New perspectives on markers implicated in signalling pathways that advance diabetic nephropathy and its therapeutic approaches
DOI:
https://doi.org/10.18203/2319-2003.ijbcp20243845Keywords:
Diabetic nephropathy, Biomarkers, Inflammation, Metabolic changes, Haemodynamic changes, End-stage renal diseaseAbstract
Diabetic nephropathy is the chronic loss of kidney function occurring due to diabetes mellitus. Due to increased sugar levels, there is disfunctioning of glomeruli, loss of protein in urine, and decrease in the levels of serum albumin that mainly leads to edema. The progression of renal disfunctioning starts when glomerular filtration rate is greater than 90ml/min. A large body of evidence indicates that oxidative stress is the main attributor involved in the progression of macro-vascular complications of diabetes. (ROS), NAD(P)H oxidase, advanced glycation end products (AGE), polyol pathway, uncoupled nitric oxide synthase (NOS), mitochondrial respiratory chain via oxidative phosphorylation, protein kinase C, mitogen-activated protein kinases, cytokines and transcription factors eventually cause increased expression of extracellular matrix (EC) genes with progression to fibrosis and end stage renal disease. Apart from these well-established pathways, major markers in the kidney disease which could work as potential targets has been explored like MCP-1, BMP-7, p38 MAPK, MiR-130b, HSP-27, AKT which further needs more research as they have shown promising results in their early level of studies. The present review aims to investigate the molecular targets involved in diabetic nephropathy, and to comprehend the intricate signalling pathways, such as JAK/STAT, BMP-7–Smad1/5/8 pathway, RhoA/ROCK, caspases, to which the aforementioned markers have either an independent or dependent relationship. If these signalling pathways are properly studied, these markers may aid in the treatment of the disease and its associated secondary effects such as nephropathy.
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References
Sagoo MK, Gnudi L. Diabetic Nephropathy: An Overview. Methods Mol Biol. 2020;2067:3-7.
Deferrari G, Repetto M, Calvi C, Ciabattoni M, Rossi C, Robaudo C. Diabetic nephropathy: from micro-to macroalbuminuria. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association-European Renal Association. 1998;13(8):11-5.
Remuzzi G, Schieppati A, Ruggenenti P. Nephropathy in patients with type 2 diabetes. New England J of Med. 2002;346(15):1145-51.
Cheng HT, Xu X, Lim PS, Hung KY. Worldwide epidemiology of diabetes-related end-stage renal disease, 2000–2015. Diabetes Care. 2021;44(1):89-97.
Zeng LF, Xiao Y, Sun L. A glimpse of the mechanisms related to renal fibrosis in diabetic nephropathy. Renal Fibrosis: Mechanisms and Therapies. 2019:49-79.
A Adeshara K, G Diwan A, S Tupe R. Diabetes and complications: cellular signaling pathways, current understanding and targeted therapies. Current drug targets. 2016;17(11):1309-28.
Uwaezuoke SN. The role of novel biomarkers in predicting diabetic nephropathy: a review. Int J of Nephrol and Renovas Dis. 2017;2:221-31.
Deshmane SL, Kremlev S, Amini S, Sawaya BE. Monocyte chemoattractant protein-1 (MCP-1): an overview. J Interf Cytok Res. 2009;29(6):313-26.
Shimizu H, Bolati D, Higashiyama Y, Nishijima F, Shimizu K, Niwa T. Indoxyl sulfate upregulates renal expression of MCP-1 via production of ROS and activation of NF-κB, p53, ERK, and JNK in proximal tubular cells. Life sciences. 2012;90(13):525-30.
Sodhi A, Biswas SK. Monocyte chemoattractant protein-1-induced activation of p42/44 MAPK and c-Jun in murine peritoneal macrophages: a potential pathway for macrophage activation. Journal of interferon & cytokine research. 2002;22(5):517-26.
Tesch GH. MCP-1/CCL2: a new diagnostic marker and therapeutic target for progressive renal injury in diabetic nephropathy. Am J Physiology-Renal Physiol. 2008;294(4):697-701.
Wada T, Furuichi K, Segawa-Takaeda C. MIP-1α and MCP-1 contribute to crescents and interstitial lesions in human crescentic glomerulonephritis. Kidney international. 1999;56(3):995-1003.
Furuichi K, Wada T, Iwata Y. CCR2 signaling contributes to ischemia-reperfusion injury in kidney. J Am Soc Nephrol. 2003;14(10):2503-15.
Cheng J, Encarnacion MM, Warner GM, Gray CE, Nath KA, Grande JP. TGF-β1 stimulates monocyte chemoattractant protein-1 expression in mesangial cells through a phosphodiesterase isoenzyme 4-dependent process. Am J Physiol-Cell Physiol. 2005;289(4):959-70.
Pegorier S, Campbell GA, Kay AB, Lloyd CM. Bone morphogenetic protein (BMP)-4 and BMP-7 regulate differentially transforming growth factor (TGF)-β1 in normal human lung fibroblasts (NHLF). Respiratory Res. 2010;11(1):1-10.
Aluganti Narasimhulu C, Singla DK. The role of bone morphogenetic protein 7 (BMP-7) is inflammation in heart diseases. Cells. 2020;9(2):280.
Sampath KT, Grgurevic L, Vukicevic S. Bone Morphogenetic Protein-7 and Its Role in Acute Kidney Injury and Chronic Kidney Failure. Bone Morphogenetic Proteins: Systems Biology Regulators. 2017:271-91.
Manson SR, Niederhoff RA, Hruska KA, Austin PF. The BMP-7–Smad1/5/8 pathway promotes kidney repair after obstruction induced renal injury. The J Urol. 2011;185(6):2523-30.
Zhang Y, Zhang Q. Bone morphogenetic protein-7 and Gremlin: New emerging therapeutic targets for diabetic nephropathy. Biochemical and biophysical research communications. 2009;383(1):1-3.
Meng XM, Chung AC, Lan HY. Role of the TGF-β/BMP-7/Smad pathways in renal diseases. Clinical science. 2013;124(4):243-54.
Myllarniemi M, Lindholm P, Ryynanen MJ. Gremlin-mediated decrease in bone morphogenetic protein signaling promotes pulmonary fibrosis. Am J Respirat Crit Care Med. 2008;177(3):321-9.
Bierhaus A, Humpert PM, Morcos M. Understanding RAGE, the receptor for advanced glycation end products. J Mol Med. 2005;83:876-86.
Hofmann MA, Drury S, Fu C. RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell. 1999;97(7):889-901.
Brett J, Schmidt AM, Du Yan S. Survey of the distribution of a newly characterized receptor for advanced glycation end products in tissues. Am J Pathol. 1993;143(6):1699.
Senatus LM, Schmidt AM. The AGE-RAGE axis: implications for age-associated arterial diseases. Frontiers in Genetics. 2017;8:187.
Rane MJ, Song Y, Jin S. Interplay between Akt and p38 MAPK pathways in the regulation of renal tubular cell apoptosis associated with diabetic nephropathy. Am J Physiology-Ren Physiol. 2010;298(1):49-61.
Berthier CC, Zhang H, Schin M. Enhanced expression of Janus kinase–signal transducer and activator of transcription pathway members in human diabetic nephropathy. Diabetes. 2009;58(2):469-77.
Haddad JJ, Land SC. Redox/ROS regulation of lipopolysaccharide‐induced mitogen‐activated protein kinase (MAPK) activation and MAPK‐mediated TNF‐α biosynthesis. British J Pharmacol. 2002;135(2):520-36.
Simon AR, Rai U, Fanburg BL, Cochran BH. Activation of the JAK-STAT pathway by reactive oxygen species. Am J Physiology-Cell Phys. 1998;275(6):1640-52.
Ortiz A, Bustos C, Alonso J, et al. Involvement of tumor necrosis factor-alpha in the pathogenesis of experimental and human glomerulonephritis. Advances in Nephrol Necker Hosp. 1995;24:53-77.
Bertani T, Abbate M, Zoja C, et al. Tumor necrosis factor induces glomerular damage in the rabbit. The Am J Pathol. 1989;134(2):419.
Navarro-González JF, Jarque A, Muros M, Mora C, García J. Tumor necrosis factor-α as a therapeutic target for diabetic nephropathy. Cytokine & growth factor Rev. 2009;20(2):165-73.
Quattrocchio G, Roccatello D. IgG4-related nephropathy. J Nephrol. 2016;29(4):487-93
Watanabe T, Yamashita K, Fujikawa S. Involvement of activation of toll‐like receptors and nucleotide‐binding oligomerization domain–like receptors in enhanced IgG4 responses in autoimmune pancreatitis. Arthri Rheum. 2012;64(3):914-24.
Cortazar FB, Stone JH. IgG4-related disease and the kidney. Nature Reviews Nephrol. 2015;11(10):599-609.
Gambardella S, Morano S, Cancelli A. Urinary IgG4: an additional parameter in characterizing patients with incipient diabetic nephropathy. Diabetes Research (Edinburgh, Scotland). 1989 Apr 1;10(4):153-7.
Sedeek M, Callera G, Montezano A. Critical role of Nox4-based NADPH oxidase in glucose-induced oxidative stress in the kidney: implications in type 2 diabetic nephropathy. Am J Physiol-Renal Physiol. 2010;299(6):1348-58.
Ma Y, Shi J, Wang F. MiR‐130b increases fibrosis of HMC cells by regulating the TGF‐β1 pathway in diabetic nephropathy. J Cell Biochemis. 2011;120(3):4044-56.
Devarajan P. Neutrophil gelatinase‐associated lipocalin (NGAL): a new marker of kidney disease. Scandinavian J Clin Labor Invest. 2008;68(241):89-94.
Abbasi F, Moosaie F, Khaloo P. Neutrophil gelatinase-associated lipocalin and retinol-binding protein-4 as biomarkers for diabetic kidney disease. Kidney and Blood Pressure Research. 2020;45(2):222-32.
Nielsen SE, Schjoedt KJ, Astrup AS, et al. Neutrophil Gelatinase‐Associated Lipocalin (NGAL) and Kidney Injury Molecule 1 (KIM1) in patients with diabetic nephropathy: a cross‐sectional study and the effects of lisinopril. Diabetic Medicine. 2010;27(10):1144-50.
Hingorani AD, Sharma P, Jia H, Hopper R, Brown MJ. Blood pressure and the M235T polymorphism of the angiotensinogen gene. Hypertension. 1999;28(5):907-11.
Fogarty DG, Harron JC, Hughes AE, Nevin NC, Doherty CC, Maxwell AP. A molecular variant of angiotensinogen is associated with diabetic nephropathy in IDDM. Diabetes. 1996;45(9):1204-8.
Strutz F, Okada H, Neilson EG. The role of the tubular epithelial cell in renal fibrogenesis. Clinical and experimental nephrology. 2001;5:62-74.
Zakeri SM, Meyer H, Meinhardt G. Effects of trovafloxacin on the IL-1-dependent activation of E-selectin in human endothelial cells in vitro. Immunopharmacology. 2000;48(1):27-34.
Topley NI, Floe.ge JÜ, Wessel KL, et al. Prostaglandin E2 production is synergistically increased in cultured human glomerular mesangial cells by combinations of IL-1 and tumor necrosis factor-alpha 1. J Immunol (Baltimore, Md.: 1950). 1989;143(6):1989-95.
Elmarakby AA, Sullivan JC. Relationship between oxidative stress and inflammatory cytokines in diabetic nephropathy. Cardiovascular therapeutics. 2012;30(1):49-59.
Garrido C, Brunet M, Didelot C, Zermati Y, Schmitt E, Kroemer G. Heat shock proteins 27 and 70: anti-apoptotic proteins with tumorigenic properties. Cell cycle. 2006;5(22):2592-601.
Tikoo K, Meena RL, Kabra DG, Gaikwad AB. Change in post‐translational modifications of histone H3, heat‐shock protein‐27 and MAP kinase p38 expression by curcumin in streptozotocin‐induced type I diabetic nephropathy. Brit J Pharmacol. 2008;153(6):1225-31.
Xu H, Zeng L, Peng H, Chen S, Jones J, Chew TL, et al. HMG-CoA reductase inhibitor simvastatin mitigates VEGF-induced “inside-out” signaling to extracellular matrix by preventing RhoA activation. Am J Physiology-Renal Physiol. 2006;291(5):995-1004.
Kolavennu V, Zeng L, Peng H, Wang Y, Danesh FR. Targeting of RhoA/ROCK signaling ameliorates progression of diabetic nephropathy independent of glucose control. Diabetes. 2008;57(3):714-23.
Huang C, Shen S, Ma Q. Blockade of KCa3. 1 ameliorates renal fibrosis through the TGF-β1/Smad pathway in diabetic mice. Diabetes. 2013;62(8):2923-34.
Huang C, Yi H, Shi Y. KCa3. 1 mediates dysregulation of mitochondrial quality control in diabetic kidney disease. Front Cell Dev Biol. 2021;9:573814.
Huang C, Zhang L, Shi Y. The KCa3. 1 blocker TRAM34 reverses renal damage in a mouse model of established diabetic nephropathy. PLoS One. 2018 Feb 9;13(2):e0192800.
Manson SR, Niederhoff RA, Hruska KA, Austin PF. The BMP-7–Smad1/5/8 pathway promotes kidney repair after obstruction induced renal injury. J Urol. 2011;185(6):2523-30.
Habib HA, Heeba GH, Khalifa MM. Comparative effects of incretin-based therapy on early-onset diabetic nephropathy in rats: Role of TNF-α, TGF-β and c-caspase-3. Life Sci. 2021;278:119624.
Lestarini A, Aryastuti AA, Witari NP. MCP-1 serum levels were higher in patient with diabetic nephropathy among Balinese. Ind J Pub Heal. 2020;11(02):1351.
Tanji N, Markowitz GS, Fu C. Expression of advanced glycation end products and their cellular receptor RAGE in diabetic nephropathy and nondiabetic renal disease. J Am Soc Nephrol. 2000;11(9):1656-66.
Adhikary L, Chow F, Nikolic-Paterson DJ, et al. Abnormal p38 mitogen-activated protein kinase signalling in human and experimental diabetic nephropathy. Diabetologia. 2004;47:1210-22.
Sharma D, Gondaliya P, Tiwari V, Kalia K. Kaempferol attenuates diabetic nephropathy by inhibiting RhoA/Rho-kinase mediated inflammatory signalling. Biomed & Pharmacother. 2019;109:1610-9.