Reduced renal methylarginine metabolism protects against progressive kidney damage

Abstract

Nitric oxide (NO) production is diminished in many patients with cardiovascular and renal disease. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthesis, and elevated plasma levels of ADMA are associated with poor outcomes. Dimethylarginine dimethylaminohydrolase-1 (DDAH1) is a methylargininemetabolizing enzyme that reduces ADMAlevels.We reported previously that a DDAH1 gene variant associated with increased renal DDAH1 mRNA transcription and lower plasma ADMA levels, but counterintuitively, a steeper rate of renal function decline. Here,we test the hypothesis that reduced renal-specificADMAmetabolism protects against progressive renal damage. Renal DDAH1 is expressed predominately within the proximal tubule. A novel proximal tubule-specific Ddah1 knockout (Ddah1PT2/2) mouse demonstrated tubular cell accumulation ofADMAand lowerNOconcentrations, but unaltered plasmaADMAconcentrations. Ddah1PT2/2mice were protected fromreduced kidney tissuemass, collagendeposition, andprofibrotic cytokine expression in two independent renal injurymodels: folate nephropathy and unilateral ureteric obstruction. Furthermore, a study of two independent kidney transplant cohorts revealed higher levels of human renal allograft methylargininemetabolizing enzyme gene expression associated with steeper function decline. We also report an association among DDAH1 expression, NO activity, and uromodulin expression supported by data from both animal and humanstudies, raising thepossibility that kidneyDDAH1expression exacerbates renal injury through uromodulinrelated mechanisms. Together, these data demonstrate that reduced renal tubular ADMA metabolism protects against progressive kidney function decline. Thus, circulatingADMAmay be an imprecise marker of renalmethylarginine metabolism, and therapeutic ADMA reduction may even be deleterious to kidney function.