Effects of aging and uninephrectomy on renal changes in Tsukuba hypertensive mice (2024)

Renal dysfunction is accelerated by various factors such as hypertension, aging and diabetes. Glomerular hyperfiltration, considered one of the major risk factors leading to diabetic nephropathy, is often encountered in diabetic patients. However, the interrelationship of these risk factors during the course and development of renal dysfunction has not been fully elucidated. In this study, the effects of aging and uninephrectomy (UNx)‑induced hyperfiltration on renal changes were investigated in Tsukuba hypertensive mice (THM) carrying both human renin and angiotensinogen genes. In THM, the urinary albumin/creatinine (Alb/Cr) ratio was elevated with age without a concomitant increase in the plasma Cr concentration. Moreover, the urinary neutrophil gelatinase‑associated lipocalin/Cr (NGAL/Cr) ratio, the renal monocyte chemoattractant protein‑1 (MCP‑1) mRNA expression and the renal collagen typeIα2 (COL1A2) mRNA expression were also increased with age. Age‑related albuminuria in THM is likely caused by renal tubular damage, enhanced inflammatory response and tubulointerstitial fibrosis. Furthermore, following UNx, the urinary Alb̸Cr ratio and the plasma Cr concentration were increased in THM. The urinary NGAL/Cr ratio and the renal MCP‑1 and COL1A2 mRNA expression were not affected by UNx. These results suggested that UNx‑induced albuminuria in THM was caused by glomerular dysfunction, rather than renal tubular injury. In conclusion, this study demonstrated for the first time the effects of aging and UNx on renal changes in THM. These findings strongly reinforce the significance of applying a diversity of therapeutic approaches to the management of renal dysfunction.


Chronic kidney disease (CKD) is a major publichealth concern worldwide because of the increasing prevalence ofend-stage renal failure requiring dialysis or kidneytransplantation and the increased risk of morbidity and mortalitydue to cardiovascular diseases (16). Agingleads to renal structural changes and functional decline. Imaiet al(7) and Coresh etal(8) suggested that theprevalence of CKD increases with age. Moreover, a significantlyhigher prevalence of CKD was reported in hypertensive patientscompared to normotensive subjects (8,9). Highsystemic blood pressure leads to pressure elevation in theglomerular capillaries, which is associated with renal vasculardysfunction. Elevated pressure in the glomerular capillariesresults in glomerular sclerosis, increased albuminuria anddecreased glomerular filtration rate (10). Furthermore, glomerularhyperfiltration is often observed during the early stages ofdiabetes and may contribute to the development of diabeticnephropathy (11,12). Thus, the progression of CKD isaffected by various risk factors such as aging, hypertension andhyperfiltration. However, the interrelationship of individual riskfactors during the course of renal dysfunction has not been fullyelucidated.

Tsukuba hypertensive mice (THM) are transgenic micecarrying both human renin and angiotensinogen genes. These animalsare prone to developing hypertension (1315).Kai et al(16,17) observed albuminuria and glomerularsclerosis in 28-week-old THM. Thus, the THM is a useful model ofhypertensive nephropathy induced by overproduction of angiotensinII.

In the present study, the effects of aging anduninephrectomy (UNx)-induced hyperfiltration on renal dysfunctionwere investigated in THM, as was the interrelationship of riskfactors during the development of renal disease under hyper-tensiveconditions.

Materials and methods


Male THM were purchased from RIKEN BioResourceCenter (Ibaraki, Japan) with the support of the NationalBio-Resource Project of the Ministry of Education, Culture, Sports,Science and Technology of Japan. Age-matched male C57BL/6J mice,used as genetic background-matched wild-type mice (WTM), werepurchased from Clea Japan Co., Ltd. (Tokyo, Japan). The mice werehoused in a room maintained at 22±2°C with 55±5% relative humidity,exposed to a 12:12-h light-dark cycle and allowed free access tofood and water. The animal experiments were performed in accordancewith the ethical guidelines established by the Experimental AnimalCare and Use Committee of Mitsubishi Tanabe Pharma Corporation.


THM and WTM, 22–26 weeks of age, were subjected toUNx or sham operation under sevoflurane (Maruishi PharmaceuticalCo. Ltd., Osaka, Japan) anesthesia. For UNx, the abdomen was openedthrough a left paramedian incision and the left kidney was exposed.The renal vessels and ureter were carefully isolated, ligated witha silk thread and the distal portions were cut. Control animalsunderwent sham operation. The mice were sacrificed at 6 weeks aftersurgery.

Sample collection

Prior to sacrifice, 24-, 36-, 48- and 60-week-oldmale THM and WTM, uninephrectomized THM (UNx-THM) and WTM (UNx-WTM)and sham-operated THM (sham-THM) and WTM (sham-WTM), were placedindividually in metabolic cages (Shinano Manufacturing Co., Ltd.,Tokyo, Japan) for 24-h urine collection. Urine samples werecentrifuged at 1,000 × g for 10 min at 20°C and the supernatantswere stored at −20°C until analysis. The mice were anesthetizedwith sevoflurane and sacrificed by whole blood collection from theabdominal aorta. Blood samples were centrifuged at 3,000 × g for 5min at 4°C and the plasma was separated and stored at −80°C untilanalysis. Immediately after the animals were sacrificed, the wholekidneys of 24-, 36-, 48- and 60-week-old THM and WTM were isolatedand stored in RNAlater® solution (Life Technologies,Inc., Gaithersburg, MD, USA) at −80°C until RNA extraction andanalysis. In the UNx experiment, approximately half of the rightkidneys were isolated and stored in RNAlater solution, then storedat −80°C until analysis. Part of the remaining halves of the rightkidneys were fixed with 2.5% glutaraldehyde in phosphate buffer,post-fixed in 1% osmium tetroxide and embedded in epoxy resinblocks for examination under an electron microscope. The remainingparts of the right kidneys were fixed with 10% formalin andembedded in paraffin blocks for staining with periodicacid-Schiff's base.

Measurement of markers of renalfunction

Urinary albumin (Alb) and neutrophilgelatinase-associated lipocalin (NGAL) concentrations weredetermined by the Mouse Albumin ELISA kit (Shibayagi Co., Ltd.,Gunma, Japan) and Mouse Lipocalin-2/NGAL Quantikine ELISA kit(R&D Systems Inc., Minneapolis, MN, USA), respectively. Urinaryand plasma creatinine (Cr) concentrations were measured by Jaffe'smethod using the Creatinine-Test-Wako (Wako Pure ChemicalIndustries, Ltd., Osaka, Japan). Alb and NGAL excretion wereexpressed as the Alb/Cr and NGAL/Cr ratios, respectively.

Measurement of mRNA expression

Total RNA was isolated from the kidneys usingTRIzol® reagent (Life Technologies, Inc.). Reversetranscription to cDNA of 1 μg of total RNA from each samplewas performed using the High Capacity RNA-to-cDNA kit (LifeTechnologies, Inc.). Real-time polymerase chain reaction (PCR) wasperformed on a 7500 Fast Real-Time PCR system (Life Technologies,Inc.), using specific TaqMan Gene Expression assays for monocytechemoattractant protein-1 (MCP-1) (Mm00441242_m1) and renalcollagen type I α 2 (COL1A2) (Mm00483888_m1) (Life Technologies,Inc.), according to the manufacturer's instructions. Expressionlevels of target genes were normalized to the levels of 18S rRNAwhich was measured with the TaqMan® Ribosomal RNAControl Reagents kit (Life Technologies, Inc.).

Histology and electron microscopy

The glomerular sclerosis index (GSI) was calculatedaccording to the method previously described by Simokama etal(18). Glomerular lesionswere graded from 0 to 4+ on the basis of the extent of glomerulardamage and evidence of tuft involvement, as follows: 0, no evidenceof lesions; 1+, ≤25% of tufts affected by sclerosis; 2+, tuftinvolvement of 25–50%; 3+, tuft involvement of 50–75%; 4+, almostcomplete tuft involvement. For each kidney, the sum of the resultsfor 20 glomeruli was defined as the GSI. The structural integrityof the glomerular filtration barrier was confirmed by examinationunder an electron microscope. Semi-thin sections from each epoxyresin block, stained with toluidine blue, were used to select areasfor electron microscopic examination. Ultra-thin sections werestained with uranyl acetate and lead citrate and examined under anH-7500 electron microscope (Hitachi, Ltd., Tokyo, Japan).

Statistical analysis

Values were presented as the mean ± standard errorof the mean (SEM), unless otherwise stated. The results wereanalyzed using GraphPad Prism version 5.02 (GraphPad Software,Inc., San Diego, CA, USA). Linear regression analysis was performedto calculate the slope of the age-related changes in THM and WTM.Analysis of variance was used to compare the slopes between THM andWTM. The significance of differences between UNx- and sham-THM, orUNx- and sham-WTM, was evaluated using the Student's t-test.Probabilities <5% (P<0.05) were considered to indicate astatistically significant difference.


Effects of aging on glomerular andtubular injury in THM

The urinary Alb/Cr and NGAL/Cr ratios in 60-week-oldTHM were higher than those in 60-week-old WTM (785.5±167.1 vs.97.5±55.5 μg/mg and 802.2±194.6 vs. 65.8±9.2 mg/mg,respectively). THM and WTM exhibited a linear increase in theurinary Alb/Cr ratio with age, with a slope [95% confidenceinterval (CI)] of 17.8 (10.1–25.6) (r2=0.363, P<0.01)and 2.45 (0.267–4.63) (r2=0.123, P<0.05),respectively. The slope of THM was significantly steeper than thatof WTM (Fig. 1A and B). Inaddition, a linear increase in the urinary NGAL/Cr ratio with agewas also demonstrated by a slope (95% CI) of 18.4 (10.4–26.4)(r2=0.365, P<0.01) for THM and 1.11 (0.395–1.82)(r2=0.212, P<0.01) for WTM. The age-related increasein the urinary NGAL/Cr ratio was more pronounced in THM (Fig. 1C and D). As shown in Fig. 2A and B, a more marked increase inrenal MCP-1 mRNA expression with age was observed in THM, comparedto that in WTM. Renal COL1A2 mRNA expression increased with age inTHM, but not in WTM (Fig. 2C andD). Plasma Cr concentration, a marker of glomerulardysfunction, was not affected by age in THM or WTM (Fig. 3A and B).

Figure1Effect of aging on urinaryalbumin/creatinine (Alb/Cr) and neutrophil gelatinase-associatedlipocalin (NGAL)/Cr ratios in Tsukuba hypertensive mice (THM) andwild-type mice (WTM) (n=9–10). Urinary Alb/Cr ratio: (A) THM: slope(95% CI) 17.8 (10.1–25.6), r2=0.363, P<0.01 and (B)WTM: slope (95% CI) 2.45 (0.267–4.63), r2= 0.123,P<0.05. Urinary NGAL/Cr ratio: (C) THM: slope (95% CI) 18.4(10.4–26.4), r2= 0.365, P<0.01 and (D) WTM: slope(95% CI) 1.11 (0.395–1.82), r2=0.212, P<0.01. Solidline: regression line; dotted lines: 95% CI of the slopes of theregression line. Significant differences were observed in theslopes of the urinary Alb/Cr ratio and NGAL/Cr ratio between THMand WTM (P<0.01).
Figure2Effect of aging on renal monocytechemoattractant protein-1 (MCP-1) and collagen type I α 2 (COL1A2)expression in Tsukuba hypertensive mice (THM) and wild-type mice(WTM) (n=5). MCP-1 expression: (A) THM: slope (95% CI) 0.142(0.0925–0.191), r2=0.671, P<0.01 and (B) WTM: slope(95% CI) 0.0267 (0.0137–0.0397), r2= 0.510, P<0.01.COL1A2 expression: (C) THM: slope (95% CI) 0.0251 (0.0159–0.0343),r2= 0.647, P<0.01 and (D) WTM: slope (95% CI)−0.00463 (−0.00857 to −0.000695), r2=0.254, P<0.05.Solid line: regression line; dotted lines: 95% CI of the slopes ofthe regression line. Significant differences were observed inslopes of the expression of MCP-1 and COL1A2 mRNA between THM andWTM (P<0.01).
Figure3Effect of aging on plasma creatinine(Cr) concentration in (A) Tsukuba hypertensive mice (THM) and (B)wild-type mice (WTM) (n=10). THM: P=0.890 and wild-type mice (WTM):P=0.975. Solid line: regression line; dotted lines: 95% confidenceinterval (CI) of the slopes of the regression line. No significantdifference was observed in the slopes between THM and WTM.
Effects of UNx on glomerular and tubularinjury in THM

The urinary Alb/Cr ratio in UNx-THM wassignificantly higher than that in sham-THM (Fig. 4A). By contrast, the urinary NGAL/Crratio was unaffected by UNx in THM (Fig. 4B). In WTM, the urinary Alb/Cr ratiowas slightly decreased following UNx (Fig. 4A). The urinary NGAL/Cr ratio wasunaffected by UNx (Fig. 4B).Expression of renal MCP-1 and COL1A2 mRNA was similar between UNxand sham animals in both THM and WTM (Fig. 5A and B).

Figure4Effect of uninephrectomy (UNx) on (A)urinary albumin/creatinine (Alb/Cr) ratio and (B) urinaryneutrophil gelatinase-associated lipocalin (NGAL)/Cr ratio inTsukuba hypertensive mice (THM) and wild-type mice (WTM) (n=9–10).Data are expressed as the means ± standard error of the mean (SEM).*P<0.05, **P<0.01 vs. sham-operatedmice.
Figure5Effect of uninephrectomy (UNx) on (A)monocyte chemoattractant protein-1 (MCP-1) and (B) collagen type Iα 2 (COL1A2) expression in the kidneys of Tsukuba hypertensive mice(THM) (n=4 and 5, respectively). Expression of both was normalizedwith 18S ribosomal RNA. Data are expressed as the means ± standarderror of the mean (SEM).

The plasma Cr concentration was significantlyincreased in UNx-THM, but not in UNx-WTM (Fig. 6). However, GSI did not increasefollowing UNx in THM (Fig. 7A) andthere were no significant differences in the structure of thepodocytes and foot processes, slit diaphragms or glomerularbasem*nt membrane (GBM) thickness between UNx-THM and sham-THM(Fig. 7B).

Figure6Effect of uninephrectomy (UNx) onplasma creatinine (Cr) concentration in Tsukuba hypertensive mice(THM) and wild-type mice (WTM) (n=9–10). Data are expressed as themeans ± standard error of the mean (SEM). **P<0.01vs. sham-THM.
Figure7Effect of uninephrectomy (UNx) onglomerular sclerosis and filtration barrier in Tsukuba hypertensivemice (THM). (A) Effect of UNx on glomerular sclerosis index (GSI)score in THM (n=10). Data are expressed as the means ± standarderror of the mean (SEM). (B) Electron micrographs of typicalglomerular filtration barrier in sham- and UNx-THM. Arrows: slitdiaphragms; arrowheads: glomerular basem*nt membrane (GBM).


As mentioned above, various risk factors, such ashypertension, aging and hyperfiltration, affect the progression ofCKD (1,11,19,20).In the present study, the interrelationship of these risk factorswas investigated. The results indicated that aging and UNx exerteda similar effect on the development of albuminuria in THM. Of note,although the urinary NGAL/Cr ratio and renal MCP-1 and COL1A2 mRNAexpression were increased with age in THM, these alterations werenot observed in UNx-THM. Plasma Cr concentration was elevated byUNx only in THM. These results demonstrated that age- andUNx-related renal changes differed on a qualitative level.

Albuminuria may result from changes in glomerularfiltration, as well as from reduced reabsorption of filteredalbumin by the proximal tubule (21,22).Therefore, the effect of aging on the urinary NGAL/Cr ratio wasinvestigated. In THM, the urinary NGAL/Cr ratio increased with age.There was no effect of aging on plasma NGAL levels in THM (data notshown) and the reabsorption of NGAL by the tubular epithelial cellsafter glomerular filtration has been well-characterized (23). Thus, the present study hasdemonstrated that urinary NGAL may be considered as a biomarker oftubular damage. These observations suggest that the development ofalbuminuria in THM was accelerated by aging and that age-relatedrenal changes were induced by renal tubular damage.

In the kidney, MCP-1 plays an important role inrecruiting monocytes/macrophages to the injured tubulointerstitialtissue (24). Furthermore, COL1A2is associated with tubulointerstitial fibrosis (25). In this study, the levels of renalMCP-1 and COL1A2 mRNA expression increased with age in THM. Renaltubular inflammation and tubulointerstitial fibrosis contributed tothe progression of renal tubular damage and renal dysfunction(26,27). Thus, the results of this study havedemonstrated that the age-related albuminuria observed in THM wascaused by renal tubular damage.

Shimokama et al(18) reported moderate focal segmentalglomerular sclerosis in THM. However, this study did notdemonstrate an increase in plasma Cr concentration with age in THM.In addition, aging exerted no effects on the glomerular filtrationbarrier (data not shown). Taken together, these observationsstrongly suggest that age-related albuminuria in THM was mainlycaused by renal tubular damage rather than glomerulardysfunction.

UNx induces glomerular hyperfiltration and isassociated with albuminuria in experimental animal models (28). An increased urinary Alb/Cr ratio wasobserved following UNx in THM in the present study. However, theurinary NGAL/Cr ratio and renal MCP-1 and COL1A2 mRNA levels wereunaffected by UNx, indicating that UNx-related renal changesdiffered from those induced by aging. Moreover, these resultsdemonstrated that UNx-induced albuminuria was not caused by renaltubular injury.

In the present study, the plasma Cr concentrationwas increased following UNx in THM, suggesting that glomerulardysfunction developed in UNx-THM. The glomerular filtration barrieris formed by three layers: the innermost fenestrated vascularendothelium, the GBM and the podocyte layer (29). Glomerular size selectivity ismaintained by the GBM and the slit pore diaphragm between the footprocesses of podocytes (29).However, no progression of glomerular sclerosis, loss of slitdiaphragms or increased GBM thickness was observed when comparingUNx-THM to sham-THM. Therefore, UNx exerted no effect on theintegrity of the glomerular filtration barrier and the UNx-inducedalbuminuria in THM may not be attributed to changes in glomerularsize selectivity.

Charge selectivity is attributed to the anionicsites of the glomerular endothelial surface layer (ESL) (30). Loss of the glomerular ESL has beenassociated with albuminuria in patients with diabetic nephropathyand in an experimental animal model (31,32).In the present study, the loss of anionic charges in the GBM andESL was not assessed in UNx-THM. Therefore, further investigationsare required to elucidate the involvement of a charge-selectiveglomerular filtration barrier in renal dysfunction of UNx-THM.

In conclusion, this study has demonstrated thataging and hyperfiltration accelerated the development ofalbuminuria in hypertensive mice and that these renal changesdiffered in origin. Age-related albuminuria was mainly caused byrenal tubular damage and UNx-induced albuminuria was due toglomerular dysfunction. These findings indicate that thepathophysiology of CKD is complicated. A diversity of therapeuticapproaches must be applied to the treatment of renal dysfunction toaddress the possible implicated factors.


The authors would like to thank Dr M.Nagasaki, Dr A. Umeda, Dr R. Yamauchi, Dr H. Doi, Dr K. Kikkawa, DrM. Nishio, Mr. Y. Egi, Mr. K. Fujitaka, Ms. Y. Ogawa, Mr. K. Fujikiand Ms. A. Yamazaki of Mitsubishi Tanabe Pharma Corporation fortheir support and for their help with the statistical analysis.



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Effects of aging and uninephrectomy on renal changes in Tsukuba hypertensive mice (2024)
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