaired. Dur- ing volume expansion the high sensitivity was only slightly reduced, and was not reset to a lower level as it was in the MNS rats. We also found that the inter- stitial pressure was normal both under control conditions and during volume ex- pansion. A change in interstitial pressure could therefore not explain the im- paired TGF resetting. The mechanism of action, speculatively, seems to be as follows. There is an increased transmembrane electrolyte transport in red cells and proximal tubular cells of MHS rats. Many cells in the MHS rat appear to have this transport ab- normality (4). If the abnormal transport occurs also in the macula densa cells, an increase in chloride o r sodium chloride transport may activate the feedback and explain the high sensitivity that develops in this situation. The impaired resetting during volume expansion will then keep GFR low and retain fluids and electrolytes even when there is a volume overload. The result will be a rise in arterial blood pressure. Both the volume expansion and the increase in blood pressure can then restore the TGF sensitivity to a normal level. Thus, in a limited sense it appears that the high arterial pressure in the MHS rats exists in order to prevent the kidney from retaining an even greater extracellular volume of fluid. These studies have convinced us that the TGF mechanism plays an in 1. 2 . 3. 4. 178 important r o l e in the development and maintenance of arterial hypertension the MHS rats. REFERENCES Agerup, B . & Persson, A.E.G.: Modulation of proximal tubular hydraulic conductivity by peritubular capillary oncotic pressure. Acta Physiol Scand 115:355-359,1982. Bianchi, G., Fox, U., Difrancesco, C.F., Giovanetti, A.M. & Pagetti, D.: Blood pressure changes produced by kidney crosstransplantation between spontaneously hypertensive rats and normotensive rats. Clin Sci Mol Med 47:435-448,1974. 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Physiol Rev 59:958-1006,1979. Wunderlich,P., Persson,E., Schnermann,J., Ulfendah1,H. & Wolgast,M.: Hy- drostatic pressure in the subcapsular interstitial space o f rat and dog kidneys. Pflugers Arch 328:307-319,1971. 75-81,1983. 5. 6. 7. 8 . 9. 10. 11. 1 2 . 13. 14. 15. 16. 1 7 . 18. 19. 20. Address for reprints A. Erik G. Persson Department of Urology University Hospital S-751 85 Uppsala Sweden 179