Age-Related Changes in Renal Function, Membrane Protein Metabolism, and Na,K-ATPase Activity and Abundance in Hypokalemic F344 × BNF1 Rats

Abstract

Background: Potassium depletion is a common electrolyte abnormality in elderly humans, usually as a consequence of diuretic use or poor oral intake. Hypokalemia is associated with a number of changes in renal function and an increase in some renal membrane transporters; its growth-promoting effect in young animals is well known. With aging, the renal adaptation to a number of challenges is often diminished. We hypothesized that aging is related to decreases in renal function, renal membrane protein metabolism, as well as Na,K-ATPase protein abundance and activity in both control animals as well as in those with potassium depletion. Objective: We examined the effects of dietary-induced hypokalemia in true-aged nonobese rats (30 months old) on renal function, cortical brush border membrane (BBM) and basolateral membrane (BLM) protein metabolism, and Na,K-ATPase protein abundance and activity. We compared the results obtained to those seen in their 4-month-old counterparts similarly treated. Methods: Young (4-month-old) and senescent (30-month-old) male Fisher 344 × Brown-Norway F₁ rats (F344 × BNF₁) were fed either a normal or potassium-deficient diet for 7 days. At 24 h, the U-¹⁴C-leucine incorporation was measured for determination of protein metabolism in renal BBM and BLM. Cortical BLM vesicle and microdissected proximal convoluted tubule (PCT) Na,K-ATPase activities were determined along with Western blot analysis of the cortical BLM α₁ subunit of Na,K-ATPase. Metabolic and renal function parameters were also examined. Results: Hypokalemia caused hyperbicarbonatemia, hyperglycemia, and azotemia, but only in the senescent animals. The aged control rats had a higher basal level of urine volume, ammonium excretion, and fractional excretion of chloride. By contrast, aging in the F344 × BNF₁ rats was associated with a decrease in plasma aldosterone (by 35%) and phosphate (by 40%) levels as compared with their young controls. Hypokalemia resulted in a significant reduction of plasma aldosterone and a rise in muscle sodium concentration in both age groups; it significantly increased renal BBM and BLM protein concentrations in the young group, while these parameters remained unchanged in the senescent rats. The aged potassium-depleted animals showed a 14% decrease in BBM protein biosynthesis, but there were no changes in the young hypokalemic rats. Both potassium-depleted elderly and young rats had a significant reduction (by 33%) in BLM protein biosynthesis. Hypokalemia significantly increased the Na,K-ATPase activity in both cortical BLM vesicles and in microdissected PCT. The percentage increase in microdissected PCT segments (Na,K-ATPase activity) in elderly potassium-depleted animals was significantly less than that seen in hypokalemic young ones. Aging, per se, was associated with decreased basal microdissected PCT Na,K-ATPase activity in control animals. Hypokalemia had no effect on cortical BLM α₁ subunit Na,K-ATPase protein abundance in either age group. Conclusions: The present study provides the first evidence in nonobese aged rats as to the metabolic parameters, renal function, renal cortical membrane protein metabolism, and transporter Na,K-ATPase activity and abundance during potassium depletion. The aged nonobese F344 × BNF₁ rats responded differently from their young nonobese counterparts following potassium depletion. These differences may contribute substantially to the effects often encountered in elderly humans receiving diuretics or having a poor dietary potassium intake.