FOLLISTATIN TREATMENT IN FOLIC ACID INDUCED RENAL FIBROSIS

M YEN LEE1,2, P TEMPLE-SMITH2, D NIKOLIC-PATERSON1

1Department of Nephrology, Monash Health and Monash University Centre for Inflammatory Diseases, Clayton, Australia, 2Department of Obstetrics and Gynaecology, Monash Health and Monash University, Clayton, Australia

Aim: To investigate whether recombinant follistatin can suppress renal interstitial fibrosis in a mouse model of folic acid nephropathy (FAN).
Background: Renal interstitial fibrosis is a common pathologic feature in progressive kidney disease, but we lack effective anti-fibrotic therapies. Activin A, a member of the transforming growth factor beta superfamily of cytokines, is upregulated in animal models of renal fibrosis including unilateral ureter obstruction and diabetic kidney disease. Follistatin is a secreted protein that binds to and inhibits the function of Activin A. We evaluated the therapeutic potential of recombinant follistatin (FST288) in the FAN model.
Methods: Male C57BL/6 mice (n=8/9 group) were administered 250mg/kg folic acid. Urine was collected on day 3. Mice were treated once daily with 2mg/kg FST288 (Paranta Biosciences) or vehicle by intraperitoneal injection from day 6 until being killed on day 14. Normal mice were controls. Renal function, inflammation and fibrosis were assayed.
Results: Vehicle-treated animals developed renal function impairment (12.1±2.4 vs 7.2±1.7 umol/L plasma creatinine in normals; P<0.01), with focal areas of the cortex exhibiting tubular damage, macrophage and myofibroblast infiltration and collagen IV deposition. RT-PCR analysis of kidney tissue showed increased levels of Collagen I, CD68, -SMA and Activin A mRNA. Treatment with FST288 did not affect renal dysfunction (10.5±1.8 umol/L plasma creatinine; P=NS). Similarly, FST288 treatment did not affect histologic damage or reduce mRNA levels of collagen I, CD68, a-SMA or ActA (all P=NS). The day 3 urine KIM-1 to creatinine ratio was not different between FST288 and vehicle treated groups, confirming an equivalent induction of acute kidney injury.
Conclusion: FST288 treatment did not provide protection against renal interstitial inflammation or fibrosis in the FAN model.


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