CHOLESTEROL TRANSPORT AND KIDNEY DISEASE

Cholesterol and other lipids are critical for normal cell function. Disorders in their metabolism and transport have been implicated in numerous diseases and conditions1-3, including Atherosclerosis, Niemann Pick Type C, Alzheimer’s Disease, Parkinson’s Disease, Huntington’s Disease, and Chronic Kidney Diseases (Focal Segmental Glomerulosclerosis, Alport Syndrome, Diabetic Kidney Disease).

In chronic kidney diseases, cholesterol accumulates in the kidneys’ filtration system (glomerular podocytes), due in part to impaired efflux (transport out of the cell) resulting from reduced expression of the cholesterol transporters ABCA1 and ABCG13,4.  The lipid accumulation causes distorted podocyte structure, damaged podocyte foot processes, and podocyte detachment and loss, which impairs kidney filtration resulting in proteinuria (leakage of protein in the urine) and disease progression2-5.

Cholesterol Transport and Kidney Disease

Image from D’Agati, et al: N Engl J Med 2011; 365:2398-2411

References

  1. Coisne C, Tilloy S, Monflier E, Wils D, Fenart L, Gosselet F. Cyclodextrins as Emerging Therapeutic Tools in the Treatment of Cholesterol-Associated Vascular and Neurodegenerative Diseases. Molecules. 2016;21(12):1748. Published 2016 Dec 20
  2. Merscher-Gomez S, Guzman J, Pedigo CE, Lehto M, Aguillon-Prada R, Mendez A, Lassenius MI, Forsblom C, Yoo T, Villarreal R, Maiguel D, Johnson K, Goldberg R, Nair V, Randolph A, Kretzler M, Nelson RG, Burke GW 3rd, Groop PH, Fornoni A; FinnDiane Study Group. Cyclodextrin protects podocytes in diabetic kidney disease. Diabetes 2013; Nov; 62(11):3817-27. doi: 10.2337/db13-0399. Epub 2013 Jul 8
  3. Mitrofanova A, Molina J, Varona Santos J, Guzman J, Morales XA, Ducasa GM, Bryn J, Sloan A, Volosenco I, Kim JJ, Ge M, Mallela SK, Kretzler M, Eddy S, Martini S, Wahl P, Pastori S, Mendez AJ, Burke GW, Merscher S, Fornoni A. Hydroxypropyl-β-cyclodextrin protects from kidney disease in experimental Alport syndrome and focal segmental glomerulosclerosis. Kidney International, Volume 94 , Issue 6 , 1151 – 1159
  4. Pedigo CE, et.al.; Local TNF causes NFATc1-dependent cholesterol mediated podocyte injury. J Clin Invest; 2016;126(9): 3336-3350
  5. D’Agati VD, Kaskel FJ, Falk RJ. Focal Segmental Glomerulosclerosis. N Engl J Med 2011; 365:2398-2411