Journal of Hypertension:
Juxtamedullary preglomerular vascular injury precedes glomerular and tubulointerstitial injuries during the development of hypertension
Kono, Yumikoa; Horii, Taikoa; Nishiyama, Akirab
aDepartment of Cardiovascular Surgery
bPharmacology, Kagawa University Medical School, Kagawa, Japan
Correspondence to Akira Nishiyama, MD, PhD, Department of Pharmacology, Kagawa University Medical School, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan. Tel: +81 87 891 2125; fax: +81 87 891 2126; e-mail: email@example.com
Chronic kidney disease (CKD) is a major public health problem and a risk factor for all-cause mortality and cardiovascular disease . Although the mechanisms underlying the occurrence of CKD are extremely complex, hypertension is the most important independent risk factor for CKD . Therefore, blood pressure control is necessary for kidney protection in hypertensive patients with CKD .
Accumulating evidence has indicated that morphologic changes initially develop in the juxtamedullary cortex and then extend toward the superficial cortex during the development of hypertension. In spontaneously hypertensive rats, afferent arteriolopathy and glomerular sclerosis are observed primarily in the juxtamedullary nephrons . Nagasawa et al. showed that albuminuria was associated with juxtamedullary nephron injury in stroke-prone spontaneously hypertensive rats fed a high-salt diet. They also showed that blood pressure reduction by treatment with an L-type calcium channel antagonist, nifedipine, attenuated the progression of albuminuria with a concomitant improvement in the juxtamedullary nephron injury. These findings are consistent with the concept that the albuminuria is a result of juxtamedullary nephron injury induced by blood pressure elevation.
In hypertensive type 2 diabetic Otsuka Long-Evans Tokushima Fatty rats with nephrotic range albuminuria, juxtamedullary glomerular podocyte injury reached a severe condition more rapidly than superficial glomerular podocyte injury . In these animals, treatment with an angiotensin II (AngII) receptor blocker (ARB) resulted in a marked reduction in the albuminuria with regression of the superficial glomerular podocyte injury, whereas severely damaged juxtamedullary glomerular podocyte were not affected by ARB treatment. Interestingly, blood pressure reduction with nonspecific vasodilators (combination of hydralazine, reserpine, and hydrochlorothiazide) did not attenuate the glomerular podocyte injury, but partially attenuated the progression of albuminuria. These data suggest that the moderate effects of nonspecific vasodilators on the progression of albuminuria are simply associated with changes in the glomerular hemodynamics induced by blood pressure reduction, and are not mediated through podocyte protection. To investigate whether renal injury is induced by blood pressure or AngII, Mori and Cowley  utilized servo-control techniques in unanesthetized salt-treated AngII-infused hypertensive rats. By using these techniques, the left kidney perfusion pressure could be continuously servo-controlled at normal levels, whereas the right kidney was exposed to hypertension. The results revealed that the right kidney showed tubular necrosis and interstitial fibrosis at the outer medullary region, which was accompanied by glomerular sclerosis and interlobular arterial injury, although these renal changes were not obvious in the left kidney. These data suggested that in high salt-treated AngII-infused hypertensive rats, renal damage in the juxtamedullary cortex was predominantly induced by renal arterial pressure elevation during the development of AngII-dependent hypertension.
In the current issue of Journal of Hypertension, Skogstrand et al. carefully investigated the time-dependent changes in the vascular and tubulointerstitial structures in two-kidney one-clip (2K1C) renal hypertensive rats. The results showed that the perivascular collagen deposition in the juxtamedullary preglomerular vessels was already increased in the early phase (16 weeks after clipping), at which time tubulointersitial injury was not yet apparent. Based on these observations, the authors suggest that in the nonclipped kidneys of 2K1C hypertensive rats, juxtamedullary preglomerular vascular damage occurs first and contributes as a general mechanism responsible for hypertension-dependent tubulointerstitial injury.
Skogstrand et al. also speculate that if progression of tubulointerstitial injury in the juxtamedullary cortex is accompanied by juxtamedullary preglomerular vascular injury induced by perfusion pressure elevation, evaluation of juxtamedullary preglomerular vascular injury should be important for predicting the onset of CKD later in life. In this regard, Sofue et al. retrospectively analyzed adult living-donor kidney transplants and showed that arteriosclerotic vasculopathy in the donated kidney is an important pathological factor that underlies future impaired function of renal allografts from marginal donors. Sofue et al. did not separately evaluate the preglomerular vascular damage in the superficial and juxtamedullary glomeruli. However, their findings are consistent with the hypothesis based on the observations of Skogstrand et al. that evaluation of preglomerular vascular injury may be a useful predictor for future of hypertensive CKD patients and that it has important implications for therapeutic strategies aimed at renal injury.
Skogstrand et al. also speculate that the efficiency of autoregulation to control interlobular perfusion pressure is impaired in the juxtamedullary cortex. In this regard, several studies have indicated that, in addition to anatomical heterogeneities between juxtamedullary and superficial nephrons, there are several functional differences in the control of juxtamedullary and superficial glomerular hemodynamics during the development of hypertension . Unfortunately, however, Skogstrand et al. did not measure any parameters of renal hemodynamics and function. There are also several other limitations to this study. For example, the authors suggest the importance of matrix metalloproteinases (MMP-2 and MMP-9) and tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) for the perivascular collagen metabolism, but their actual activities were not measured. Furthermore, although it has been demonstrated that both the occurrence of microalbuminuria and the degree of overt albuminuria can be considered as predictors for the occurrence and/or progression of CKD , the authors did not investigate the time-dependent changes in the urinary excretion rate of albumin. Further studies will be expected to address these issues.
In conclusion, Skogstrand et al. carefully investigated the time-dependent morphological changes in the nonclipped kidneys of 2K1C rats. Their current findings clearly indicate that juxtamedullary preglomerular vascular injury precedes glomerular and tubulointerstitial injuries during the development of hypertension. The precise pathophysiological mechanisms and the application of these findings to possible therapies remain to be investigated. Nevertheless, their findings suggest the possibility that perivascular deposition of collagen and myofibroblasts is a predictor for hypertensive renal injury later in life. In clinical practice, we usually perform a renal needle biopsy for the diagnosis of a renal injury. As superficial tissues are generally collected by this method, the juxtamedullary nephrons are rarely observable. Therefore, it is particularly important for nephrologists to always bear in mind that the juxtamedullary nephrons may already be injured and the possible existence of this injury should be taken into account when treating patients who are developing hypertension.
Conflicts of interest
There are no conflicts of interest.
1. Chronic kidney Disease Prognosis Consortium, Matsushita K, van der Velde M, Astor BC, Woodward M, Levey AS, de Jong PE, et al
. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet
2. Hanratty R, Chonchol M, Havranek EP, Powers JD, Dickinson LM, Ho PM, et al. Relationship between blood pressure and incident chronic kidney disease in hypertensive patients. Clin J Am Soc Nephrol
3. Appel LJ, Wright JT Jr, Greene T, Agodoa LY, Astor BC, Bakris GL, et al. AASK Collaborative Research GroupIntensive blood-pressure control in hypertensive chronic kidney disease. N Engl J Med
4. Hultström M, Leh S, Skogstrand T, Iversen BM. Upregulation of tissue inhibitor of metalloproteases-1 (TIMP-1) and procollagen-N-peptidase in hypertension-induced renal damage. Nephrol Dial Transplant
5. Nagasawa T, Mori T, Ohsaki Y, Yoneki Y, Guo Q, Sato E, et al. Albuminuria indicates the pressure-associated injury of juxtamedullary nephrons and cerebral strain vessels in spontaneously hypertensive stroke-prone rats. Hypertens Res
6. Ihara G, Kiyomoto H, Kobori H, Nagai Y, Ohashi N, Hitomi H, et al. Regression of superficial glomerular podocyte injury in type 2 diabetic rats with overt albuminuria: effect of angiotensin II blockade. J Hypertens
7. Mori T, Cowley AW Jr. Role of pressure in angiotensin II-induced renal injury: chronic servo-control of renal perfusion pressure in rats. Hypertension
8. Skogstrand T, Leh S, Paliege A, Reed RK, Vikse BE, Bachmann S, et al
. Arterial damage precedes the development of interstitial damage in the nonclipped kidney of two-kidney, one-clip hypertensive rats. J Hypertens
9. Sofue T, Inui M, Kiyomoto H, Moritoki M, Nishioka S, Nishijima Y, et al. Preexisting arteriosclerotic intimal thickening in living-donor kidney reflects allograft function. Am J Nephrol
10. Ito S, Nagasawa T, Abe M, Mori T. Strain vessel hypothesis: a viewpoint for linkage of albuminuria and cerebro-cardiovascular risk. Hypertens Res
11. Ito S. Cardiorenal connection in chronic kidney disease. Clin Exp Nephrol
© 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins