Les liaisons dangereuses: the inextricable link between blood pressure and kidney. The hypertensive rat strains as a possibility to untangle it

Sironi, Luigia,b; Gelosa, Paoloa

Journal of Hypertension:
doi: 10.1097/HJH.0b013e328353e0ee
Editorial Commentaries
Author Information

aDepartment of Pharmacological Sciences, University of Milan

bCentro Cardiologico Monzino, I.R.C.C.S., Milan, Italy

Correspondence to Dr Luigi Sironi, Department of Pharmacological Sciences, University of Milan, Via G. Balzaretti 9, 20133 Milan, Italy. Tel: +39 02 503 18291; fax: +39 02 503 18250; e-mail: luigi.sironi@unimi.it

Article Outline

Hypertension is a major risk factor for cerebrovascular and cardiovascular disorders and for end-stage renal disease. However, the link between blood pressure (BP) and kidney function is particularly intricate. Indeed, hypertension is not only cause but also effect of established kidney disease. The pathophysiological consequences of this nexus are well known, but the mechanisms by which BP tends to rise in renal failure are as yet to be fully elucidated. Notably, the direct contribution of BP to the development of renal tissue damage remains poorly understood. Important information could be gathered from several studies in animal models of hypertension, in particular in animals spontaneously developing high BP [1]. The review by Hultström [2] published on this issue of the Journal of Hypertension describes the pathological processes observable in the renal structure of the spontaneously hypertensive rat (SHR). Interestingly, the author chronologically organizes the sequence of the pathological processes occurring in the kidney of spontaneously hypertensive rats (SHR): a collapse of the glomeruli follows the initial vascular media hypertrophy, at the juxtamedullary cortex level. Thereafter, tubular atrophy ensues. The author reports and convincingly discusses substantial evidence suggesting that renal damage in the SHR is due to altered pressure-dependent autoregulation of renal blood flow.

In the last decade, our group has accumulated several data on another spontaneously hypertensive strain that is closely related to SHR, the spontaneously hypertensive stroke-prone rat (SHRSP) [3–5]. In agreement with the description of SHR in the review by Hultström, we observed histological changes of the SHRSP vascular structure, accompanied by a focal effacement of the foot processes of glomerular podocytes and preceding tubular atrophy [5,6]. Substantial experimental evidence – obtained with histological, functional, and proteomic approaches – show highly remarkable differences in the development of renal lesions in SHRSP as compared with SHR [7–9]. With respect to SHR, the SHRSP develops a more severe and more rapid BP increase [7]; this phenomenon could be at the origin of the different scores of renal damage. In particular, differences in the onset of hypertension could influence the adaptive changes in renal vessels, rendering the SHR more resistant to hypertensive injuries.

Is it the BP that is the only contributor to the ‘proneness’ to develop renal damage? Some authors suggest that the different susceptibility of SHRSP to renal damage may also be due to different genetic factors [10,11]. Churchill et al.[11] have elegantly investigated this aspect by using a cross-transplantation approach. In particular, uninephrectomized SHRSP and SHR recipients were transplanted with kidneys from SHR and SHRSP, respectively. This approach allows evaluating the susceptibility to renal damage in kidneys preserved in the same host and exposed to the same BP profile and the same metabolic environment. Both native and transplanted SHRSP kidneys showed significantly more renal damage as compared to the transplanted and native SHR kidneys. These results suggest that, when exposed to the same BP level and dietary regimen of the SHR, the SHRSP kidney is intrinsically more susceptible to renal injury. Genetic differences in the structural and/or functional characteristics of the renal vasculature or in the local tissue mediators, e.g. the renin–angiotensin system or sympathetic system [12], might play a role in the development of renal damage. Gigante et al.[9], who investigated the contribution of genetic factors to the enhanced susceptibility to renal damage of SHRSP in an SHRSP/SHR F2 intercross by means of a genotype/phenotype cosegregation analysis, reached the same conclusions. In fact, their results demonstrated that the susceptibility to renal damage is influenced by several genetic loci, acting independently from high BP levels. Furthermore, under similar experimental conditions of BP, the renal blood flow and hemodynamic behaviors were different in SHRSP and SHR, suggesting that the predisposition to develop renal damage is BP independent [8].

In conclusion, data collected by the available animal models of hypertension seem to indicate that in addition to a direct effect of BP, other (genetic and/or acquired) factors intrinsic to the kidney could be involved in the susceptibility to the BP challenge. A full elucidation of these aspects could help clarify the link between BP and renal damage, in turn opening new possibilities in the treatment of renal and cardiovascular diseases.

Back to Top | Article Outline


Conflicts of interest

There are no conflicts of interest.

Back to Top | Article Outline


1. Dornas WC, Silva ME. Animal models for the study of arterial hypertension. J Biosci 2011; 36:731–737.
2. Hultström M. Development of structural kidney damage in spontaneously hypertensive rats. J Hypertens 2012; 30:1087–1091.
3. Ballerio R, Gianazza E, Mussoni L, Miller I, Gelosa P, Guerrini U, et al. Gender differences in endothelial function and inflammatory markers along the occurrence of pathological events in stroke-prone rats. Exp Mol Pathol 2007; 82:33–41.
4. Gelosa P, Banfi C, Gianella A, Brioschi M, Pignieri A, Nobili E, et al. Peroxisome proliferator-activated receptor {alpha} agonism prevents renal damage and the oxidative stress and inflammatory processes affecting the brains of stroke-prone rats. J Pharmacol Exp Ther 2010; 335:324–331.
5. Gianella A, Nobili E, Abbate M, Zoja C, Gelosa P, Mussoni L, et al. Rosuvastatin treatment prevents progressive kidney inflammation and fibrosis in stroke-prone rats. Am J Pathol 2007; 170:1165–1177.
6. Gelosa P, Pignieri A, Fandriks L, de Gasparo M, Hallberg A, Banfi C, et al. Stimulation of AT2 receptor exerts beneficial effects in stroke-prone rats: focus on renal damage. J Hypertens 2009; 27:2444–2451.
7. Sironi L, Tremoli E, Miller I, Guerrini U, Calvio AM, Eberini I, et al. Acute-phase proteins before cerebral ischemia in stroke-prone rats: identification by proteomics. Stroke 2001; 32:753–760.
8. Abu-Amarah I, Bidani AK, Hacioglu R, Williamson GA, Griffin KA. Differential effects of salt on renal hemodynamics and potential pressure transmission in stroke-prone and stroke-resistant spontaneously hypertensive rats. Am J Physiol Renal Physiol 2005; 289:F305–313.
9. Gigante B, Rubattu S, Stanzione R, Lombardi A, Baldi A, Baldi F, Volpe M. Contribution of genetic factors to renal lesions in the stroke-prone spontaneously hypertensive rat. Hypertension 2003; 42:702–706.
10. Churchill PC, Churchill MC, Griffin KA, Picken M, Webb RC, Kurtz TW, Bidani AK. Increased genetic susceptibility to renal damage in the stroke-prone spontaneously hypertensive rat. Kidney Int 2002; 61:1794–1800.
11. Rubattu S, Volpe M, Kreutz R, Ganten U, Ganten D, Lindpaintner K. Chromosomal mapping of quantitative trait loci contributing to stroke in a rat model of complex human disease. Nat Genet 1996; 13:429–434.
12. Griffin KA, Churchill PC, Picken M, Webb RC, Kurtz TW, Bidani AK. Differential salt-sensitivity in the pathogenesis of renal damage in SHR and stroke prone SHR. Am J Hypertens 2001; 14:311–320.
© 2012 Lippincott Williams & Wilkins, Inc.