Role of renal tubular programed cell death in diabetic kidney disease

Abstract

The pathogenic mechanism of diabetic kidney disease (DKD) is involved in various functions; however, its inadequate characterisation limits the availability of effective treatments. Tubular damage is closely correlated with renal function and is thought to be the main contributor to the injury observed in early DKD. Programed cell death (PCD) occurs during the biological development of the living body. Accumulating evidence has clarified the fundamental role of abnormalities in tubular PCD during DKD pathogenesis. Among PCD types, classical apoptosis, autophagic cell death, and pyroptosis are the most studied and will be the focus of this review. Our review aims to elucidate the current knowledge of the mechanism of DKD and the potential therapeutic potential of drugs targeting tubular PCD pathways in DKD.

Keywords: apoptosis; autophagy; diabetic kidney disease; programed cell death; pyroptosis; review.

FIGURE 1

Normal kidney structure

FIGURE 2

Cell death of renal tubular epithelial cells under high glucose

FIGURE 3

Pharmacological effects targeting Bim protein and related pathways on the TECs apoptosis and autophagy in DKD. High glucose induced the upregulation of transcription factors, FOXO1 and FOXO3a, and then Bim expression was increased and initiated BAX/BAK‐mediated mitochondria‐dependent apoptosis, which further inhibited the autophagy of TECs (black arrows in the middle). The inhibitory effect of prostaglandin E1 on the TECs apoptosis involved two pathways. On one hand, prostaglandin E1 reduced the ET‐1 and Ang II levels to suppress the apoptosis (orange line). On the other hand, prostaglandin E1 attenuated high glucose‐induced Bim expression by inhibiting phosphorylated JNK (red line). Calcium dobesilate exerted the protective function against TECs apoptosis by downregulating the expression of Bim (light blue line). Salidroside inhibited the apoptosis of TECs by targeting Bim protein (green line). Glibenclamide aggravated TECs apoptosis by inhibiting Bcl‐2 and upregulating Bax and suppressed autophagy (black line on the left side). In contrast, the therapeutic effect of gliclazide on the inhibition of TECs apoptosis was achieved by increasing Bcl‐2 expression and suppressing Bax expression (yellow line). The 2D structure of drug was acquired from PubChem database. TECs: tubular epithelial cells; ET‐1: endothelin‐1; Ang II: angiotensin II; JNK: c‐Jun N‐terminal kinase; FOXO1: forkhead box protein O1; FOXO3a: forkhead box protein O3a; Bim: Bcl‐2 interacting mediator