Sirtuin Family and Diabetic Kidney Disease

Abstract

Diabetes mellitus (DM) is gradually attacking the health and life of people all over the world. Diabetic kidney disease (DKD) is one of the most common chronic microvascular complications of DM, whose mechanism is complex and still lacks research. Sirtuin family is a class III histone deacetylase with highly conserved NAD⁺ binding domain and catalytic functional domain, while different N-terminal and C-terminal structures enable them to bind different deacetylated substrates to participate in the cellular NAD⁺ metabolism. The kidney is an organ rich in NAD⁺ and database exploration of literature shows that the Sirtuin family has different expression localization in renal, cellular, and subcellular structures. With the progress of modern technology, a variety of animal models and reagents for the Sirtuin family and DKD emerged. Machine learning in the literature shows that the Sirtuin family can regulate pathophysiological injury mainly in the glomerular filtration membrane, renal tubular absorption, and immune inflammation through various mechanisms such as epigenetics, multiple signaling pathways, and mitochondrial function. These mechanisms are the key nodes participating in DKD. Thus, it is of great significance for target therapy to study biological functions of the Sirtuin family and DKD regulation mechanism in-depth.

Keywords: NAD+; Sirtuin (SIRT); diabetes; diabetic kidney disease; kidney.

Figure 1

Physiological structure of nephron and pathologic process of diabetic kidney diseases. Left: whole kidney structure; middle: healthy nephron structure; right: the pathological changes of DKD.

Figure 2

Cellular NAD⁺ metabolism induced by Sirtuin family. The enzymatic activity of the Sirtuin family is mainly to remove the acetyl group from the target protein. Firstly, NAD⁺ is cut into NAM and ADP-ribose, and the acetyl group on the target protein is transferred to ADP-ribose to form acetyl-ADP-ribose. Therefore, some members of the Sirtuin family can also play a role in ADP ribosyltransferase. The increase of NAD⁺ levels is closely related to the activation of the Sirtuin family members during moderate fasting and caloric restriction. On the contrary, aging, cancer, cardiovascular and cerebrovascular diseases as well as metabolic diseases such as insulin resistance lead to a decrease in NAD⁺ levels, which is related to the decrease in Sirtuin family activity. Mammalian cells can produce NAD⁺ from Tryptophan via the Kynurenine pathway or from NA, one of the forms of vitamin B3, via the Preiss-Handler pathway, while most NAD⁺ is recovered from NAM and NR via the Salvage pathway. NAD⁺ can be reduced to NADH during glycolysis, fatty acid oxidation, and the TCA cycle. NAD⁺ also acts as a substrate for enzymes such as Sirtuins, producing NAM as a byproduct, and affects metabolism, genomic stability, gene expression, inflammation, circadian rhythm, and stress resistance. This response pattern of the Sirtuin family is extensive. SIRT1, SIRT6, and SIRT7 exist in the nucleus, SIRT2 exists in the cytoplasm, while SIRT3, SIRT4, and SIRT5 exist in the mitochondrion. Abbreviations: Ac, acetylation; eNAMPT, extracellular nicotinamide phosphoribosyltransferase; ETC, electron transport chain; iNAMPT, intracellular nicotinamide phosphoribosyltransferase; MNAM, N ¹-methylnicotinamide; NA, nicotinic acid; NAD⁺, nicotinamide adenine dinucleotide; NADH, nicotinamide adenine dinucleotide; NADK, NAD⁺ kinase; NADP/NADPH, nicotinamide adenine dinucleotide phosphate; NAM, nicotinamide; NAMN, nicotinamide mononucleotide; NAPRT, nicotinic acid phosphoribosyltransferase; NMN, nicotinamide mononucleotide; NMNAT, nicotinamide mononucleotide adenylyltransferases; NR, nicotinamide riboside; NRK1&2, nicotinamide riboside kinases 1 and 2; TCA, tricarboxylic acid.

Figure 3

Heatmap of human Sirtuin family genes with different cell type markers. Single cell transcriptomics data for kidney tissues and peripheral blood mononuclear cells were analyzed. These datasets were respectively retrieved from the Single Cell Expression Atlas (https://www.ebi.ac.uk/gxa/sc/home), the Human Cell Atlas (https://www.humancellatlas.org/), the Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/), the Allen Brain Map (https://portal.brain-map.org/), and the European Genome-phenome Archive (https://www.ebi.ac.uk/ega/).

Figure 4

Correlation of human Sirtuin family transcriptome in renal tissues. The analysis was performed on data from RNA-seq of unfractionated tissue samples, which contained a mixed cell population. Across the respective sample sets the reference transcripts within each cell type panel correlated highly with each other, but not with those in the other panels. An integrative co-expression analysis was performed to determine the expression profile of each gene; genes highly correlated with all transcripts in only one reference panel were classified as enriched in that cell type.

Figure 5

Schematic diagram of Sirtuin family. The Sirtuin family is a deacetylase with an NAD⁺ binding domain that consumes NAD⁺ to regulate energy metabolism. Sirtuin family regulates mesangial cell proliferation and hypertrophy, podocytes apoptosis, glucose metabolism in proximal tubules, and renal tubular injury in DKD pathophysiological changes through epigenetics of acetylation and dephosphorylation, NAD⁺ induced mitochondrial function, and multiple signaling pathway targets. It also participates in podocytes mediated renal tubular cells, endothelial cells, and macrophages crosstalk. (A) renal injury of Sirtuin family in DKD; (B) specific mechanism of Sirtuin family in DKD.