Progression of renal failure with anaemia and multiple effects of angiotensin-converting enzyme inhibitor in rats with renal mass reduction.
Several factors such as proteinuria and renal fibrosis may be important in the progression of many forms of chronic renal diseases. The purposes of the current study were to investigate the progressive renal failure of the rats with surgical renal mass reduction (RMR) and the effect of the angiotensin-converting enzyme (ACE) inhibitor, lisinopril, and to document correlation of several factors associated with progressive renal failure. Rats were subtotal (5/6) nephrectomized by resection of the renal poles and sham-operated. The functional, histological and haematological changes of the rats were studied for up to 10 weeks. After 2 weeks of RMR, oral administration of lisinopril (10 mg kg(-1) per day) was performed for 8 weeks. RMR resulted in progressive renal failure with proteinuria, monocyte/macrophage (ED1+) infiltration, anaemia as assessed by haemoglobin and haematocrit (Htc), renal hypertrophy as assessed by left kidney to body weight ratio (BKW/BW), and renal fibrosis as assessed by glomerular lesions and tubulointerstitial changes. Lisinopril exhibited renoprotection with antiproteinuric effect and inhibition of monocyte/macrophage (ED1+) infiltration. However, beneficial effect of lisinopril on anaemia was not observed. At 10 weeks after surgery, severity of proteinuria positively correlated with plasma creatinine (Pcr), BKW/BW, histological damage, and systolic blood pressure, and negatively correlated with haemoglobin. Severity of tubulointerstitial changes positively correlated with Pcr and blood urea nitrogen, and negatively correlated with haemoglobin and Htc. Moreover, monocyte/macrophage (ED1+) infiltration positively correlated with severity of proteinuria and tubulointerstitial changes. These findings strongly support that proteinuria, monocyte/macrophage infiltration and renal fibrosis appear to play principal roles in the progressive renal failure with anaemia and renoprotection of ACE inhibition may be mediated by multiple actions of ACE inhibitor. The present study confirms that rats with RMR is useful to explore target molecules for renoprotective drugs and evaluate renoprotective effect of new molecular entities.
Yatsu
Takeyuki
T
Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
Sanagi
Masanao
M
Fujimori
Akira
A
Tomura
Yuichi
Y
Hayashi
Kazumi
K
Tanahashi
Masayuki
M
Inagaki
Osamu
O
D000704:Analysis of Variance; D000740:Anemia / Q000150:complications / Q000503:physiopathology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D007668:Kidney / Q000473:pathology / Q000601:surgery; D017706:Lisinopril / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D011507:Proteinuria / Q000209:etiology; D051381:Rats; D017208:Rats, Wistar; D051437:Renal Insufficiency / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*
D000806:Angiotensin-Converting Enzyme Inhibitors; D017706:Lisinopril