Male, but not female, spontaneously hypertensive rats (SHR) have sustained renal injury following a single ischemic insult progressing to chronic kidney disease (CKD).
Authors: Mohamed Riyaz , Sullivan Jennifer C. 
Published: April 2020

Renal ischemia‐reperfusion (IR) injury is a major cause of acute kidney injury (AKI), which is an independent risk factor for the development of CKD and all‐cause mortality. Clinical and pre‐clinical studies further support sex differences in incidence and mortality rates of AKI and a higher tendency to develop AKI to CKD transition than females. Hypertension is a common co‐morbid condition associated with AKI and CKD. Despite the prevalence of hypertension and the importance of blood pressure (BP) control in maintaining renal health, little is known regarding the impact of hypertension on AKI recovery and AKI to CKD progression. The goal of the current study was to test the hypothesis that hypertensive males will have greater IR injury than hypertensive females resulting in more rapid CKD progression. 13 wk old male and female SHR were subjected to sham or 30‐minute warm bilateral ischemia followed by reperfusion (n=5–6). Blood, a 24 hr urine sample and kidneys were collected 1 week post‐IR to assess renal injury. Systolic blood pressure (BP) measured weekly by tail cuff method. Plasma creatinine (Pcr) and urine protein creatinine ratio (UPCR) remained elevated at 1‐week post IR in male SHR compared sham (Pcr PIR=0.03, Psex=0.05; PIR*sex=0.04; ACR PIR=0.005, Psex=0.0005; PIR*sex=0.005); Pcr and UPCR returned to baseline in SHR females. Consistent with this finding, histological examination of SHR kidneys 7 days post‐IR showed increases in vascular congestion (Psex*IR=0.002) and tubular damage (Psex*IR=0.001) compared to sham only in males. However, glomerular filtration rate (GFR) and systolic BP was not altered in both male and female SHR at 1‐week post IR. To determine if this was sustained dysfunction or simply delayed recovery, additional 13 wk old male and female SHR were subjected to sham or 30‐minute warm bilateral ischemia followed by 20 weeks of reperfusion. Plasma and urine were collected weekly (n=3–4). Male SHR showed progressive increases in UPCR (PIR<0.05) and systolic BP up to 20 weeks post‐IR compared to respective shams (PIR=0.001). Whereas in SHR female, UPCR remains at baseline up to 16‐week post IR compared to respective sham. However, at 20 weeks of post IR, both male and female SHR exhibit increase in UPCR compared to respective sham control; although the increase in UPCR was greater in males (PIR=0.0002, Psex=0.01; PIR*sex=0.09). Male SHR also exhibited decreases in glomerular filtration rate (GFR) (PIR=0.007, Psex=0.02; PIR*sex=0.12) and increases in systolic BP (PIR=0.008, Psex=0.0001; PIR*sex=0.27) compared to SHR female at 20 weeks post‐IR. In conclusion, our data demonstrated that impaired renal recovery following IR in SHR males results in exaggerated progression towards CKD compared females.Support or Funding InformationWork was supported by R01 HL127091 and P01 HL134604.
Kidney function and systolic BP in male and female SHR at 1 and 20‐week of post‐IR.

Male SHR

UPCR

GFR (mL/min)

Systolic BP (mmHg)

1 week post IR

Sham

1.14 ± 0.23

2.95±0.33

187±8

IR

3.44±1.37

2.55±0.28

192±6

20 week post IR

Sham

1.70±0.26

2.58±0.5

205±10

IR

4.50±0.85

1.10±0.67

225±4

Female SHR

1 week post IR

Sham

0.77±0.47

3.24±0.34

164±10

IR

0.79±0.34

3.35±0.68

166±3

20 week post IR

Sham

1.10±0.54

2.96±1.09

167±9

IR

2.72±0.46

2.83±0.44

177±9

ACR= Urine Protein Creatinine Ratio; GFR=Glomerular Filtration Rate; BP= Blood Pressure.