INVITED REVIEW
Mesangial cell protein kinase C isozyme activation in the diabetic milieu

Catharine I. Whiteside and John A. Dlugosz

University Health Network, Department of Medicine, University of Toronto, Toronto, Ontario, Canada M5S 1A8


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
EXPRESSION OF MESANGIAL CELL...
ALTERED RESPONSE OF MESANGIAL...
HOW DOES HIGH GLUCOSE...
OUTCOMES OF MESANGIAL CELL...
SUMMARY AND FUTURE DIRECTIONS
REFERENCES

High-glucose-induced activation of mesangial cell protein kinase C (PKC) contributes significantly to the pathogenesis of diabetic nephropathy. Excess glucose metabolism through the polyol pathway leads to de novo synthesis of both diacylglyerol (DAG) and phosphatidic acid, which may account for increased mesangial cell PKC-alpha , -beta , -delta , -epsilon , and -zeta activation/translocation observed within 48-h exposure to high glucose. Raised intracellular glucose causes generation of reactive oxygen species that may directly activate PKC isozymes and enhance their reactivity to vasoactive peptide signaling. In both diabetic rodent models of diabetes and cultured mesangial cells, PKC-beta appears to be the key isozyme required for the enhanced expression of transforming growth factor-beta 1, initiation of early accumulation of mesangial matrix protein, and increased microalbuminuria. Enhanced collagen IV expression by mesangial cells in response to vasoactive peptide hormone stimulation, e.g., endothelin-1, requires PKC-beta , -delta , -epsilon and -zeta . Loss of mesangial cell contractility to potent vasoactive peptides and coincident F-actin disassembly are due to high-glucose-activation of PKC-zeta . Inhibition of mesangial cell PKC isozyme activation in high glucose may prove to be the next important treatment for diabetic nephropathy.

diacylglycerol; polyol pathway; collagen IV; reactive oxygen species; endothelin-1


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
EXPRESSION OF MESANGIAL CELL...
ALTERED RESPONSE OF MESANGIAL...
HOW DOES HIGH GLUCOSE...
OUTCOMES OF MESANGIAL CELL...
SUMMARY AND FUTURE DIRECTIONS
REFERENCES

KIDNEY DISEASE ASSOCIATED with diabetes is the leading cause of chronic renal insufficiency in North America (69). Clinical trials have demonstrated that high glucose is the principal cause of renal damage in both type 1 (12) and 2 diabetes (68). Although the underlying genetic predisposition to this microvascular complication remains elusive (53), investigation of cellular and molecular mechanisms has identified an integrated group of signaling and gene expression systems triggered directly or indirectly by high glucose (65). Altered mesangial cell function in high glucose is central to the pathogenesis of progressive diabetic glomerulopathy. Progressive accumulation of mesangial matrix due to increased synthesis and decreased degradation of mesangial extracellular matrix proteins, including collagen IV (1, 42, 59) and fibronectin (49), ultimately obliterates the glomerular capillary loops, leading to renal failure. In the diabetic milieu, mesangial cells are transformed into a sclerotic phenotype by the direct effects of high glucose (4), including enhanced expression of autocrine growth factors (54), and by intraglomerular hypertension caused by high-glucose-induced loss of afferent arteriolar contractility (73). In the search for the cellular mechanisms of diabetic complications, a pivotal role for protein kinase C (PKC) is recognized in every cell type targeted by the toxic effects of high glucose (45). The following describes high-glucose-induced activation of mesangial cell PKC as a major contributor to the initiation and propagation of diabetic glomerulosclerosis.


    EXPRESSION OF MESANGIAL CELL ISOZYMES
TOP
ABSTRACT
INTRODUCTION
EXPRESSION OF MESANGIAL CELL...
ALTERED RESPONSE OF MESANGIAL...
HOW DOES HIGH GLUCOSE...
OUTCOMES OF MESANGIAL CELL...
SUMMARY AND FUTURE DIRECTIONS
REFERENCES

The PKC family of at least 12 isozymes is classified into conventional PKC-alpha , -beta I, -beta II, and -gamma , which require Ca2+ and are activated by diacylglycerol (DAG) or phorbol ester; novel PKC-delta , -epsilon , -eta , and -theta , which are Ca2+ independent and activated by DAG or phorbol ester (60); and atypical PKC-zeta and -lambda , which are neither Ca2+ nor DAG sensitive (75). The expression pattern and response of specific PKC isozymes to growth factors confer unique cellular phenotypic characteristics, including differentiation during development, maintenance of a normal differentiated state (32, 56), or generation of an abnormal phenotype in response to pathogenic stimuli, e.g., high glucose. The function of individual PKC isozymes is likely conferred, in part, by their subcellular localization and binding to specific anchoring proteins after activation and translocation (9, 46). Furthermore, differences in the individual domain structure of the PKC isozymes allows for the identification of pharmacological agents that have isozyme-selective modulation (30, 70).

In cultured mesangial cells, expression of PKC-alpha , -beta I, -beta II, -delta , -epsilon , and -zeta has been reported by most investigators (2, 6, 26, 33, 36, 55). Koya et al. (39) confirmed the detection of PKC-beta I in both cultured mesangial cells and isolated glomeruli, although they reported that PKC-beta II expression was less abundant. We have consistently demonstrated the presence of PKC-alpha , -beta II, -delta , -epsilon , and -zeta in glomeruli isolated from normal and streptozotocin (STZ)-induced diabetic rats (5) and the identical expression of the same PKC isozymes, as well as PKC-beta I, in primary cultured rat mesangial cells (11, 18, 31, 36). Using immunogold labeling of normal and STZ-diabetic rat glomeruli examined by transmission electron microscopy, we have identified that mesangial, visceral epithelial, and endothelial cells all express PKC-alpha , -beta II, -delta , and -epsilon (5).


    ALTERED RESPONSE OF MESANGIAL CELL-SPECIFIC PKC ISOZYMES IN HIGH GLUCOSE
TOP
ABSTRACT
INTRODUCTION
EXPRESSION OF MESANGIAL CELL...
ALTERED RESPONSE OF MESANGIAL...
HOW DOES HIGH GLUCOSE...
OUTCOMES OF MESANGIAL CELL...
SUMMARY AND FUTURE DIRECTIONS
REFERENCES

The effects of high glucose on glomerular cell PKC isozyme expression and activity have been identified using animal models of diabetes and in cultured cells. Kikkawa et al. (37) were the first to report increased mesangial cell membrane content of PKC-alpha and -zeta after 3 and 5 days of high-glucose exposure, taken as evidence of translocation and probable activation of these isozymes. In primary cultured rat and human mesangial cells, Koya et al. (39) detected increased cell membrane PKC-alpha and -beta I after 4 days of high glucose. After exposure of primary cultured rat mesangial cells to 30 mM glucose, our laboratory has observed that total cellular PKC-delta is significantly increased at 24 h (13) and total PKC-alpha , -beta II, and -epsilon are increased by 48 h (36). These findings indicate enhanced expression or decreased degradation of these particular isozymes in high glucose. Immunoblotting of mesangial cellular fractions revealed increased membrane and nuclear PKC-alpha , -delta , and -epsilon after 48 h in 30 mM glucose (36) and enhanced recovery of membrane-associated PKC-zeta as early as 24 h of high-glucose exposure (13). Under the same conditions, we observed by confocal immunofluorescence imaging a high-glucose-induced pattern of mesangial cell PKC -alpha , -beta II, -delta , and -epsilon translocation characterized by enhanced fluorescence labeling of the plasma membrane, the nucleus (including nuclear membrane), and, possibly, cytoskeletal elements (36, 76). By immunoblotting the cytosolic and membrane cellular fractions of glomeruli isolated from the STZ-diabetic rat, we and others have demonstrated increased membrane recovery of PKC-alpha , -delta , and -epsilon , suggesting an activation/translocation pattern of these PKC isozymes in the diabetic milieu (5, 24, 37, 39).

Many laboratories have identified increased total PKC activity in both glomeruli from STZ-diabetic rats (10, 39, 61) and primary mesangial cells cultured in high glucose (4, 8, 11, 25, 36) by analyzing PKC-specific substrate phosphorylation in total cell lysates or cellular fractions. Recently, our laboratory reported increased PKC-delta and -zeta activity in primary rat mesangial cells exposed to high glucose for 24 h, as analyzed by immunoprecipitating these isozymes from total cell lysate or membrane fractions and measuring phosphorylation of isozyme-specific substrates. This approach enables a more sensitive and specific detection of the activity of individual PKC isozymes. The exact mechanisms whereby mesangial cell PKC isozymes appear to be sequentially activated in high glucose over 24-48 h remain to be elucidated.


    HOW DOES HIGH GLUCOSE CAUSE MESANGIAL CELL PKC ACTIVATION?
TOP
ABSTRACT
INTRODUCTION
EXPRESSION OF MESANGIAL CELL...
ALTERED RESPONSE OF MESANGIAL...
HOW DOES HIGH GLUCOSE...
OUTCOMES OF MESANGIAL CELL...
SUMMARY AND FUTURE DIRECTIONS
REFERENCES

Entry of glucose into mesangial cells through GLUT1 transport raises the intracellular concentration of glucose, reflecting the hyperglycemic state (28, 29). Entry of excess glucose into intermediate metabolic pathways stimulates interactive signaling mechanisms, which directly or indirectly activate PKC isozymes. The following describes the roles of the polyol pathway and the generation of reactive oxygen species contributing to the enhanced responsiveness of mesangial cell PKC isozymes in high glucose.

The Polyol Pathway

The polyol pathway converts glucose to sorbitol and, subsequently, fructose, generating an increased ratio of NADH/NAD+ (64). This change in redox potential drives conversion of glycolytic triose phosphate intermediates, produced during glycolysis or metabolism through the pentose phosphate pathway, into the second messengers phosphatidic acid and DAG. De novo synthesized DAG may directly activate conventional and novel PKC isozymes, whereas phosphatidic acid may activate PKC-zeta (43). In cultured mesangial cells, aldose reductase inhibition prevents the accumulation of membrane-associated DAG observed within 24 h of exposure to high glucose (11) and also prevents the translocation pattern of PKC-delta and -epsilon caused by 48 h of high glucose (36). By contrast, in the same mesangial cell preparation, two different aldose reductase inhibitors failed to prevent high-glucose-enhanced translocation of PKC-alpha and -beta (36). These data are in keeping with high-glucose-induced activation of PKC-alpha and -beta by a mechanism(s) that is independent of the polyol pathway.

In diabetic animal models and human studies where aldose reductase inhibitors were used to treat or prevent diabetic nephropathy, the outcomes remain controversial (44, 50, 51, 52). We have demonstrated that treatment of STZ-diabetic rats with tolrestat prevents glomerular hyperfiltration, glomerular hypertrophy, and increased microalbuminuria but does not prevent fractional mesangial expansion in the first 12 wk of diabetes (15). Our results indicate that the polyol pathway may be linked to some, but not all, mechanisms of diabetes-induced early progressive glomerulosclerosis in this model. The finding of increased aldose reductase mRNA in the peripheral blood mononuclear cells of human subjects with type 1 diabetes and nephropathy, compared with levels of mRNA in age- and diabetes-duration-matched subjects without nephropathy or in nondiabetic controls, suggests that upregulation of aldose reductase expression is associated with an increased risk for nephropathy (58).

Another potential action of aldose reductase is to detoxify dicarbonyls, such as methylglyoxal and 3-deoxyglucosone, and lipid dialdehydes generated in excess by raised intracellular glucose (16). Hence, the role of the polyol pathway, and in particular the contribution of aldose reductase activity, to the pathogenesis of diabetic nephropathy is complex. Further studies are needed to identify the independent contributions to, and relative importance of, the polyol pathway to individual PKC isozyme activation and to the detoxification of dicarbonyls.

Reactive Oxygen Species

Reactive oxygen species, such as hydrogen peroxide (H2O2), superoxide anion, and hydroxyl radical, are generated during oxidative stress and implicated in the mechanisms of diabetic nephropathy (47, 48). Excess glucose metabolism, including oxidation, is required for mesangial cell generation of reactive oxygen species in the diabetic milieu (22). During conversion of glucose to sorbitol, the NADP+/NADPH ratio is increased and causes glutathione depletion and accumulation of reactive oxygen species (41). In many cell types, reactive oxygen species are generated as second messengers during signal transduction by agonists implicated in microvascular complications of diabetes, e.g., angiotensin II (20), platelet-derived growth factor (63), and advanced glycation end products (AGE) (72). The role of reactive oxygen species in mediating the effects of high glucose is inferred by the efficacy of antioxidants in preventing phenotypic changes in cultured mesangial cells, e.g., increased transforming growth factor (TGF)-beta 1 and collagen production (62, 66) and early progressive diabetic nephropathy in the STZ-diabetic rat (23, 40). Collagen production in cultured mesangial cells exposed to high glucose is prevented by taurine (67) or vitamin E (66).

Evidence is mounting for a mechanistic link between the generation of reactive oxygen species and consequent activation of mesangial cell PKC isozymes in high glucose (21). Ha and Lee (22) reported that in cultured rat mesangial cells, high glucose generates H2O2 within 1 h and inhibition of PKC blocks high-glucose- or H2O2-induced TGF-beta 1 and fibronectin mRNA expression and protein synthesis. These findings suggest that reactive oxygen species produced in high glucose directly or indirectly stimulate PKC. One mechanism for direct activation by reactive oxygen species is through redox changes in sulfhydryl groups on PKC isozyme cysteine-rich regions. These redox changes may also render individual PKC isozymes more responsive to DAG activation during signal transduction (19). Taken together, these data support a role for high-glucose activation of PKC and subsequent matrix protein expression through reactive oxygen species-dependent pathways.


    OUTCOMES OF MESANGIAL CELL PKC ISOZYME ACTIVATION
TOP
ABSTRACT
INTRODUCTION
EXPRESSION OF MESANGIAL CELL...
ALTERED RESPONSE OF MESANGIAL...
HOW DOES HIGH GLUCOSE...
OUTCOMES OF MESANGIAL CELL...
SUMMARY AND FUTURE DIRECTIONS
REFERENCES

The activation of mesangial cell PKC, through either the direct effects of high glucose described above or the autocrine and paracrine action of vasoactive peptides such as angiotensin II and endothelin (ET)-1, results in the enhanced expression of TGF-beta 1 and extracellular matrix proteins (54, 71). The importance of individual PKC isozyme activation in the diabetic milieu initiating early diabetic nephropathy was first identified by Ishii et al. (34). This group discovered that the compound LY-333531, which specifically inhibits PKC-beta I and -beta II, when administered orally to STZ-diabetic rats, not only prevents an elevated glomerular filtration rate, increased albumin excretion rate, and increased retinal circulation time but also overexpression of mRNA for glomerular TGF-beta 1 and extracellular matrix proteins (39). LY-333531 also prevents progressive mesangial expansion in the type 2 diabetic db/db mouse model (38). Scivittaro et al. (57) have identified that proteins rich in intracellular advanced glycation end products selectively activate mesangial cell PKC-beta II through a mechanism involving oxidative stress, implicating no requirement for DAG. Cohen et al. (7) have identified that glycated albumin stimulates mesangial cell PKC-beta activity, which is linked to the increased expression of collagen IV. The exact role of PKC-beta in the early pathogenesis of diabetic retinopathy and nephropathy is presently being investigated in human clinical trials using LY-333531.

Vasoactive peptides such as angiotensin II are expressed normally in small quantities to maintain hemodynamic stability and may contribute to glomerular autoregulation. In the diabetic state, enhanced expression of peptide growth factors by mesangial cells, e.g., ET-1 (27), and other renal cells, e.g., angiotensin II (74), may contribute to the pathogenesis of diabetic nephropathy because mesangial cells constitutively express high-affinity receptors for these vasoactive peptides. Both ET-1 (14) and angiotensin II (Whiteside C, unpublished observations) stimulate mesangial cell PKC-alpha , -delta , and -epsilon . We have observed that the pattern of mesangial cell PKC-delta and -epsilon translocation in response to ET-1 changes from cytosol-to-membrane distribution in normal glucose to cytosol-to-particulate (cytoskeleton/nucleus) in high glucose (18), in keeping with our confocal immunofluorescence imaging data (76). These findings suggest a change in compartmentalization and, possibly, the function of these PKC isozymes in the diabetic milieu.

Downstream of DAG-sensitive PKC isozymes is their activation of mitogen-activated protein kinases, particularly extracellular signal-regulated kinase (ERK)1/2, which are necessary for mesangial cell growth and enhanced gene expression, including growth factors and extracellular matrix proteins (17, 35). In both mesangial cells cultured in high glucose (18, 25) and glomeruli isolated from STZ-diabetic rats (3), ERK1/2 protein expression is unchanged but its activity (basal) is significantly increased compared with normal-glucose controls and is PKC dependent. Isono et al. (35) identified that high-glucose-enhanced mesangial cell TGF-beta 1 and extracellular matrix protein expression is mediated through ERK1/2. In cultured mesangial cells, high-glucose-enhanced ERK1/2 activity in response to ET-1 is entirely PKC dependent (18). Hence, high glucose causes amplification of signaling through PKC pathways. Recently, we have reported that high-glucose-enhanced expression of collagen IV by mesangial cells, when stimulated with ET-1, requires the action of specific PKC isozymes (31). The independent effect of each PKC isozyme was revealed by transient transfection of dominant negative cDNAs, which inhibit the action of individual PKC isozymes. ET-1-stimulated collagen IV expression is also dependent on the activation of ERK1/2. Using this dominant negative-transfection strategy, we demonstrated that ET-1 activation of ERK1/2 is necessary and dependent on PKC-delta , -epsilon , and -zeta . We also showed that PKC-beta is necessary for ET-1 stimulation of mesangial cell collagen IV expression but that this is ERK1/2 independent (31). These data suggest that the PKC isozymes stimulated by ET-1 have hierarchical or redundant functions in the signaling cascades leading to collagen IV expression and that basal activities of PKC-beta and -zeta are required for the high-glucose-enhanced mesangial cell expression of this key extracellular matrix protein, contributing to diabetic glomerulosclerosis.

Mesangial cells exposed to high glucose for 24 h lose their normal contractile responsiveness to vasoactive peptides and demonstrate a cytoskeletal pattern of F-actin disassembly and depolymerization (13). The lack of a mesangial cell contractile response in high glucose mimics the hypocontractility observed in afferent and, to a lesser extent, efferent glomerular arteriolar smooth muscle cells in the diabetic milieu (73). The exact cellular mechanism linking high glucose to loss of normal contraction in response to vasoactive peptides or to arterial pressure in the afferent arteriole remains elusive. We recently reported that mesangial cell PKC-zeta demonstrates increased membrane association and enhanced activity in high glucose after 24 h (13). Inhibition of PKC-zeta with a cell-permeant, myristoylated PKC-zeta peptide inhibitor restored the normal contractile response of cultured mesangial cells to stimuli such as ET-1 (13) and prevented mesangial cell F-actin disassembly. These are the first data to link the effects of high glucose causing mesangial cell hypocontractility and cytoskeletal dysfunction to a specific PKC isozyme. Further investigation is required to identify whether a similar mechanism causes glomerular arteriolar vascular smooth muscle cell dysfunction in high glucose.


    SUMMARY AND FUTURE DIRECTIONS
TOP
ABSTRACT
INTRODUCTION
EXPRESSION OF MESANGIAL CELL...
ALTERED RESPONSE OF MESANGIAL...
HOW DOES HIGH GLUCOSE...
OUTCOMES OF MESANGIAL CELL...
SUMMARY AND FUTURE DIRECTIONS
REFERENCES

In high glucose, mesangial cell PKC isozyme activity is enhanced both in the basal state and in response to vasoactive growth peptides. Increasing evidence supports a linkage between abnormal glucose metabolism through the polyol pathway and other mechanisms that generate reactive oxygen species and the increased activity of PKC isozymes in the diabetic state. PKC-beta is a major pathogenic PKC isozyme contributing to early progressive diabetic nephropathy. Other PKC isozymes, including PKC-zeta , may also be important. Future investigation will focus on elucidating the relevance of PKC isozymes in maintaining normal mesangial cell function and further delineating their contributions to high-glucose-mediated transformation of mesangial cells into a sclerotic phenotype. The development of specific PKC isozyme inhibitors, in addition to LY-333531, may prove useful for future targeted drug interventions in the treatment and prevention of diabetic nephropathy.


    FOOTNOTES

Address for reprint requests and other correspondence: C. Whiteside, Medical Sciences Bldg., Rm. 7302, 1 King's College Circle, Univ. of Toronto, Toronto, ON, Canada M5S 1A8 (E-mail: catharine.whiteside{at}utoronto.ca).

10.1152/ajprenal.00014.2002


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
EXPRESSION OF MESANGIAL CELL...
ALTERED RESPONSE OF MESANGIAL...
HOW DOES HIGH GLUCOSE...
OUTCOMES OF MESANGIAL CELL...
SUMMARY AND FUTURE DIRECTIONS
REFERENCES

1.   Adler, SG, Feld S, Striker L, Striker G, LaPage J, Esposito C, Aboulhosn J, Barba L, Cha DR, and Nast CC. Glomerular type IV collagen in patients with diabetic nephropathy with and without additional glomerular disease. Kidney Int 57: 2084-2092, 2000[ISI][Medline].

2.   Amiri, F, and Garcia R. Regulation of angiotensin II receptors and PKC isoforms by glucose in rat mesangial cells. Am J Physiol Renal Physiol 276: F691-F699, 1999[Abstract/Free Full Text].

3.   Awazu, M, Ishikura K, Hida M, and Hoshiya M. Mechanisms of mitogen-activated protein kinase activation in experimental diabetes. J Am Soc Nephrol 10: 738-745, 1999[Abstract/Free Full Text].

4.   Ayo, SH, Radnik R, Garoni JA, Troyer DA, and Kreisberg JI. High glucose increases diacylglycerol mass and activates protein kinase C in mesangial cell cultures. Am J Physiol Renal Fluid Electrolyte Physiol 261: F571-F577, 1991[Abstract/Free Full Text].

5.   Babazono, T, Kapor-Drezgic J, Dlugosz JA, and Whiteside C. Altered expression and subcellular localization of diacylglycerol-sensitive protein kinase C isoforms in diabetic rat glomerular cells. Diabetes 47: 668-676, 1998[Abstract].

6.   Choudhury, G, Biswas P, Grandaliano G, and Abboud HE. Involvement of PKC-alpha in PDGF-mediated mitogenic signaling in human mesangial cells. Am J Physiol Renal Fluid Electrolyte Physiol 265: F634-F642, 1993[Abstract/Free Full Text].

7.   Cohen, MP, Ziyadeh FN, Lautenslager GT, Cohen JA, and Shearman CW. Glycated albumin stimulation of PKC-beta activity is linked to collagen IV in mesangial cells. Am J Physiol Renal Physiol 276: F684-F690, 1999[Abstract/Free Full Text].

8.   Cosio, FG. Effects of high glucose concentrations on human mesangial cell proliferation. J Am Soc Nephrol 5: 1600-1609, 1995[Abstract].

9.   Csukai, M, and Mochly-Rosen D. Pharmacologic modulation of protein kinase C isozymes: the role of RACKs and subcellular localization. Pharmacol Res 39: 253-259, 1999[ISI][Medline].

10.   DeRubertis, FR, and Craven PA. Activation of protein kinase C in glomerular cells in diabetes; mechanisms and potential link to the pathogenesis of diabetic glomerulopathy. Diabetes 43: 1-8, 1994[Abstract].

11.   Derylo, B, Babazono T, Glogowski E, Kapor-Drezgic J, Hohman T, and Whiteside C. High glucose-induced mesangial cell altered contractility: role of the polyol pathway. Diabetologia 41: 507-515, 1998[ISI][Medline].

12.   Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes-mellitus. N Engl J Med 329: 977-986, 1993[Abstract/Free Full Text].

13.   Dlugosz, JA, Munk S, Ispanovic E, Goldberg HJ, and Whiteside CI. Mesangial cell filamentous-actin disassembly and mesangial cell and hypocontractility in high glucose are mediated by protein kinase C-zeta . Am J Physiol Renal Physiol 282: F151-F163, 2002[Abstract/Free Full Text].

14.   Dlugosz, JA, Munk S, Zhou XP, and Whiteside CI. Endothelin-1-induced mesangial cell contraction involves the activation of protein kinase C-alpha , -delta , and -epsilon . Am J Physiol Renal Physiol 275: F423-F432, 1998[Abstract/Free Full Text].

15.   Donnelly, SM, Zhou XP, Huang J, and Whiteside CI. Prevention of early glomerulopathy with tolrestat in the streptozotocin-induced diabetic rat. J Biochem Cell Biol 74: 355-362, 1996.

16.   Dunlop, M. Aldose reductase and the role of the polyol pathway in diabetic nephropathy. Kidney Int 58, Suppl77: S3-S12, 2000[ISI].

17.   Fumo, PF, Kuncio GS, and Ziyadeh FN. PKC and high glucose-induced transcriptional activation of collagen alpha 1(IV) in a reporter mesangial cell line. Am J Physiol Renal Fluid Electrolyte Physiol 267: F632-F638, 1994[Abstract/Free Full Text].

18.   Glogowski, EA, Tsiani E, Zhou XP, Fantus IG, and Whiteside CI. High glucose alters the response of mesangial cell protein kinase C isoforms to endothelin-1. Kidney Int 55: 486-499, 1999[ISI][Medline].

19.   Gopalakrishna, R, and Jaken S. Protein kinase C signaling and oxidative stress. Free Radic Biol Med 28: 1349-1361, 2000[ISI][Medline].

20.   Griendling, KK, Minieri CA, Ollerenshaw JD, and Alexander RW. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res 74: 1141-1148, 1994[Abstract].

21.   Ha, H, and Kim KH. Pathogenesis of diabetic nephropathy: the role of oxidative stress and protein kinase C. Diabetes Res Clin Prac 45: 147-151, 1999[ISI][Medline].

22.   Ha, H, and Lee HB. Reactive oxygen species as glucose signaling molecules in mesangial cells cultured under high glucose. Kidney Int 58, Suppl77: S19-S25, 2000[ISI].

23.   Ha, H, Yu MR, and Kim KH. Melatonin and taurine reduce early glomerulopathy in diabetic rats. Free Radic Biol Med 26: 944-950, 1999[ISI][Medline].

24.   Haller, H, Baur E, Quass P, Behrend M, Lindschau C, Distler A, and Luft FC. High glucose concentrations and protein kinase C isoforms in vascular smooth muscle cells. Kidney Int 47: 1057-1067, 1995[ISI][Medline].

25.   Haneda, M, Araki S, Togawa M, Sugimoto T, Isono M, and Kikkawa R. Mitogen-activated protein kinase cascade is activated in glomeruli of diabetic rats and glomerular mesangial cells cultured under high glucose conditions. Diabetes 46: 847-853, 1997[Abstract].

26.   Haneda, M, Kikkawa R, Sugimoto T, Koya D, Araki S, Togawa M, and Shigeta Y. Abnormalities in protein kinase C and MAP kinase cascade in mesangial cells cultured under high glucose conditions. J Diabetes Comp 9: 246-248, 1995[ISI][Medline].

27.   Hargrove, GM, Dufresne J, Whiteside CI, and Wong NCW Diabetes mellitus increases endothelin-1 gene transcription in rat kidney. Kidney Int 35: 629-637, 2000.

28.   Heilig, CW, Brosius FC, III, and Henry DN. Glucose transporters of the glomerulus and the implications for diabetic nephropathy. Kidney Int 52, Suppl60: S91-S99, 1997.

29.   Heilig, CW, Concepcion LA, Riser BL, Freytag SO, Zho M, and Cortes P. Overexpression of glucose transporters in rat mesangial cells cultured in a normal glucose milieu mimics the diabetic phenotype. J Clin Invest 96: 1802-1814, 1995[ISI][Medline].

30.   Hofmann, J. The potential for isozyme-selective modulation of protein kinase C. FASEB J 11: 649-669, 1997[Abstract/Free Full Text].

31.   Hua, H, Goldberg HJ, Fantus IG, and Whiteside CI. High glucose-enhanced mesangial cell ERK1/2 activation and alpha 1(IV) collagen expression in response to endothelin-1: role of specific PKC isozymes. Diabetes 50: 2376-2383, 2001[Abstract/Free Full Text].

32.   Hug, H, and Sarre TH. Protein kinase C isozymes: divergence in signal transduction? Biochem J 291: 329-343, 1993[ISI][Medline].

33.   Huwiler, A, Schulze-Lohoff E, Fabbro D, and Pfeilschifter J. Immuno-characterization of protein kinase C isoenzymes in rat kidney glomeruli, and cultured glomerular epithelial and mesangial cells. Exp Nephrol 1: 19-25, 1993[ISI][Medline].

34.   Ishii, H, Jirousek MR, Koya D, Takagi G, Xia P, Clermont A, Bursell SE, Kern TS, Ballas LM, Heath WF, Stramm LE, Feener EP, and King GL. Amelioration of vascular dysfunctions in diabetic rats by an oral PKC beta  inhibitor. Science 272: 728-731, 1996[Abstract].

35.   Isono, M, Iglesias-de la Cruz MC, Chen S, Wong SW, and Ziyadeh FN. Extracellular signal-regulated kinase mediates stimulation of TGF-beta 1 and matrix by high glucose in mesangial cells. J Am Soc Nephrol 11: 2222-2230, 2000[Abstract/Free Full Text].

36.   Kapor-Drezgic, J, Zhou X, Babazono T, Dlugosz JA, Hohman T, and Whiteside C. Effect of high glucose on mesangial cell protein kinase C-delta and -epsilon is polyol pathway-dependent. J Am Soc Nephrol 10: 1193-1203, 1999[Abstract/Free Full Text].

37.   Kikkawa, R, Haneda M, Uzu T, Koya D, Sugimoto T, and Shigeta Y. Translocation of protein kinase C alpha  and zeta  in rat glomerular mesangial cells cultured under high glucose conditions. Diabetologia 37: 838-841, 1994[ISI][Medline].

38.   Koya, D, Haneda M, Nakagawa H, Isshiki K, Sato H, Maeda S, Sugimoto T, Yasuda H, Kashiwagi A, Ways DK, King GL, and Kikkawa R. Amelioration of accelerated diabetic mesangial expansion by treatment with a PKC beta inhibitor in diabetic db/db mice, a rodent model for type 2 diabetes. FASEB J 14: 439-447, 2000[Abstract/Free Full Text].

39.   Koya, D, Jirousek MR, Lin YW, Ishii H, Kuboki K, and King GL. Characterization of protein kinase C beta  isoform activation on the gene expression of transforming growth factor-beta , extracellular matrix components, and prostanoids in the glomeruli of diabetic rats. J Clin Invest 100: 115-126, 1997[Abstract/Free Full Text].

40.   Koya, D, Lee IK, Ishii H, Hanoh H, and King GL. Prevention of glomerular dysfunction in diabetic rats by treatment of D-alpha -tocopherol. J Am Soc Nephrol 8: 426-435, 1997[Abstract].

41.   Lee, AY, and Chung SS. Contributions of polyol pathway to oxidative stress in diabetic cataract. FASEB J 13: 23-30, 1999[Abstract/Free Full Text].

42.   Leehey, DJ, Song RH, Alavi N, and Singh AK. Decreased degradative enzymes in mesangial cells cultured in high glucose media. Diabetes 44: 929-935, 1995[Abstract].

43.   Limatola, C, Schaap D, Moolenar WH, and van Blitterswijk WJ. Phosphatidic acid activation of protein kinase C-zeta overexpressed in COS cells: comparison with other protein kinase C isotypes and other acidic lipids. Biochem J 304: 1001-1008, 1994[ISI][Medline].

44.   McAuliffe, AV, Brooks BA, Fisher EJ, Molyneaux LM, and Yue DK. Administration of ascorbic acid and an aldose reductase inhibitor (tolrestat) in diabetes: effect on urinary albumin excretion. Nephron 80: 277-284, 1998[ISI][Medline].

45.   Meier, M, and King GL. Protein kinase C activation and its pharmacological inhibition in vascular disease. Vasc Med 5: 173-185, 2000[ISI][Medline].

46.   Mochly-Rosen, D, and Gordon AS. Anchoring proteins for protein kinase C: a means for isozyme selectivity. FASEB J 12: 35-42, 1998[Abstract/Free Full Text].

47.   Nishikawa, T, Edelstein D, and Brownlee M. The missing link: a single unifying mechanism for diabetic complications. Kidney Int 58, Suppl77: S26-S30, 2000[ISI].

48.   Nishikawa, T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, Giardino I, and Brownlee M. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycemic damage. Nature 404: 787-790, 2000[ISI][Medline].

49.   Oh, JH, Ha H, Yu MR, and Lee HB. Sequential effects of high glucose on mesangial cell transforming growth factor-beta 1 and fibronectin synthesis. Kidney Int 54: 1872-1878, 1998[ISI][Medline].

50.   Passariello, N, Sepe J, Marrazzo G, De Cicco A, Peluso A, Pisano MC, Sgambato S, Tesauro P, and D'Onfofrio F. Effect of aldose reductase inhibitor (tolrestat) on urinary albumin excretion rate and glomerular filtration rate in IDDM subjects with nephropathy. Diabetes Care 16: 789-795, 1993[Abstract].

51.   Pedersen, MM, Christiansen JS, and Mogensen CE. Reduction of glomerular filtration in normoalbuminuric IDDM patients by 6 months of aldose reductase inhibition. Diabetes 40: 527-531, 1991[Abstract].

52.   Ranganathan, S, Krempf M, Feraille E, and Charbonnel B. Short term effect of an aldose reductase inhibitor on urinary albumin excretion rate and glomerular filtration rate in type 1 diabetic patients with incipient nephropathy. Diabetes Metab 19: 257-261, 1993[ISI].

53.   Rippin, JD, Patel A, and Bain SC. Genetics of diabetic nephropathy. Best Pract Res Clin Endocrinol Metab 15: 345-358, 2001[ISI][Medline].

54.   Rossert, J, Terraz-Durasnel C, and Brideau G. Growth factors, cytokines, and renal fibrosis during the course of diabetic nephropathy. Diabetes Metab 26: 16-24, 2000[ISI][Medline].

55.   Saxena, R, Saksa BA, Fields AP, and Ganz MB. Activation of Na+/H+ exchanger in mesangial cells is associated with translocation of PKC isoforms. Am J Physiol Renal Fluid Electrolyte Physiol 265: F53-F60, 1993[Abstract/Free Full Text].

56.   Saxena, R, Saksa BA, Hawkins KS, and Ganz MB. Protein kinase C beta I and beta II are differentially expressed in the developing glomerulus. FASEB J 8: 646-653, 1994[Abstract/Free Full Text].

57.   Scivittaro, V, Ganz MB, and Jaken S. AGEs induce oxidative stress and activate protein kinase C-beta II in neonatal mesangial cells. Am J Physiol Renal Physiol 278: F676-F683, 2000[Abstract/Free Full Text].

58.   Shah, VO, Dorin DL, Sun Y, Braun M, and Zager PG. Aldose reductase expression is increased in diabetic nephropathy. J Clin Endocrinol Metab 82: 2294-2298, 1997[Abstract/Free Full Text].

59.   Singh, R, Song RH, Alavi N, Pegoraro AA, Singh AK, and Leehey DJ. High glucose decreases matrix metalloproteinase-2 activity in rat mesangial cells via transforming growth factor-beta 1. Exp Nephrol 9: 249-257, 2001[ISI][Medline].

60.   Sossin, WS, and Schwartz JH. Ca2+-independent protein kinase Cs contain an amino-terminal domain similar to the C2 consensus sequence. Trends Biochem Sci 18: 207-208, 1993[ISI][Medline].

61.   Studer, DK, Craven PA, and Derubertis FR. Role for protein kinase C in the mediation of increased fibronectin accumulation in mesangial cells grown in high-glucose medium. Diabetes 42: 118-126, 1993[Abstract].

62.   Studer, RK, Craven PA, and DeRubertis F. Antioxidant inhibition of protein kinase C-signaled increase in transforming growth factor-beta in mesangial cells. Metabolism 46: 918-925, 1997[ISI][Medline].

63.   Sundaresan, M, Yu ZX, Ferrans VJ, Irani K, and Finkel T. Requirement for H2O2 for platelet-derived growth factor signal transduction. Science 270: 296-299, 1995[Abstract].

64.   Tilton, RG, Baier D, Harlow JE, Smith SR, Ostrow E, and Williamson JR. Diabetes-induced glomerular dysfunction: link to a more reduced ratio of NADH/NAD+. Kidney Int 41: 778-788, 1992[ISI][Medline].

65.   Tomlinson, DR. Mitogen-activated protein kinases as glucose transducers for diabetic complications. Diabetologia 42: 1271-1281, 1999[ISI][Medline].

66.   Trachtman, H. Vitamin E prevents glucose-induced lipid peroxidation and increased collagen production in cultured rat mesangial cells. Microvasc Res 47: 232-239, 1994[ISI][Medline].

67.   Trachtman, H, Futterweit S, and Bienkowski RS. Taurine prevents glucose-induced lipid peroxidation and increased collagen production in cultured rat mesangial cells. Biochem Biophys Res Commun 191: 759-765, 1993[ISI][Medline].

68.   United Kingdom Prospective Diabetes Study Group. An intensive blood glucose control policy with sulphonylurease or insulin reduces the risk of diabetic complications in patients with type 2 diabetes. Lancet 352: 837-853, 1998[ISI][Medline].

69.  United States Renal Data System. USRDS Annual Report [Online]. USRDS. http://www.usrds.org/2001pdf/b.pdf [2001].

70.   Way, KJ, Chou E, and King GL. Identification of PKC-isoform-specific biological actions using pharmacological approaches. Trends Pharmacol Sci 21: 181-187, 2000[ISI][Medline].

71.   Wolf, G, and Ziyadeh FN. Molecular mechanisms of diabetic renal hypertrophy. Kidney Int 56: 393-405, 1999[ISI][Medline].

72.   Yan, SD, Schmidt AM, and Anderson GM. Enhanced cellular oxidant stress by the interaction of advanced glycosylation end products with their receptors/binding proteins. J Biol Chem 269: 9889-9897, 1994[Abstract/Free Full Text].

73.   Zatz, R, Dunn BR, Meyer TW, Andersen S, Rennke HG, and Brenner BM. Prevention of diabetic glomerulopathy by pharmacological amelioration of glomerular capillary hypertension. J Clin Invest 77: 1925-1930, 1986[ISI][Medline].

74.   Zhang, SL, To C, Filep JG, Ingelfinger JR, Carriere S, and Chan JS. Effect of renin-angiotensin system blockade on the expression of the angiotensinogen gene and induction of hypertrophy in rat kidney proximal tubular cells. Exp Nephrol 9: 109-117, 2001[ISI][Medline].

75.   Zhou, G, Wooten MW, and Coleman ES. Regulation of atypical zeta -protein kinase C in cellular signaling. Exp Cell Res 214: 1-11, 1994[ISI][Medline].

76.   Zhou, XP, Li C, Dlugosz J, Munk S, and Whiteside C. Mesangial cell actin disassembly in high glucose mediated by protein kinase C and the polyol pathway. Kidney Int 51: 1797-1808, 1997[ISI][Medline].


Am J Physiol Renal Fluid Electrolyte Physiol 282(6):F975-F980
0363-6127/02 $5.00 Copyright © 2002 the American Physiological Society