Nephrol Dial Transplant (2003) 18: 24712474

DOI: 10.1093/ndt/gfg427

After all those fat years: renal consequences of obesity

Gunter Wolf

Department of Medicine, Division of Nephrology, Rheumatology and Osteology, University of Hamburg,

Hamburg, Germany

Keywords: adipocyte; diabetes type 2; hypertension;leptin; obesity; progression of renal disease

Bigger is not better

Our genetic background and physiological homeo-stasis, orchestrated through endocrine and neuronalnetworks, are optimized for a world with intermittentfood supply and permit us to survive periods ofstarvation [1]. However, these systems are counterpro-ductive in our current industrial society with fast-foodrestaurants, an abundance of high energy food and anincreasingly sedentary life-style. The consequence is analarming increase in obese adults and, even moredisturbing, of overweight children [1]. The conse-quences of obesity such as the metabolic syndromewith its ultimate development of type 2 diabetesmellitus, cardiovascular diseases, an increased inci-dence of certain types of cancer, musculoskeletaldisorders and pulmonary diseases are well known.What about renal diseases? Almost 30 years ago,Weisinger et al. [2] described focal-segmental glomer-ulosclerosis with nephrotic syndrome in four extremelyobese patients. Only two of them exhibited hyperten-sion by ofce blood pressure measurements [2]. Inthe following years, several case reports describingglomerulosclerosis in very obese patients have beenpublished, but this entity was considered as rare andrather bizarre. However, a recent study showed adramatic increase of histologically proven renal diseasein obese patients in the absence of diabetes [3]. Thepatients had rapidly progressive renal disease [4].Furthermore, obesity is an important risk factor forthe progression of renal disease in IgA nephropathy [5],and is also associated with an enhanced risk of chronicgraft dysfunction after renal transplantation [6].On the other hand, overweight patients with a bodymass index (BMI) >27 kg/m2 with various chronicrenal diseases experienced a signicant reduction in

proteinuria after only moderate weight loss [7]. Aproblem with all these studies is the fact that con-founding factors such as hypertension were not totallyruled out.

Adipose tissue as a source of hormones andcytokines

Fat cells are much more than a passive store of excessenergy. Adipose tissue is a source of various hormonesthat may very well inuence renal function [8,9]. Anincomplete list of these factors is shown in Table 1.Some of these hormones and growth factors couldreach the kidney and exert their pathophysiolog-ical effects [8]. For example, transgenic mice withangiotensinogen expression restricted to adiposetissue have increased circulating angiotensinogen, andthe angiotensin II thus generated has renal effects[10]. Overexpression of angiotensinogen in adipocytesleads to hypertension [10]. Thus, the adipose tissuereninangiotensinogen system could exert direct effectson the kidney. The detrimental effects of continuouslyenhanced angiotensin II concentrations on renal func-tion and structure are well appreciated [11]. Althoughnot the subject of this review, an increase in localformation of angiotensin II in adipose tissue probablycontributes to the development of insulin resistance andpromotes the metabolic syndrome [12]. Renal effects oftumour necrosis factor- (TNF-) through the induc-tion of proinammatory cytokines and theprobrogenic role of plasminogen activator inhibitor-1 (PAI-1) have been studied in detail. Other factorssuch as adiponectin may inhibit some of TNF-s

Table 1. Some hormones, cytokines and growth factors producedin adipose tissue

AngiotensinogenReninTNF-Interleukin-6LeptinPlasminogen activator inhibitor-1 (PAI-1)TGF-ResistinAdiponectin

Nephrol Dial Transplant 18(12) ERAEDTA 2003; all rights reserved

Correspondence and offprint requests to: Gunter Wolf, MD,University of Hamburg, University Hospital Eppendorf,Department of Medicine, Division of Nephrology, Rheumatologyand Osteology, Pavilion N26, Martinistrae 52, D-20246 Hamburg,Germany. Email: Wolf@uke.uni-hamburg.de

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proinammatory effects, but circulating adiponectinlevels are paradoxically lower in obese individuals andpatients with type 2 diabetes [9].

What about leptin?

Leptin, the product of the ob gene, is a satiety factorproduced in adipocytes. It acts on specic receptorslocalized in the hypothalamus and inuences otherneurohormones [13]. Leptin suppresses food intakeby inhibiting neuropeptide Y and by increasingmelanocyte-stimulating hormone (MSH), and decreas-ing agouti-related peptide, an antagonist of MSH at theMC4 receptor [14]. Interestingly, an experimentallyinduced disruption of the MSH system induces salt-sensitive hypertension, indicating a central role for thesepeptides in blood pressure regulation [15]. Leptincentrally stimulates sympathetic nerve action; trans-genic mice overexpressing leptin are hypertensive andhave elevated urinary catecholamine excretion [16].However, despite high circulating leptin concentrations,obese individuals are characterized by a relative leptinresistance [17]. The molecular mechanisms of this leptinresistance are subject to active current research andmaybe heterogeneous. As a small peptide hormone, leptin iscleared by the kidney [14,18]. Consequently, patientswith impaired renal function have high circulatingleptin concentrations.Mice with a decient leptin gene (ob/ob) as well as

animals with a defect for the long leptin receptor (db/db)are both obese and develop type 2 diabetes. However,only db/db mice with high circulating leptin concentra-tions show histological changes reminiscent of diabeticnephropathy, whereas the kidneys of ob/obmice appearrelatively normal [18]. This provided the impetus for usto study whether leptin could have direct renal effects[18]. Leptin stimulates the proliferation of cultured ratglomerular endothelial cells [19]. Angiotensin II andleptin have additive proliferative effects on glomerularendothelial cells [19]. This proliferation is cell typespecic because mesangial cells failed to replicate in thepresence of leptin [19]. Glomerular endothelial cellsexpress the short leptin receptor previously thoughtto act solely as a clearance receptor without signaltransduction. However, leptin induces STAT1 phos-phorylation, suggesting active signal transduction,but further studies are necessary to dene whetherthe signals are indeed mediated through the shortleptin receptor [19]. Moreover, leptin induces mRNAexpression andprotein secretionof transforming growthfactor- (TGF-) in glomerular endothelial cells [19].Leptin increases the expression of TGF- type IIreceptors on mesangial cells from the rat and fromdb/db mice, suggesting that the long leptin receptor isnot necessary for this effect [20]. In addition, exogenousleptin increases cellular glucose uptake and enhancedtype I collagen synthesis [20]. The addition of bothTGF- and leptin increases mesangial cell type Icollagen secretion more than either stimulus alone[20]. These ndings suggest a paracrine TGF- pathway

between glomerular endothelial and mesangial cellsthat is mediated by leptin. Leptin-induced TGF- fromendothelial cells could easily reach mesangial cellswhere it binds to the leptin-induced upregulated TGF-type II receptors [18]. The consequence is an increase inextracellular matrix deposition. To test a potential rolefor leptin in vivo, recombinant leptin was infusedwith osmotic minipumps into normal rats. Short-terminfusion for 72 h stimulated glomerular TGF-,expression and increased in parallel the number ofcells expression proliferating cell nuclear antigen(PCNA). After 3 weeks of leptin infusion into rats,glomerular expression of type IV collagen was sig-nicantly enhanced compared with pair-fed controls[19]. Leptin did no inuence blood pressure, butproteinuria was signicantly enhanced in leptin-infusedanimals [19]. These studies provide for the rst timeevidence that leptin exerts pathophysiological effects inthe kidney. However, retrospective measurements ofserum leptin at a single time point did not correlate withthe decline in renal function in non-diabetic patientsfrom the Modication of Diet in Renal Disease Study(MDRD [21]).

Obesity and kidney function and structure

Obese patients without diabetes mellitus type 2 exhibita signicant increase in glomerularltration rate (GFR),compared with controls with normal BMI [22]. Thishyperltration is caused by dilation of the afferentarteriole [22]. One explanation for these haemodynamicchanges could be an activated glomerulo-tubularfeedback caused by enhanced sodium reabsorption inthe proximal tubule. Leptin, through activation of thesympathetic nervous system as well as direct effects onangiotensin II and insulin, could contribute to theincrease in sodium reabsorption. It is intriguing tospeculate that fat tissue may contribute to the increasein angiotensin II that enhances sodium transport.Glomerular hyperltration is a well known patho-physiological link to glomerulosclerosis and proteinuria[11]. In addition, many animal studies demonstratedthat chronic intravenous or intracerebroventricularinfusion of leptin increases sympathetic activity inthe kidneys and induces hypertension [23]. Fat tissuecompletely encapsulates the kidney of obese animalsand increases intrarenal pressure [23]. This mechanismis similar to the well known wrap kidney model,originally developed by Grollmann in the 1940s. Thismechanism may increase blood pressure further inobese individuals [24]. In addition, this observationmay also explain why abdominal obesity correlatesbetter with hypertension than BMI [23].In an experimental study in dogs, Henegar et al. [25]

found that a high calorie diet induces within no morethan 7 weeks an increase inmean arterial blood pressureand GFR. Moreover, histological changes includingglomerular cell proliferation, thickening of glomerularand tubular basement membranes, increased matrixexpansion and glomerular TGF- expression were

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present [25]. These structural ndings are similar tothose reported by us in leptin-infused rats [19].

What could be done?

It is obvious that life-style changes with weight lossare the key element of any successful therapy ofobesity [26]. However, although it has been shown thatinitial successful weight loss is possible with severalstructured programmes, only a few patients maintaintheir reduced weight [26]. Many clinical diet trialshave shown a high drop-out rate [27]. Treatmentwith anti-obesity substances such as orlistat andsibutramine have modest weight-reducing effects, butcarry the denite risk of side effects [26]. A consistenteffective treatment for hypertension is mandatory.First line therapies are angiotensin-converting enzyme(ACE) inhibitors because of the pathophysiological roleof the reninangiotensin system in obesity-mediatedrenal changes and hypertension [26]. Some clinicalobservations suggest that -blockers are associatedwith additional weight gain [26]. Although it is prema-ture to make general recommendations, clinical studiesindicate that acarbose, metformin and ACE inhibitorsmay delay development of type 2 diabetes in obesesubjects [28]. Consequently, an interdisciplinary man-agement of type 2 diabetes is necessary to preventnephropathy [29]. The family physician needs experthelp for dealing with this important problem.

Conclusion

Although the incidence of obesity-related glomerulo-sclerosis is increasing, which carries a poor renalprognosis, overweight is probably more important asa progression factor in patients with known primarychronic renal diseases. Certainly, more research isneeded to understand better how obesity inuencesrenal function. The adipocyte is a source of severalhormones, including leptin, that may have detrimentaleffects on the kidney, indicating that fat tissue itselfcould be a major culprit. Our genetic hardwiringwith neuronalhormonal loops mainly fostering energyconservation served our ancestors in times of starvationwell, but poses a major problem for successful weightreduction. Nevertheless, structured weight reductionand control programmes may help to overcome thisdifculty. Good luck!

Acknowledgements. Many of the views expressed in this article weredeveloped together with my friend and colleague Fuad N. Ziyadeh,MD, University of Pennsylvania, Philadelphia, USA.

Conict of interest statement. None declared.

References

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2. Weisinger JR, Kempson RL, Eldrige FL, Swenson RS. Thenephrotic syndrome: a complication of massive obesity. AnnIntern Med 1974; 81: 440447

3. Kambham N, Markowitz GS, Valeri Am, Lin J, DAgati VD.Obesity-related glomerulopathy: an emerging epidemic. KidneyInt 2001; 59: 14981509

4. Praga M, Hernandez E, Morales E et al. Clinical features andlong-term outcome of obesity-associated focal segmental glomer-ulosclerosis. Nephrol Dial Transplant 2001; 16: 17901798

5. Bonnet F, Deprele C, Sassolas A et al. Excessive body weightas a new independent risk factor for clinical and pathologicalprogression in primary IgA nephritis. Am J Kidney Dis 2001;37: 720727

6. Meier-Krische HU, Arndorfer JA, Kaplan B. The impact ofbody mass index on renal transplant outcomes: a signicantindependent risk factor for graft failure and patient death.Transplantation 2002; 73: 7074

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21. Sarnak MJ, Poindexter A, Wang SR et al. Serum C-reactiveprotein and leptin as predictors of kidney disease progression inthe Modication of Diet in Renal Disease Study. Kidney Int2002; 62: 22082215

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DOI: 10.1093/ndt/gfg322

Senescence of renal cells: molecular basis and clinical implications

Anette Melk

Division of Nephrology and Immunology, University of Alberta, Edmonton, Canada

Keywords: allograft nephropathy; cellular senescence;kidney ageing; p16INK4a; renal senescence; telomere

Introduction

Age-associated changes of the kidney are important notonly because normal ageing alters renal function butalso because of the high frequency of end-stage renaldisease in the elderly (ERAEDTA Registry Report2000). Old kidneys perform poorly when transplanted,and donor age is a major determinant of graft survival[1]. It has been proposed that interactions betweenageing and diseases may contribute to these problems.Understanding the mechanisms of declining organfunction with age may be instructive concerning themechanisms of decline in disease states, since stressmight accelerate ageing changes. Kidney ageing is alsoof interest as a general model for organ ageing, becauserenal function can be assessed with relative ease inclinical practice and has been quantied in longitudinalstudies [2]. The molecular basis of ageing changes inorgans is not known, but organ ageing may reectaspects of cellular senescence which are understoodbetter now than a few years ago.Here, I will review recent progress in dening the

molecular changes and pathways involved in cellularsenescence, their relative contribution in cells fromdifferent species, in particular human and mouse, andtheir relevance to renal ageing and disease.

Terms and denitions

Cellular senescence describes a phenotype of perma-nent and irreversible growth arrest shown by mamma-lian cells in culture. Originally described in humanbroblasts by Hayick and Moorhead [3], this termwas used synonymously with replicative senescence.However, in recent years, the concept of cellularsenescence has been expanded to include other formsof permanent, irreversible cell-cycle arrest. The reasonfor this extension comes partly from the observationthat mouse embryonic broblasts in culture do not usereplicative senescence to cease replication, but shareother senescence features with human broblasts suchas altered morphology, greater heterogeneity, expres-sion of senescence-associated -galactosidase (SA--GAL) and accumulation of lipofuscin granules. Thishad been referred to as premature senescence, stress-induced senescence and most recently stimulationand stress-induced senescent-like arrest (STASIS) [4].The term renal senescence reects the structural andfunctional phenotype associated with aged kidneys.

The phenotype of renal senescence

The phenotype of human renal senescence can bedescribed as a phenotype of loss: the loss of mass,particularly in cortex [5,6], and the loss of function, asreected by increased renal vascular resistance, reducedrenal plasma ow and increased ltration fraction [6,7].The glomerular ltration rate (GFR), as described bymultiple equations such as CockcroftGault [8] andMDRD [9], is not an ideal measurement to assess thismalfunction. Although studies in selected populations[2,10], excluding all renal diseases, hypertension and

Nephrol Dial Transplant 18(12) ERAEDTA 2003; all rights reserved

Correspondence and offprint requests to: Anette Melk, MD, PhD,Division of Nephrology and Immunology, University of Alberta,250 Heritage Medical Research Centre, Edmonton, Alberta, T6G2S2, Canada. Email: anettemelk@yahoo.de

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