Sustained tubulo-interstitial protection in SHRs by transient losartan treatment: an effect of decelerated aging?
BACKGROUND
Hypertensive target organ damage shows characteristics of accelerated cell turnover and aging. This might have developed during the evolution of hypertension. In the kidney, high cell turnover is mainly restricted to tubular cells. It was the aim of this study to investigate whether a transient intervention in spontaneously hypertensive rats (SHRs) leads to reduced tubular cell turnover and attenuates the renal aging process and tubulo-interstitial damage in the long-term.


METHODS
SHRs (i) were prehypertensively (weeks 4-8) treated with losartan (ii) or hydralazine (iii) (20 and 4 mg/kg/day, respectively) and compared to Wistar-Kyoto (WKY) rats (iv). Groups were investigated at weeks 8 and 72 (except iii). At both time points tubular cell proliferation (proliferative cell nuclear antigen) and systolic blood pressure (SBP) were evaluated. At week 72, aging parameters such as telomere length were assessed. Renal damage was semiquantitatively assessed (scale: 0-4) by measuring the parenchyma (atrophy) and vasculature (media thickness).


RESULTS
Treatments equipotently reduced SBP in young SHRs (P < 0.01) but only losartan reduced renal proliferation (proliferative cell nuclear antigen: (i) 2.8 +/- 0.8, (ii) 1.3 +/- 0.3, (iii) 3.0 +/- 0.6, (iv) 0.1 +/- 0.1 cells/mm(2)). In SHRs treated with losartan(SHR-Los) tubular proliferation remained reduced and renal telomere length was significantly greater than in untreated SHRs (fold: (i) 1.0 +/- 0.1, (ii) 2.8 +/- 0.3, P < 0.01). Untreated SHRs (median 2.0, range 1-3; P < 0.007), but not SHR-Los (median 1.0, range 0-2; P = 0.06) demonstrated more tubular atrophy than WKY rats (median 0.5, range 0-1).


CONCLUSIONS
Transient losartan treatment reduces cell-turnover not only acutely but also for a prolonged period after drug withdrawal. This results in the long-term in reduced aging and attenuated tubulo-interstitial damage, suggesting there exists a modulating effect of angiotensin II (ANGII)-antagonism on long-term cell turnover.
Baumann
Marcus
M
Department of Pharmacology and Toxicology, CARIM, University Maastricht, The Netherlands. Marcus.baumann@lrz.tum.de
Bartholome
Roger
R
Peutz-Kootstra
Carine J
CJ
Smits
Jos F M
JF
Struijker-Boudier
Harry A J
HA
D000375:Aging / Q000502:physiology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D006965:Hyperplasia; D006977:Hypertension, Renal / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D007684:Kidney Tubules / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY
D047228:Angiotensin II Type 1 Receptor Blockers; D019808:Losartan