Abstract P107: Adam 10 & 17 Double-knockout Impairs Renal And Vascular Functions And Induces Hypertension By Altering The Renal Proteomic Profiles

Background: ADAM 10 & 17, the two most well-known members of disintegrin and metalloproteinases (ADAMs), are responsible for the cleavage of diverse transmembrane proteins into bioactive molecules in the renal tubular cells. Objective: The purpose of this study is to understand the effects of ADAM 10 & 17 double-knockout (DKO) on renal and vascular functions using the renal tubular cell-specific ADAM 10 & 17 DKO mice. Results: We tested the renal and vascular functions in three groups (n=10-15 per group) of male and female wild-type (WT), vehicle, and DKO mice. The urine output ( P < 0.05) and glomerular filtration rate ( P < 0.01) of DKO mice were significantly lower than those of WT and vehicle control groups. The urinary sodium ( P < 0.0001) and potassium ( P < 0.01) excretion in DKO mice were also significantly reduced. Consistently, we found a significant decrease in urea ( P < 0.0001) and creatinine ( P < 0.0001) clearance in DKO mice, suggesting that the renal function is impaired when both ADAM 10 & 17 are depleted. In addition, the pulse wave velocity ( P < 0.0001), and blood pressure including systolic blood pressure ( P -value < 0.0001), diastolic blood pressure ( P < 0.0001), and mean blood pressure ( P < 0.0001) levels of DKO mice were significantly higher than those of WT and vehicle controls, indicating that ADAM 10 & 17 depletion impairs renal and vascular functions and causes hypertension. This phenomenon is further supported by the evidence that DKO mice showed a slower relaxation response to acetylcholine, compared to WTs. Next, to understand the changes in proteomic profiles in DKO kidneys, we performed proteomic analysis of WT and DKO kidney tissues and identified ~100 differentially expressed proteins (DEPs). These DEPs are highly enriched in drug metabolism, metabolic pathways, and TGF-beta signaling, PPAR-signaling and AGE-RAGE signaling pathways, suggesting that ADAM 10 & 17 may play a role in renal cellular metabolism, cell growth, differentiation, and apoptosis. Conclusions: The depletion of ADAM 10 & 17 impairs the renal and vascular functions likely via disrupting the cellular metabolism and homeostasis.