Abstract P208: N-acetyl-seryl-aspartyl-lysyl-proline Prevents Renal Fibrosis in Dahl Salt-sensitive Rats by an Early Upregulation of miR Let-7b

Abstract

We recently showed that N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), a natural tetrapeptide with antifibrotic properties prevented high salt-induced albuminuria and renal damage including fibrosis in Dahl Salt-Sensitive (SS) rats and their consomic SS13BN controls. However, the mechanism of this antifibrotic effect is unknown. MicroRNAs (miRNAs) have been shown to be important endogenous regulators of several physiological and pathophysiological conditions. The miRNA let-7 family has been suggested as a negative regulator of profibrotic processes in many diseases and its downregulation has been associated with renal fibrosis. Here, we hypothesized that in SS rats, the antifibrotic effect of Ac-SDKP on high salt-induced renal fibrosis is due to an upregulation of miRNA let-7b expression. Dahl SS and consomic SS13BN rats were fed either 0.23% NaCl (low salt, LS) or 4% NaCl (high salt, HS) diet and infused with vehicle (Veh) or Ac-SDKP (1.6 mg/kg/day) subcutaneously via osmotic minipump for 1 week. Animals were divided into the following groups: LS + Veh, HS + Veh and HS + Ac-SDKP. HS increased the systolic blood pressure (SBP) in SS rats, but not in SS13BN rats. Ac-SDKP did not affect SBP. In both strains, one week of HS diet increased albuminuria. Ac-SDKP prevented HS-induced albuminuria. In SS rats, HS-induced a significant downregulation of the renal cortex miR-let 7b expression measured by quantitative RT-PCR (HS + Veh 0.27±0.16 vs. LS + Veh 1.00±0.09; P=0.005), whereas a treatment with Ac-SDKP significantly upregulated the miR-let 7b expression (HS + Ac-SDKP 2.80±0.11; P=0.002). No miR-let 7b expression difference was observed in SS13BN rats. The overexpression of miR-let 7b by Ac-SDKP is associated with a significant decrease in collagen1 mRNA expression (HS + Veh 3.89±0.74 vs. HS + Ac-SDKP 1.25±0.13; P=0.005). One week on HS diet was not sufficient to cause measurable changes in renal collagen protein. In summary, Ac-SDKP prevented albuminuria and renal cortex collagen1 mRNA expression in SS rats fed HS diet for 1 week, and this was associated with an upregulation of miRNA let-7b expression. The antifibrotic effect of Ac-SDKP on HS-induced renal fibrosis in SS rats may be in part due to preceded upregulation of miRNA let-7b expression.