Sustained kidney biochemical derangement in treated experimental diabetes: a clue to metabolic memory

Abstract

The occurrence of biochemical alterations that last for a long period of time in diabetic individuals even after adequate handling of glycemia is an intriguing phenomenon named metabolic memory. In this study, we show that a kidney pathway is gradually altered during the course of diabetes and remains persistently changed after late glycemic control in streptozotocin-induced diabetic rats. This pathway comprises an early decline of uric acid clearance and pAMPK expression followed by fumarate accumulation, increased TGF-β expression, reduced PGC-1α expression, and downregulation of methylation and hydroxymethylation of mitochondrial DNA. The sustained decrease of uric acid clearance in treated diabetes may support the prolonged kidney biochemical alterations observed after tight glycemic control, and this regulation is likely mediated by the sustained decrease of AMPK activity and the induction of inflammation. This manuscript proposes the first consideration of the possible role of hyperuricemia and the underlying biochemical changes as part of metabolic memory in diabetic nephropathy development after glycemic control.

Podocyte Bioenergetics in the Development of Diabetic Nephropathy: The Role of Mitochondria

“…Although the majority of epigenetic studies concern nuclear DNA modifications, mitoepigenetics also has an important role in a variety of diseases, including cardiovascular disease, obesity, and diabetes ( 99 ). For example, an increased methylation of D-loop region of mtDNA and subsequent reduction in the mtDNA copy number in leukocytes has been associated with insulin resistance in obesity ( 100 ), and decreased methylation of mtDNA has been linked with the reduced expression of PGC-1α and p-AMPK, and the accumulation of fumarate in diabetic kidney ( 101 ).…”

Lacking ketohexokinase-A exacerbates renal injury in streptozotocin-induced diabetic mice

“…Levels of TCA cycle intermediates including citrate, cis-aconitate, and fumarate have been reported to be elevated in diabetes and are correlated with albuminuria and kidney dysfunction in animal models of diabetes [43]. In addition, fumarate levels were increased in the kidney in STZ-induced diabetic rats [44]. In the present study, we found that no significant change of renal and urinary TCA cycle intermediates among all control mice (Figure 6c-f and Supplemental Figure 6, 7).…”

Infrared spectral markers for the nephroprotective effects ofFicus deltoideain streptozotocin-induced diabetic rats

“…Sustained kidney biochemical alterations have been observed in these kidney cells even after tight glycemic control [10]. According to previous reports [11,12], there was a positive correlation between the structural and biochemical changes of the kidney tissue and the infrared (IR) absorption spectra.…”