The recent and ongoing worldwide increase in the prevalence of obesity parallels the increase in the incidence of chronic kidney disease (CKD). This association suggests an implication of lipotoxicity in the development of kidney diseases. The increased influx of lipids into the kidney can be explained in the context of the “Adipose Tissue Expandability Hypothesis”. This hypothesis states that the adipose tissue has a limited expansion capability, which is different for each individual, and once this limit is reached, the adipose tissue cannot store any more lipids and will thus release them into the bloodstream. The accumulation of lipids in the kidney is known as renal lipotoxicity. Renal lipotoxicity is known to cause detrimental effects on the kidney by several mechanisms of action including reclusion of pro-inflammatory factors, oxidative and ER stress development, insulin resistance (IR), lipid metabolism deregulation or renin-angiotensin aldosterone system overactivation. Isoform peroxisome proliferator-activated receptor gamma (PPARγ) seems to play an important role in the development of this lipotoxicity as proven by several studies in -animals and cultured cells. Thus, PPARγ agonists are of -interest in the therapeutic approach to treat CKD in the context of obesity. This review aims to summarize our current knowledge of the mechanism by which lipotoxicity affects renal structure and function using in vivo and in vitro models as examples focusing on PPARγ.

Keywords:
Obesity, Adipose tissue expandability, Lipotoxicity, Peroxisome proliferator-activated receptor gamma, Chronic kidney disease
1.
Virtue S, Vidal-Puig A: Adipose tissue expandability, lipotoxicity and the metabolic syndrome – an allostatic perspective. Biochim Biophys Acta 2010; 1801: 338–349.
2.
de Vries AP, Ruggenenti P, Ruan XZ, Praga M, Cruzado JM, Bajema IM, et al: Fatty kidney: emerging role of ectopic lipid in obesity-related renal disease. Lancet Diabetes Endocrinol 2014; 2: 417–426.
3.
Rüster C, Wolf G: Adipokines promote chronic kidney disease. Nephrol Dial Transplant 2013; 28(suppl 4):iv8– iv14.
4.
Zhu Q, Scherer PE: Immunologic and endocrine functions of adipose tissue: implications for kidney disease. Nat Rev Nephrol 2018; 14: 105–120.
5.
Lan HY, Bacher M, Yang N, Mu W, Nikolic-Paterson DJ, Metz C, et al: The pathogenic role of macrophage migration inhibitory factor in immunologically induced kidney disease in the rat. J Exp Med 1997; 185: 1455–1465.
6.
Welsh GI, Hale LJ, Eremina V, Jeansson M, Maezawa Y, Lennon R, et al: Insulin signaling to the glomerular podocyte is critical for normal kidney function. Cell Metab 2010; 12: 329–340
7.
Li C, Lin Y, Luo R, Chen S, Wang F, Zheng P, et al: Intrarenal renin-angiotensin system mediates fatty acid-induced ER stress in the kidney. Am J Physiol Renal Physiol 2016; 310: F351–F363.
8.
Sieber J, Lindenmeyer MT, Kampe K, Campbell KN, Cohen CD, Hopfer H, et al: Regulation of podocyte survival and endoplasmic reticulum stress by fatty acids. Am J Physiol Renal Physiol 2010; 299:F821–F829.
9.
Martínez-García C, Izquierdo-Lahuerta A, Vivas Y, Velasco I, Yeo TK, Chen S, et al: Renal lipotoxicity-associated inflammation and insulin resistance affects actin cytoskeleton organization in podocytes. PLoS One 2015; 10: e014229.
10.
Kershaw EE, Flier JS: Adipose tissue as an endocrine organ. J Clin Endocrinol Metab 2004; 89: 2548–2556.
11.
Berl T, Henrich W: Kidney-heart interactions: epidemiology, pathogenesis, and treatment. Clin J Am Soc Nephrol 2006; 1: 8–18.
12.
D’Agati VD, Chagnac A, de Vries AP, Levi M, Porrini E, Herman-Edelstein M, et al: Obesity-related glomerulopathy: clinical and pathologic characteristics and pathogenesis. Nat Rev Nephrol 2016; 12: 453–471.
13.
Ristow M, Müller-Wieland D, Pfeiffer A, Krone W, Kahn CR: Obesity associated with a mutation in a genetic regulator of adipocyte differentiation. N Engl J Med 1998; 339: 953–959.
14.
Medina-Gomez G, Yetukuri L, Velagapudi V, Campbell M, Blount M, Jimenez-Linan M, et al: Adaptation and failure of pancreatic beta cells in murine models with different degrees of metabolic syndrome. Dis Model Mech 2009; 2: 582–592
15.
Martínez-García C, Izquierdo A, Velagapudi V, Vivas Y, Velasco I, Campbell M, et al: Accelerated renal disease is associated with the development of metabolic syndrome in a glucolipotoxic mouse model. Dis Model Mech 2012; 5: 636–648.
16.
Luzar B, Ferluga D: Role of lipids in the progression of renal disease in systemic lupus erythematosus patients. Wien Klin Wochenschr 2000; 112: 716–721.
17.
Rutkowski JM, Wang ZV, Park AS, Zhang J, Zhang D, Hu MC, et al: Adiponectin promotes functional recovery after podocyte ablation. J Am Soc Nephrol 2013; 24: 268–282.
18.
Corrales P, Izquierdo-Lahuerta A, Medina-Gómez G: Maintenance of kidney metabolic homeostasis by PPAR gamma. Int J Mol Sci 2018; 19: 2063–2074.
19.
Lee YJ, Han HJ: Troglitazone ameliorates high glucose-induced EMT and dysfunction of SGLTs through PI3K/Akt, GSK-3β, Snail1, and β-catenin in renal proximal tubule cells. Am J Physiol Renal Physiol 2010; 298:F1263–F1275.
20.
Arima S, Kohagura K, Takeuchi K, Taniyama Y, Sugawara A, Ikeda Y, et al: Biphasic vasodilator action of troglitazone on the renal microcirculation. J Am Soc Nephrol 2002; 13: 342–349.
21.
Benson SC, Pershadsingh HA, Ho CI, Chittiboyina A, Desai P, Pravenec M, et al: Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARgamma-modulating activity. Hypertension 2004; 43: 993–1002.
© 2019 S. Karger AG, Basel
2019
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.