Autophagy and Mitophagy in Diabetic Kidney Disease-A Literature Review

Abstract

Autophagy and mitophagy are critical cellular processes that maintain homeostasis by removing damaged organelles and promoting cellular survival under stress conditions. In the context of diabetic kidney disease, these mechanisms play essential roles in mitigating cellular damage. This review provides an in-depth analysis of the recent literature on the relationship between autophagy, mitophagy, and diabetic kidney disease, highlighting the current state of knowledge, existing research gaps, and potential areas for future investigations. Diabetic nephropathy (DN) is traditionally defined as a specific form of kidney disease caused by long-standing diabetes, characterized by the classic histological lesions in the kidney, including mesangial expansion, glomerular basement membrane thickening, nodular glomerulosclerosis (Kimmelstiel-Wilson nodules), and podocyte injury. Clinical markers for DN are albuminuria and the gradual decline in glomerular filtration rate (GFR). Diabetic kidney disease (DKD) is a broader and more inclusive term, for all forms of chronic kidney disease (CKD) in individuals with diabetes, regardless of the underlying pathology. This includes patients who may have diabetes-associated kidney damage without the typical histological findings of diabetic nephropathy. It also accounts for patients with other coexisting kidney diseases (e.g., hypertensive nephrosclerosis, ischemic nephropathy, tubulointerstitial nephropathies), even in the absence of albuminuria, such as a reduction in GFR.

Keywords: AMPK-mTOR-Sirt1 pathway; PINK1/Parkin pathway; autophagy; diabetic nephropathy; mitochondrial dysfunction; mitophagy.

Figure 1

Molecular mechanism of autophagy: cytosolic components are included in autophagosomes. The autophagosome fuses with the lysosome becomes autophagolysosome and then degrade the cytosolic components.

Figure 2

Molecular mechanisms of mitophagy: there are three well-described pathways of mitophagy: PINK1-PARK2 pathway, BNIP3/NIX receptor pathway, and FUNDC1 receptor pathway.

Figure 3

Autophagy and mitophagy in Diabetic Nephropathy and potential therapeutic targets. Autophagy prevents tubular hypertrophy, endoplasmic reticulum (ER) stress, accumulation of AGEs (advanced glycation end products), and loss of podocytes. Mitophagy inhibits mitochondria specific oxidative stress (mROS—mitochondria-derived reactive oxygen species), attenuates NLRP3 inflammasome-mediated tubular injury (NLR family pyrin domain containing 3), inflammation and fibrosis, AS-IV, astragaloside IV; CoQ10, coenzyme Q10; MitoQ, mitoquinone; mTORC1, mechanistic target of rapamycin (mTOR) kinase complex 1; SGLT2, Naþ-glucose cotransporter-2; SIRT1, sirtuin; TFEB, transcription factor EB; ULK1, uncoordinated-51-like protein kinase 1.

Figure 4

The potential mechanisms of mitophagy in diabetic nephropathy. Impaired mitophagy leads to an accumulation of damaged mitochondria which plays an important role in the pathogenesis of diabetic nephropathy.