Targeting proximal tubule mitochondrial dysfunction attenuates the renal disease of methylmalonic acidemia

Abstract

Isolated methylmalonic acidemia (MMA), caused by deficiency of the mitochondrial enzyme methylmalonyl-CoA mutase (MUT), is often complicated by end stage renal disease that is resistant to conventional therapies, including liver transplantation. To establish a viable model of MMA renal disease, Mut was expressed in the liver of Mut −/− mice as a stable transgene under the control of an albumin (INS-Alb- Mut ) promoter. Mut −/− ;Tg INS-Alb- Mut mice, although completely rescued from neonatal lethality that was displayed by Mut −/− mice, manifested a decreased glomerular filtration rate (GFR), chronic tubulointerstitial nephritis and ultrastructural changes in the proximal tubule mitochondria associated with aberrant tubular function, as demonstrated by single-nephron GFR studies. Microarray analysis of Mut −/− ;Tg INS-Alb- Mut kidneys identified numerous biomarkers, including lipocalin-2, which was then used to monitor the response of the GFR to antioxidant therapy in the mouse model. Renal biopsies and biomarker analysis from a large and diverse patient cohort ( ClinicalTrials.gov identifier: NCT00078078) precisely replicated the findings in the animals, establishing Mut −/− ;Tg INS-Alb- Mut mice as a unique model of MMA renal disease. Our studies suggest proximal tubular mitochondrial dysfunction is a key pathogenic mechanism of MMA-associated kidney disease, identify lipocalin-2 as a biomarker of increased oxidative stress in the renal tubule, and demonstrate that antioxidants can attenuate the renal disease of MMA.

Integrated Control of Na Transport along the Nephron

“…The cause for the GFR reduction was tubuloglomerular feedback activation because it was not seen when tubuloglomerular feedback was interrupted. Similar correlations between inhibition of PCT fluid transport and GFR have been observed in a range of settings, including administration of carbonic anhydrase inhibitors, claudin2-deficient mice, mice with selective deletion of angiotensin II type 1 receptors for angiotensin II in the proximal tubule, and a mouse model of methyl malonic aciduria (11,(71)(72)(73). The causes for the GFR reduction in some of these cases appear multifactorial.…”

High expression of neutrophil gelatinase-associated lipocalin (NGAL) in the kidney proximal tubules of diabetic rats

“…Irini's research [33] supported a link between NGAL induction and the abnormal tubular mitochondrial ultrastructure in the renal tubulointerstitial disease. Since NGAL mRNA expression in the tissue and its resulting plasma concentrations were reduced after the administration of antioxidants, confirming a strong correlation between oxidative stress and NGAL.…”

Treatment of Methylmalonic Acidemia by Liver or Combined Liver-Kidney Transplantation

“…Furthermore, although GFR is a good measure of renal function, creatinine, which also has remained normal in our patients, poorly reflects it until late stages of dysfunction. 46,47 Lipocalin and cystatin C have been proposed as renal function markers in MMA. 47,48 Serum MMA decreases 60%-95% after LT or LKT, with more substantial decreases after LKT.…”

“…46,47 Lipocalin and cystatin C have been proposed as renal function markers in MMA. 47,48 Serum MMA decreases 60%-95% after LT or LKT, with more substantial decreases after LKT. 10,18,22,25,26 The urine MMA has been used as a follow-up marker.…”