Abstract: SA-PO1098

Thymosin β4 Deficiency Accelerates Renal Fibrosis and Damage in Angiotensin-II Hypertension

Session Information

Category: Hypertension

  • 1102 Hypertension: Basic and Experimental - Renal Causes and Consequences

Authors

  • Kumar, Nitin, Henry Ford Hospital, Detroit, Michigan, United States
  • Liao, Tang-Dong, Henry Ford Hospital, Detroit, Michigan, United States
  • Romero, Cesar A., Henry Ford Hospital, Detroit, Michigan, United States
  • Maheshwari, Mani, Henry Ford Hospital, Detroit, Michigan, United States
  • Carretero, Oscar A., Henry Ford Hospital, Detroit, Michigan, United States
Background

Angiotensin-II (Ang-II)-induced hypertension is associated with renal fibrosis and damage. Thymosin β4 (Tβ4) regulates cell morphology, inflammation and fibrosis in several organs and administration of exogenous Tβ4 is protective in diabetic nephropathy. However, role of endogenous Tβ4 in hypertension-induced renal damage is unknown. We hypothesize that, loss of Tβ4 accelerates renal fibrosis and damage in Ang-II hypertension.

Methods

Tβ4 knockout (Tβ4 KO) and wild-type (WT) C57BL/6 mice (n=6-14) were infused continuously for six-weeks with either Ang-II (980 ng/kg/min) or vehicle via osmotic minipumps. Blood-pressure was measured weekly by non-invasive tail-cuff method. Urinary albumin (24 hours urine collection) and renal cortex collagen were measured by ELISA and hydroxyproline assay, respectively. Renal cortex expressions of nephrin and α-smooth muscle actin (α-SMA) were evaluated by western blot.

Results

All the results are presented in table 1. In Ang-II infusion, systolic blood-pressure was not different between WT and Tβ4 KO mice (Table 1). Interestingly, urinary albuminuria was significantly higher in Tβ4 KO mice compared to WT mice by Ang-II infusion. Tβ4 is highly expressed in the glomeruli along with the high expression of nephrin, an important protein in the filtration barrier of the kidney. In Ang-II infusion, nephrin protein expression was greatly reduced in mice deficient of Tβ4, suggesting that loss of nephrin is one of the mechanisms for elevated urinary albumin in Tβ4 KO mice. Additionally, renal fibrosis in the cortex was higher in Tβ4 KO mice and this was accompanied by elevated profibrotic α-SMA protein expression. Susceptibility to Ang-II induced kidney damage in Tβ4 KO mice may be associated with the observed high mortality rate in these mice.

Conclusion

These data indicate that, in Ang-II hypertension, loss of endogenous Tβ4 caused significant renal fibrosis, damage and mortality, suggesting renal protective role of Tβ4.

Table 1
ParametersWT-VehicleTβ4 KO-VehicleWT-Ang-IITβ4 KO-Ang-II
Systolic Blood-Pressure
(mmHg)
103±4113±8164±11‡159±7*
Urinary Albumin
(μg/24hrs)
37±350±8312±35‡9143±1267*†
Nephrin Protein Expression
(Arbitrary Units)
1.23±0.121.15±0.050.89±0.07‡0.59±0.08*†
Total Collagen in Kidney
(μg/mg dry kidney weight)
10.7±0.7313.9±1.315.24±0.3‡17.91±0.65*†
Renal α-SMA Protein
(Arbitrary Units)
0.11±0.070.20±0.020.66±0.06‡0.89±0.04*†
Survival Rate
(%)
10010010057#
‡ P<0.005 WT-Vehicle versus WT-Ang-II, * P<0.005, # P<0.05 Tβ4 KO-Vehicle versus Tβ4 KO-Ang-II, † P<0.005 WT-Ang-II versus Tβ4 KO-Ang-II.

Funding

  • Other NIH Support