Role of angiotensin II type 1a receptor in renal injury induced by deoxycorticosterone acetate–salt hypertension

Q: What are the key findings of this study?

AT1a receptor deficiency significantly worsened glomerular sclerosis and elevated urinary L-FABP levels (p<0.05) in DOCA-salt hypertensive mice, which was attenuated by hydralazine.

Q: What is the clinical evidence from this study?

Population: Deoxycorticosterone acetate (DOCA)-salt hypertension-induced renal injury (n=83). Intervention: AT1a receptor gene disruption (L-FABP+/- AT1a-/-) with DOCA-salt treatment and optional hydralazine vs. Intact AT1a receptor (L-FABP+/- AT1a+/+) with DOCA-salt treatment or sham-operated controls on tap water. Primary outcome: Glomerular damage (glomerular sclerosis score, mesangial expansion, glomerular size) and tubulointerstitial damage (urinary L-FABP, PAS staining) (p=<0.05).

Q: What does this research mean for the field?

Angiotensin II type 1a receptor deficiency exacerbates glomerular sclerosis and tubulointerstitial injury in DOCA-salt hypertensive mice, which can be attenuated by blood pressure reduction with hydralazine. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Q: What question did this study set out to answer?

To investigate the in vivo role of the angiotensin II type 1a (AT1a) receptor in hypertension-induced renal damage using transgenic mouse models.

Mikako Hisamichi; Atsuko Kamijo‐Ikemori; Takeshi Sugaya; Daisuke Ichikawa; Takayuki Natsuki; Kenjiro Kimura; Yugo Shibagaki

doi:10.1096/fj.201600684rr

September 23, 2016The FASEB JournalOpen Access

Role of angiotensin II type 1a receptor in renal injury induced by deoxycorticosterone acetate–salt hypertension

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Key result

AT1a receptor deficiency worsens hypertensive glomerular sclerosis, an effect attenuated by hydralazine.

P<0.05
n=83

Why the study?

Does AT1a receptor gene deficiency exacerbate or attenuate hypertensive glomerular and tubulointerstitial renal damage in mice with DOCA-salt induced hypertension?

Key Points

To investigate the in vivo role of the angiotensin II type 1a (AT1a) receptor in hypertension-induced renal damage using transgenic mouse models.
Female transgenic mice expressing human liver-type fatty acid binding protein with or without AT1a receptor disruption (L-FABP+/- AT1a+/+ and L-FABP+/- AT1a-/-) underwent uninephrectomy and received subcutaneous deoxycorticosterone acetate (DOCA)-salt tablets plus 1% saline drinking water for 28 days.
DOCA-salt hypertensive mice were treated with or without hydralazine to determine the effects of blood pressure reduction on kidney injury.
Blood pressure, urinary biomarkers (human L-FABP, albumin, KIM-1), inflammatory and oxidative stress transcripts, and renal histopathology were assessed.
Systolic blood pressure increased similarly on days 14 and 28 in both L-FABP+/- AT1a+/+-DOCA and L-FABP+/- AT1a-/--DOCA groups compared with baselines and controls (P < 0.05).
L-FABP+/- AT1a-/--DOCA mice exhibited significantly higher urinary albumin, L-FABP, and KIM-1 levels, along with significantly greater glomerular size, mesangial matrix expansion, and glomerulosclerosis scores compared with L-FABP+/- AT1a+/+-DOCA mice (P < 0.05).
Hydralazine significantly lowered systolic blood pressure and attenuated glomerular damage, mesangial expansion, glomerulosclerosis scores, and biomarker excretion in L-FABP+/- AT1a-/--DOCA mice (P < 0.05).

Structured PICO

Does AT1a receptor gene deficiency exacerbate or attenuate hypertensive glomerular and tubulointerstitial renal damage in mice with DOCA-salt induced hypertension?

P

Population

83 female transgenic mice (7-8 weeks old) expressing human L-FABP with (n=34) or without (n=49) AT1a receptor gene disruption, subjected to uninephrectomy and followed for 28 days of DOCA-salt hypertension.

I

Intervention

AT1a receptor gene knockout (L-FABP+/- AT1a-/-) challenged with subcutaneous deoxycorticosterone acetate (DOCA, 75 mg/mouse) and 1% NaCl drinking water for 28 days, with or without oral hydralazine (4 mg/kg/d in drinking water)

C

Comparator

Transgenic mice with intact AT1a receptor (L-FABP+/- AT1a+/+) receiving DOCA-salt (n=22), DOCA-salt plus hydralazine (n=9), or sham operation with tap water (control, n=18), as well as L-FABP+/- AT1a-/- sham-operated controls (n=9)

O

Outcome

Histologic glomerular damage (glomerular size, mesangial matrix expansion, glomerulosclerosis score, type IV collagen deposition) and tubulointerstitial injury (urinary human L-FABP, urinary KIM-1, urinary albumin, PAS-stained tubulointerstitial damage score) at 28 dayssurrogate

Main Result

p-value: p=<0.05

Activation of the AT1a receptor appears necessary to maintain glomerular structural integrity and autoregulatory protection against pressure-dependent hypertensive renal damage.

Limitations

High mortality (~70%) in male mice during preliminary study restricted experiments to female mice
Short study duration of 4 weeks (28 days)
Total RNA was extracted from whole frozen kidneys containing large amounts of tubulointerstitium, which may mask glomerular-specific gene expression differences
Higher baseline body weight in the L-FABP+/- AT1a+/+-DOCA+Hyd group on day 0 may have reduced relative DOCA load on the kidneys
Approximately 70% of male mice died within 28 days of DOCA-salt administration in preliminary studies, restricting the study to female mice only
Relatively short duration of hypertensive exposure (4 weeks)
Total RNA was extracted from whole kidney tissue, so tubulointerstitial mRNA may have masked glomerular-specific gene expression changes
Baseline body weight on day 0 was significantly higher in the L-FABP+/- AT1a+/+-DOCA+Hyd group, potentially resulting in a lower relative DOCA load

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Implication

AT1a receptor activation may protect against hypertensive glomerular injury in mice; leaves open relevance to human renal disease.

Abstract

The aim of this studywas to investigate the in vivo role of angiotensin II type 1a (AT1a) receptor in renal damage as a result of hypertension by using transgenic mice with AT1a receptor gene disruption. Transgenicmice that express human liver‐type fatty acid binding protein (L‐FABP) with or without disruption of the AT1a receptor gene (L‐FABP +/− AT1a −/− , and L‐FABP +/− AT1a +/+ , respectively)were usedwith urinary L‐FABP as an indicator of tubulointerstitial damage. Those female mice were administered subcutaneously deoxycorticosterone acetate (DOCA)–salt tabletsplusdrinking water that contained1%saline for 28d after uninephrectomy. InL‐FABP +/− AT1a +/+ mice that received DOCA‐salt treatment, hypertension was induced and slight expansion of glomerular area, glomerular sclerosis, and tubulointerstitial damage were observed. In L‐FABP +/− AT1a −/− mice that received DOCA‐salt treatment, hypertensionwas similarly induced and the degree of glomerular damage was significantly more severe than in L‐FABP +/− AT1a +/+ ‐DOCAmice. Urinary L‐FABP levelswere significantly higher inL‐FABP +/− AT1a −/− ‐DOCAmice comparedwiththose in L‐FABP +/− AT1a +/+ ‐DOCAmice. Hydralazine treatment significantly attenuated renal damage that was found in L‐FABP +/− AT1a −/− ‐DOCA mice along with a reduction in blood pressure. In summary, activation of the AT1a receptor may contribute to maintenance of the glomerular structure against hypertensive renal damage.—Hisamichi, M., Kamijo‐Ikemori, A., Sugaya, T., Ichikawa, D., Natsuki, T., Hoshino, S., Kimura, K., Shibagaki, Y. Role of angiotensin II type 1a receptor in renal injury induced by deoxycorticosterone acetate–salt hypertension. FASEB J. 31, 72–84 (2017) www.fasebj.org

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Cite This Study

Hisamichi et al. (2016) studied Deoxycorticosterone acetate (DOCA)-salt hypertension-induced renal injury (n=83). AT1a receptor gene disruption (L-FABP+/- AT1a-/-) with DOCA-salt treatment and optional hydralazine vs. Intact AT1a receptor (L-FABP+/- AT1a+/+) with DOCA-salt treatment or sham-operated controls on tap water was evaluated on Glomerular damage (glomerular sclerosis score, mesangial expansion, glomerular size) and tubulointerstitial damage (urinary L-FABP, PAS staining) (p=<0.05). AT1a receptor deficiency significantly worsened glomerular sclerosis and elevated urinary L-FABP levels (p<0.05) in DOCA-salt hypertensive mice, which was attenuated by hydralazine.

synapsesocial.com/papers/6a7f2fb3dcde381c9a7c9d2b https://doi.org/10.1096/fj.201600684rr

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Role of angiotensin II type 1a receptor in renal injury induced by deoxycorticosterone acetate–salt hypertension

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Role of angiotensin II type 1a receptor in renal injury induced by deoxycorticosterone acetate–salt hypertension

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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