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Coordinately increased lysozymuria and lysosomal enzymuria induced by maleic acid
Abstract:
During the acute renal tubular dysfunction of Fanconi syndrome and type 2 renal tubular acidosis (FS/RTA2) induced by maleic acid in the unanesthetized dog, we observed: 30 minutes after the onset of FS/RTA2, the urinary excretion of lysosomal enzymes, N-acetyl-beta-glucosaminidase (NAG), beta-glucuronidase (beta-gluc) and beta-galactosidase (beta-galac), increased simultaneously with the anticipated increase in renal clearance of lysozyme; the severities of all these hyperenzymurias increased rapidly, progressively, and in parallel, all reaching a peak some 60 to 80 minutes after their onset; thereafter, while the FS/RTA2 continued undiminished in severity, the severity of the hyperenzymurias decreased rapidly, greatly, progressively, and in parallel; and sodium phosphate loading strikingly attenuated the FS/RTA2 and the hyperenzymurias. Thus, the maleic acid-induced FS/RTA2 is attended by an acute reversible-complex derangement in the renal tubular processing of proteins that: affects not only lysozyme which is normally filtered, but also NAG and other lysosomal enzymes, which are not; and is to some extent functionally separable from that of FS/RTA2. The findings suggest that the derangements in renal processing of lysozyme and lysosomal enzymes are linked, and that a phosphate-dependent metabolic abnormality in the proximal tubule can participate in the pathogenesis of both these derangements and the FS/RTA2.
Insights
Maleic acid induces Fanconi syndrome/renal tubular acidosis (FS/RTA2) in dogs, causing temporary increases in urinary lysosomal enzymes and lysozyme clearance. Phosphate supplementation reduced these effects, suggesting a link to proximal tubule metabolic abnormalities.
Area of Science:
- Nephrology
- Biochemistry
- Toxicology
Background:
- Fanconi syndrome and type 2 renal tubular acidosis (FS/RTA2) are renal tubular dysfunctions.
- Maleic acid is a known nephrotoxic agent that can induce FS/RTA2.
- The precise mechanisms of maleic acid-induced renal tubular damage are not fully understood.
Purpose of the Study:
- To investigate the acute effects of maleic acid-induced FS/RTA2 on urinary lysosomal enzyme excretion and renal lysozyme handling in dogs.
- To explore the potential role of phosphate in mitigating these renal tubular derangements.
- To elucidate the relationship between renal tubular processing of proteins and the pathogenesis of FS/RTA2.
Main Methods:
- Induction of FS/RTA2 in unanesthetized dogs using maleic acid.
- Measurement of urinary excretion of N-acetyl-beta-glucosaminidase (NAG), beta-glucuronidase (beta-gluc), and beta-galactosidase (beta-galac).
- Assessment of renal lysozyme clearance.
- Administration of sodium phosphate loading to evaluate its effect on FS/RTA2 and hyperenzymuria.
Main Results:
- Maleic acid induced acute FS/RTA2, characterized by increased urinary excretion of lysosomal enzymes (NAG, beta-gluc, beta-galac) and enhanced renal lysozyme clearance.
- These increases (hyperenzymurias) peaked 60-80 minutes after onset and then rapidly declined, despite ongoing FS/RTA2.
- Sodium phosphate loading significantly attenuated both the FS/RTA2 and the hyperenzymurias.
Conclusions:
- Maleic acid-induced FS/RTA2 involves a reversible derangement in renal tubular protein processing, affecting both filtered (lysozyme) and non-filtered (lysosomal enzymes) proteins.
- The observed derangements in lysozyme and lysosomal enzyme processing are linked and partially separable from FS/RTA2.
- A phosphate-dependent metabolic abnormality in the proximal tubule may contribute to the pathogenesis of these renal tubular dysfunctions.