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

Abstract

Diabetic Nephropathy (DN) is the leading cause of kidney failure, with an increasing incidence worldwide. Mitochondrial dysfunction is known to occur in DN and has been implicated in the underlying pathogenesis of disease. These complex organelles have an array of important cellular functions and involvement in signalling pathways; and understanding the intricacies of these responses in health, as well as how they are damaged in disease, is likely to highlight novel therapeutic avenues. A key cell type damaged early in DN is the podocyte and increasing studies have focused on investigating the role of mitochondria in podocyte injury. This review will summarise what is known about podocyte mitochondrial dynamics in DN, with a particular focus on bioenergetic pathways, highlighting key studies in this field and potential opportunities to target, enhance or protect podocyte mitochondrial function in the treatment of DN.

TangShenWeiNing Formula Prevents Diabetic Nephropathy by Protecting Podocytes Through the SIRT1/HIF-1α Pathway

“…Fibrosis represents a hallmark of progressive chronic renal disorders, potentially leading to renal failure. High blood glucose upregulates the expression fibrotic factors, further resulting in damaged glomerular filtration barrier and causing DN (29). In the current study, diabetes caused fibrosis and increased collagen I amounts in the mouse kidney, and these effects were alleviated by TSWN, suggesting that TSWN reduces renal fibrosis in diabetic mice.…”

“…DN represents a commonly detected microvascular complication of diabetes, accounting for adverse clinical outcome (28). Treatment options for DN mainly reduce albuminuria to improve the prognosis of clinical adverse events (29). At present, drugs commonly used to prevent DN and reduce albuminuria in clinic, including angiotensin receptor blockers (ARB), reduce renal fibrosis and apoptosis, and protect podocytes (30,31).…”

“…They form the last line of defense for the glomerular filtration barrier (37). Since podocytes show limited capabilities of repair and regeneration, the degree of podocyte injury is considered the main prognostic determinant of DN (29). Podocytes are critical for renal function, and constitute the primary focus in multiple renal disorders, especially DN.…”

“…Podocytes are highly specialized, terminally differentiated cells. Hyperglycemia leads to abnormalities of podocyte-associated proteins and signaling pathways, and podocyte apoptosis accelerates disease progression (2). It is known that podocytes have a limited renewal ability.…”

Metabolic reprogramming: A novel therapeutic target in diabetic kidney disease

“…The increased flux to side branches of glycolysis is another mechanism of podocyte damage in metabolic reprogramming, instead of generating pyruvate, glucose enters side branches to produce toxic metabolites, such as sorbitol, methylglyoxal, and diacylglycerol, contributing to podocyte apoptosis (Qi et al, 2018). In addition, lipotoxicity in podocytes due to decreased metabolism has recently attracted attention (Audzeyenka et al, 2022). For example, fructose was shown to drive mitochondrial metabolic reprogramming in differentiated podocytes, resulting in lipid accumulation and cell injury (Fang et al, 2021).…”