EDITORIAL

Evidence that TGF-b should be a therapeutic target in diabeticnephropathy

Diabetic nephropathy is now the most common cause ofend-stage renal disease in North America and Europe. Newevidence suggests that the majority of diabetic patients,whether insulin-dependent or not, are developing fibroticchanges in glomeruli that, if they live long enough, willmanifest as overt nephropathy. It is also clear that thecurrent therapy, optimal glycemic control combined withan angiotensin II antagonist and possibly a low protein diet,can slow, but not prevent the development or progressionof diabetic nephropathy in most patients.

At the molecular level, the pathological features offibrosis in the diabetic kidney resemble fibrosis in otherprogressive forms of renal disease, as well as in fibroticdisorders of a variety of other organs and tissues. Indeed,the most constant molecular feature of pathological tissuefibrosis leading to organ failure is overexpression of thecytokine transforming growth factor-b (TGF-b) [1]. Thesecommon molecular features between the kidney and othertissues suggest the presence of a generic process underlyingfibrotic diseases, rather than unique organ- or tissue-specific processes. The concept of a common process offibrogenesis is good news for the clinician because it impliesthat therapies effective in one fibrotic disorder may bebeneficial in a number of other disorders.

TGF-b’s fibrogenic potential is uniquely powerful be-cause of three simultaneous actions: (1) stimulation ofmatrix synthesis, (2) inhibition of matrix degradation, and(3) modulation of matrix receptor expression to facilitatecell-matrix interactions. TGF-b initiates its fibrogenic ef-fects by acting as a transcription factor for several genesinvolved in regulating matrix deposition and cell growth,including a recently discovered gene, whose product mayfunction as a cell adhesion protein. This gene is big-h3(TGF-b-induced gene human clone 3). TGF-b has beenshown to induce big-h3 in a number of cultured cell lines,and big-h3 is overexpressed in human atherosclerotic andrestenotic vascular lesions. In this issue of Kidney Interna-tional, Gilbert and coworkers provide evidence that big-h3is expressed in normal kidney and its overexpression in thediabetic kidney is closely correlated with that of TGF-b andtype IV collagen [2].

The evidence implicating TGF-b overexpression in thepathogenesis of experimental and human diabetic nephrop-athy is now overwhelming [reviewed in 3, 4]. In thepre-cytokine era a number of factors were thought to playa role in diabetic nephropathy. These factors, includinghigh levels of glucose, increased glomerular pressure andflow, mesangial cell stretch, activation of renin-angiotensinII, hypertension and non-enzymatic glycation of proteins,have all been shown to induce TGF-b production in thekidney or in cultured mesangial or tubular cells [4]. Indeed,as soon as a rat is made diabetic, glomerular expression ofTGF-b is increased along with the glomerular productionand deposition of matrix components and protease inhibi-tors induced by TGF-b [5]. Treating diabetic rats withinsulin suppresses the renal production and secretion ofTGF-b, but not to normal levels. Thus, as in humans, thedisease process is retarded, but not prevented.

Renal hypertrophy is one of the earliest findings inexperimental and human diabetes. Although called agrowth factor (all growth factors are cytokines but not allcytokines are growth factors), TGF-b inhibits the cell cyclein most types of cells, leading to an increase in volume andDNA and protein content, that is, hypertrophy. Proximaltubular cells cultured in high glucose show increased pro-duction of TGF-b and undergo hypertrophy that is blockedby a neutralizing TGF-b antibody. In two models ofspontaneous-insulin dependent diabetes, the biobreeding(BB) rat and the nonobese diabetic (NOD) mouse, thedevelopment of renal hypertrophy was closely correlatedwith the increased renal expression of TGF-b [4]. Strepto-zotocin-induced diabetic mice rapidly develop increasedrenal expression of TGF-b, collagen and fibronectin, ele-vated urinary TGF-b and renal hypertrophy. Administra-tion of a neutralizing TGF-b antibody suppressed renalTGF-b, collagen and fibronectin production, and reducedthe expected increase in kidney weight by over 50% [6].

TGF-b overexpression is also tightly linked to the devel-opment of human diabetic nephropathy [5]. The glomeruliand tubulointerstitium in humans with biopsy-proven dia-betic nephropathy show very high levels of the three TGF-bisoforms along with matrix proteins induced by TGF-b suchas fibronectin EDA1 and plasminogen activator inhibi-tor-1 (PAI-1). In an earlier study in Kidney International,the levels of TGF-b mRNA were quantitated in diabeticglomeruli dissected from human biopsies [7]. TGF-bmRNA levels were found to be elevated early in diabetic

Key words: fibrosis, matrix degredation, cell-matrix interaction, big-h3,glycemic control.

© 1998 by the International Society of Nephrology

Kidney International, Vol. 54 (1998), pp. 1390–1391

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nephropathy and to correlate with the patients’ HbA1clevels. These data, along with the evidence showing thathigh glucose induced TGF-b production in cultured renalcells, strongly suggest that poor glycemic control is a keyfactor in inducing TGF-b in the diabetic kidney. In a recentelegant clinical study, Sharma and coworkers showed thatthe human diabetic kidney is a factory for producingTGF-b and releasing it into the circulation [8]. In contrastto normal kidneys that extract TGF-b from the blood,diabetic kidneys produce and release TGF-b into the renalveins, leading to elevated plasma and urinary levels indiabetic patients.

Another clinically fascinating aspect of TGF-b is thegrowing evidence of a complex and rich interaction be-tween TGF-b and the renin-angiotensin system (RAS) inwhich both act at various points to regulate the actions ofthe other [reviewed in 9]. Conceptually, TGF-b and RASact together in tissue injury as biological “911” molecules tomaintain homeostasis and initiate repair. Indeed, not onlydo they engage in cross-talk, but they have broadly over-lapping properties. For example, angiotensin II is beingevaluated as a topical agent to enhance wound healing, andinfusion of TGF-b into volume depleted rats producedvasoconstriction and acute renal failure. Indeed, theTGF-b induced overexpression of big-3h in the diabetickidney was not in the glomerulus, but in the vascularcomponent of the juxtaglomerular apparatus and the parsrecta of proximal tubules.

The interaction of the RAS and TGF-b has importantclinical implications [9, 10]. Angiotensin II blockade re-duces tissue levels of TGF-b in kidney and heart, and thereis now a consensus that TGF-b is a key mediator of renaland cardiac fibrosis associated with activation of the RAS.In experimental and human kidney diseases, the protectiveeffect of inhibition of the RAS correlates closely with apartial suppression of TGF-b production [9, 10]. Thissuggests that more complete suppression of TGF-b shouldbe a therapeutic target in order to achieve a greateranti-fibrotic effect. There is evidence that this might beaccomplished by using higher doses of drugs that block theRAS or entirely new drug strategies may be needed. Indiverse disease models, suppressing TGF-b with neutraliz-ing TGF-b antibodies, the proteoglycan decorin or other

novel approaches has been shown to be therapeutic [1].With the discovery of big-h3 in the kidney, it joins a list oftissue markers of TGF-b bioactivity including: TGF-b,PAI-1, fibronectin EDA1, type I collagen and plasma orpossibly urinary levels of TGF-b. One of more of theseTGF-b markers could be used as a therapeutic measure ofTGF-b suppression. The clinical application of a TGF-bmarker along with a direct TGF-b antagonist combinedwith blockade of angiotensin II may prove to be synergisticand offer new hope to patients who suffer from fibroticdiseases such as diabetic nephropathy.

WAYNE A. BORDER AND NANCY A. NOBLESalt Lake City, Utah, USA

Reprint requests to Wayne A. Border, M.D., Fibrosis Research Laboratory,Division of Nephrology, University of Utah, 50 North Medical Drive, SaltLake City, Utah, 84132, USA.

REFERENCES

1. BORDER WA, NOBLE NA: Transforming growth factor-b in tissuefibrosis. N Engl J Med 331:1286–1292, 1994

2. GILBERT RE, BERKA JL, JOHNSON DW, COX A, SOULIS T, WU LL,KELLY D, JERUMS G, POLLOCK CA, COOPER ME: Renal expression ofbig-h3 (transforming growth factor-b inducible gene-h3) in normaland diabetic rats. Kidney Int 54:1052–1062, 1998

3. BORDER WA, YAMAMOTO T, NOBLE NA: Transforming growth factorb in diabetic nephropathy. Diab Metab Rev 12:309–339, 1996

4. SHARMA K, ZIYADEH FN: Hyperglycemia and diabetic kidney disease.The case for transforming growth factor-b as a key mediator. Diabetes44:1139–1146, 1995

5. YAMAMOTO T, NAKAMURA T, NOBLE NA, RUOSLAHTI E, BORDERWA: Expression of transforming growth factor-b is elevated in humanand experimental diabetic nephropathy. Proc Natl Acad Sci USA90:1814–1818, 1993

6. SHARMA K, JIN Y, GUO J, ZIYADEH FN: Neutralization of TGF-b byanti-TGF-b antibody attenuates kidney hypertrophy and the en-hanced extracellular matrix gene expression in STZ-induced diabeticmice. Diabetes 45:522–530, 1996

7. IWANO M, KUBO A, NISHINO T, SATO H, NISHIOKA H, AKAI Y,KURIOKA H, FUJII Y, KANAUCHI M, SHIIKI H, DOHI K: Quantificationof glomerular TGF-b1 mRNA in patients with diabetes mellitus.Kidney Int 49:1120–1126, 1996

8. SHARMA K, ZIYADEH FN, ALZAHABI B, MCGOWAN TA, KAPOOR S,KURNIK BRC, KURNIK PB, WEISBERG LS: Increased renal productionof transforming growth factor-b1 in patients with type II diabetes.Diabetes 46:854–859, 1997

9. BORDER WA, NOBLE NA: Interactions of TGF-b and angiotensin II inrenal fibrosis. Hypertension S31:181–188, 1998

10. NOBLE NA, BORDER WA: Angiotensin II in renal fibrosis: shouldTGF-b rather than blood pressure be the therapeutic target? SeminNephrol 17:455–466, 1997

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