Abstract 076: Sex Difference in the Effects of Dopamine D2 Receptor Specific Deletion in the Renal Proximal Tubules of Mice

Abstract

Dopamine receptor D2 (D2R) plays a significant role in kidney function by maintaining normal blood pressure (BP) and preventing renal inflammation and injury. D2R silencing in the mouse kidney increases BP and increases renal injury. To study the effects of D2R in the renal proximal tubule we generated Drd2 fl/fl , P SGLT2 ::Cre+ mice (D2R PT-/- ) that lack D2R only in the renal proximal tubule and Drd2 fl/fl , P SGLT2 ::Cre- mice (D2R PT+/+ ) that do not have the deletion. We studied male and female mice on normal salt (NS; 0.4% NaCl) and high salt (HS; 4% NaCl) diets. Mice were genotyped for Drd2 fl/fl and a smaller amplicon representing the Cre deletion mutant. On NS diet, male D2R PT-/- had higher systolic BP (SBP) measured under anesthesia than male D2R PT+/+ (113±1 vs 102±3 mmHg, n=5/group; P<0.05) and female D2R PT-/- (104±5 mmHg) or female D2R PT+/+ (106±3 mmHg). SBPs on HS diet were similar in D2R PT-/- females and males. On NS diet renal mRNA expressions of TNF-α, TGFβ1, Fn1, and Col1a1 were higher (P<0.01) in female D2R PT+/+ than in male D2R PT+/+ ; conversely the expression of the kidney injury marker, Kim-1, was higher in male than female D2R PT+/+ (P<0.01). Male D2R PT-/- expressed less (P<0.01) renal TNF-α, TGFβ1, Col1a1, cell proliferation marker Mki-67, and Fn1 than female D2R PT-/- . However, the renal expression of Kim-1 was less (P<0.01) in female than male D2R PT-/- . On HS diet, renal mRNA expressions of TNF-α, TGFβ1, and Fn-1 were similar in both male and female D2R PT+/+ and D2R PT-/- . HS diet increased (P<0.05) the expression of Col1a1 and Kim-1 in male D2R PT+/+ and D2R PT-/- but not in females of the two genotypes; HS diet also increased the expression of Mki-67 only in D2R PT-/- males. Our data show striking differences in the inflammatory response, cell proliferation, and kidney injury between males and females, with females expressing more inflammatory and proliferation markers but less injury markers than males. Deletion of the D2R in the proximal tubule increases the renal expression of extracellular matrix proteins and inflammatory and proliferation markers, effects that were more pronounced in females, except for Kim-1. The differences between males and females are maintained on HS diet, indicating that female mice have a “healthier” response to renal injury.

Anti-Inflammatory Effects of Peripheral Dopamine

“…Specific deletion of the D2R in the renal proximal tubule in male mice increased the expression of pro-inflammatory and profibrotic factors in the kidney, as well as blood pressure [ 161 ] ( Figure 3 ). Cells of the renal tubule produce pro-inflammatory and anti-inflammatory cytokines that are secreted across the apical and basolateral membranes of renal tubule cells and contribute to the development and progression of glomerular and tubular injury [ 162 , 163 , 164 ].…”