Abstract 084: Progressive Mitochondrial Dysfunction in Proximal Tubules Triggers Cortical Bioenergetic Failure in Kidneys During Salt-Sensitive Hypertension

Rationale: Proximal tubules (PT) reabsorb nearly 65% of Na + from the glomerular filtrate in the renal cortex. High salt (HS) intake imposes a metabolic stress on the PT mitochondria to meet the elevated energy demand. While renal mitochondrial dysfunction has been implicated in salt-sensitive (SS) hypertension, the progressive mitochondrial bioenergetic alterations in the PT and cortex remain poorly understood. We hypothesize that a HS diet leads to an early impairment of mitochondrial bioenergetics in the PT of SS subjects, which serves as an initiating factor for the ultimate decline in the renal cortex’s oxidative phosphorylation (OxPhos) efficiency. Methods: Dahl SS rats (9-10 weeks old) were fed a LS (0.4% NaCl) or HS (4.0% NaCl) diet for 7, 14, and 21 days (HS7, HS14, HS21; n=6/group). Cortical mitochondria (Cx m ) and PT were isolated from the kidney cortex. The PT were permeabilized by shear stress (PT p ) for mitochondrial assays. O 2 consumption rate (JO 2 ) was measured in Cx m and PT p using an Oxygraph, with substrates for complex I (pyruvate+malate; PM) and II (succinate) under state 2 (S2), state 3 (S3; ADP-stimulated), and state 5 (S5; FCCP-uncoupled). Respiratory control index (RCI) and P/O ratio were calculated to assess mitochondrial integrity and coupling efficiency. Results: Both PT p and Cx m showed a marked decline in S3 and S5 JO 2 on HS21 compared to their LS levels when energized with PM and succinate, indicating a broad decline in the OxPhos efficiency upon HS intake. Notably, at HS14, the S3 JO 2 decline was more prominent in PT p (538±10 to 477±10 pmol/sec/ml, p<0.05), with a similar but statistically insignificant trend in Cx m (595±8 to 558±28 pmol/sec/ml), when energized with succinate and similar trends with PM. This earlier and severe mitochondrial deterioration in PT p compared to Cx m indicates that the decline of OxPhos in PT per se is the initiating factor in impairing mitochondrial function in other tubular segments. Despite the S3 JO 2 decline, RCI remained preserved in both PT p and Cx m at HS14, indicating intact mitochondrial membrane integrity. Conclusion: OxPhos efficiency in PT is maintained for about 7 days of HS intake, after which it progressively declines. This may lead to the redistribution of Na + reabsorption workload to mitochondria-rich distal segments (e.g., thick ascending limbs and distal tubules), which subsequently exhibit functional decline, contributing to an overall bioenergetic impairment of the kidney by day 21.