Food Restriction Ameliorates the Development of Polycystic Kidney Disease

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by the accumulation of kidney cysts that ultimately leads to loss of renal function and kidney failure. At present, the treatment for ADPKD is largely supportive. Multiple studies have focused on pharmacologic approaches to slow the development of the cystic disease; however, little is known about the role of nutrition and dietary manipulation in PKD. Here, we show that food restriction (FR) effectively slows the course of the disease in mouse models of ADPKD. Mild to moderate (10%-40%) FR reduced cyst area, renal fibrosis, inflammation, and injury in a dose-dependent manner. Molecular and biochemical studies in these mice indicate that FR ameliorates ADPKD through a mechanism involving suppression of the mammalian target of the rapamycin pathway and activation of the liver kinase B1/AMP-activated protein kinase pathway. Our data suggest that dietary interventions such as FR, or treatment that mimics the effects of such interventions, may be potential and novel preventive and therapeutic options for patients with ADPKD.

Slowing Polycystic Kidney Disease by Fasting

“…2 This is in addition to obesity and diabetes, which are known to be primarily metabolic disorders for which a reduction in food intake acts on the primary cause of disease. 2,3 In a paper appearing in this issue of the JASN, Warner et al 1 show that FR can improve kidney disease in animal models of PKD.…”

“…4,5,[7][8][9] This has resulted in preclinical studies targeting metabolic pathways, such as glycolysis and the energy sensor AMP-activated protein kinase. 7,8,10 Warner et al 1 now show that reducing food intake to levels that do not cause malnutrition (30%-50%) achieves an impressive improvement in the progression of PKD in animal models. Warner et al 1 use the Pkd1 RC/RC hypomorphic murine model 11 and compare the outcome in mice fed ad libitum with those who are subjected to a 40% FR from 6 weeks of age to 7.5 months of age.…”

“…7,8,10 Warner et al 1 now show that reducing food intake to levels that do not cause malnutrition (30%-50%) achieves an impressive improvement in the progression of PKD in animal models. Warner et al 1 use the Pkd1 RC/RC hypomorphic murine model 11 and compare the outcome in mice fed ad libitum with those who are subjected to a 40% FR from 6 weeks of age to 7.5 months of age. Warner et al 1 show that renal size is halved in animals on a calorie-restricted diet compared with ad libitumfed animals.…”

“…Warner et al 1 use the Pkd1 RC/RC hypomorphic murine model 11 and compare the outcome in mice fed ad libitum with those who are subjected to a 40% FR from 6 weeks of age to 7.5 months of age. Warner et al 1 show that renal size is halved in animals on a calorie-restricted diet compared with ad libitumfed animals. 1 In addition, cystic index, inflammatory infiltrate, and fibrosis were also significantly decreased and reached levels comparable with those observed in age-matched wild-type animals.…”

“…Warner et al 1 show that renal size is halved in animals on a calorie-restricted diet compared with ad libitumfed animals. 1 In addition, cystic index, inflammatory infiltrate, and fibrosis were also significantly decreased and reached levels comparable with those observed in age-matched wild-type animals. At a mechanistic level, Warner et al 1 show that hexokinase 2 (Hk2), but not other enzymes involved in glycolysis or the trichloroacetic acid cycle, is upregulated in Pkd1 RC/RC and returns to baseline levels on FR.…”