Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Oct 25:8:751529.
doi: 10.3389/fmed.2021.751529. eCollection 2021.

Lipotoxic Proximal Tubular Injury: A Primary Event in Diabetic Kidney Disease

Hua Wang  1 , Shu Zhang  1 , Jia Guo  2   3
Affiliations
Review

Lipotoxic Proximal Tubular Injury: A Primary Event in Diabetic Kidney Disease

Hua Wang et al. Front Med (Lausanne). .

Abstract

The pathogenesis of diabetic nephropathy is a complex process that has a great relationship with lipotoxicity. Since the concept of "nephrotoxicity" was proposed, many studies have confirmed that lipotoxicity plays a significant role in the progression of diabetic nephropathy and causes various renal dysfunction. This review will make a brief summary of renal injury caused by lipotoxicity that occurs primarily and predominantly in renal tubules during diabetic progression, further leading to glomerular dysfunction. The latest research suggests that lipotoxicity-mediated tubular injury may be a major event in diabetic nephropathy.

Keywords: diabetic kidney disease; lipid accumulation; lipotoxicity; primary event; tubular injury.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Lipid metabolism in renal tubules and the regulation mechanism in diabetes mellitus. Tubules mainly utilize the metabolism of FAs as an energy source, and the metabolism of FAs includes catabolism and anabolism. FAs entering the renal tubules mainly come from the blood circulation. Initially, FAs are esterified in the form of VLDL and CM-TAG; then, esterified FAs are catabolized by LPL to release FAs. Extracellular FAs enter the cell by autonomous diffusion or transporters as CD36 and FABP. FAs into the cell are activated by ACS to fatty acyl-CoA, and then part of fatty acyl-CoA enters the mitochondria via CPT-1 and CPT-2 for catabolism to produce acetyl-CoA, which enters TCA to produce ATP required by the kidney; and excess fatty acyl-CoA enters the anabolic pathway to generate TAG. In addition, the product of FAO acetyl-CoA can also be transported out of mitochondria by CACT and converted to malonyl-CoA by ACC, and malonyl-CoA resynthesizes new FAs by FAS. In diabetes and high glucose conditions, the proteins are high- or down regulated in the uptake, metabolism and synthesis of FAs, which are marked in red color.
Figure 2
Figure 2
Lipotoxicity-mediated tubular injury. Tubular lipotoxicity leads to the development of a series of renal injuries including tubular epithelial cell apoptosis, inflammation and tubulointerstitial fibrosis. First, in renal tubules, lipotoxicity may cause mitochondrial dysfunction, involving massive ROS production, and inducing oxidative stress (OS) and ER stress. Second, lipotoxicity may cause OS and ER stress, which in turn may cause mitochondrial damage. At the same time, OS and ER stress may also cause damage to mitochondria. In addition, mitochondrial dysfunction, OS and ER stress together do harm to tubular cells.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Alicic RZ, Rooney MT, Tuttle KR. Diabetic kidney disease: challenges, progress, and possibilities. Clin J Am Soc Nephrol. (2017) 12:2032–45. 10.2215/CJN.11491116 - DOI - PMC - PubMed
    1. Cho NH, Shaw JE, Karuranga S, Huang Y, Da Rocha Fernandes JD, Ohlrogge AW, et al. . IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pr. (2018) 138:271–81. 10.1016/j.diabres.2018.02.023 - DOI - PubMed
    1. Rowley WR, Bezold C, Arikan Y, Byrne E, Krohe S. Diabetes 2030: insights from yesterday, today, and future trends. Popul Health Manag. (2017) 20:6–12. 10.1089/pop.2015.0181 - DOI - PMC - PubMed
    1. Tofte N, Lindhardt M, Adamova K, Bakker SJL, Beige J, Beulens JWJ, et al. . Early detection of diabetic kidney disease by urinary proteomics and subsequent intervention with spironolactone to delay progression (PRIORITY): a prospective observational study and embedded randomised placebo-controlled trial. The Lancet Diabetes & Endocrinology. (2020) 8:301–12. 10.1016/S2213-8587(20)30026-7 - DOI - PubMed
    1. Herman-Edelstein M, Scherzer P, Tobar A, Levi M, Gafter U. Altered renal lipid metabolism and renal lipid accumulation in human diabetic nephropathy. J Lipid Res. (2014) 55:561–72. 10.1194/jlr.P040501 - DOI - PMC - PubMed

LinkOut - more resources