Update on the role of Angiogenesis in Diabetes associated Nephropathy

Munish Kakkar¹, Shreeja Singh¹, Tapan Behl¹*, Sukhbir Singh¹, Neelam Sharma¹,

Hema¹, Monika Sachdeva²

¹Chitkara College of Pharmacy, Chitkara University, Punjab, India.

²Fatima College of Health Sciences, Alain, UAE.

*Corresponding Author E-mail: tapan.behl@chitkara.edu.in

ABSTRACT:

Diabetic mellitus is common worldwide health problem which brings about different rigorous complications like retinopathy, nephropathy and numerous other lethal complications. Diabetic nephropathy is the major cause for blindness and renal failure in many of the developing countries. Hyperglycemia induced diabetic nephropathy gets elicited through improved development of reactive oxygen species in multiple cell types. The starting of organ damage or kidney failure shows some symptomatic effect or morphological changes as in one or both the kidneys like expansion or enlargement of kidneys from their original size and this enlargement process is known as nephromegaly. Microalbuminuria is the best possible predictable condition proceeding towards renal failure. This review briefly discussed about the diabetic nephropathy with regard to progression, angiogenic and non-angiogenic factors involved in pathogenesis and treatment of angiogenesis in diabetic nephropathy.

KEYWORDS: Angiogenesis, Diabetic mellitus, Diabetic nephropathy, Enlargement, Nephromegaly.

INTRODUCTION:

Diabetes mellitus (DM) is one of the most common and leading disorder which is a lifetime disorder which is not curable fully. This disorder ultimately leads to renal failure¹. DM is a health problem in which the glucose consumed from the diet is the source of energy for the cells in which the insulin released from the pancreas help in maintaining the blood glucose level hence this condition occurs only when there is no insulin produced from the pancreatic cells or not used properly after sometime the glucose starts accumulating or the sugar level increases in the blood because it is not reaching the cells for the utilization^2,3. DM is categorized as type-1 and type-2. Diabetic kidney disease which basically involves the distortion of the kidney functions and mostly diabetic nephropathy (DN) is seen in chronic type-1 and type-2 diabetes. There are various diabetes associated complications named as micro-vascular like diabetic nephropathy, diabetic neuropathy, and diabetic retinopathy,^4-7 and macro-vascular complications like coronary heart disease, and hypertension^8-11.

Diabetic Nephropathy:

Increase in blood sugar level for a short span of time do not result in severe complications or any type of damage but if this condition persists for a very long time, then it leads to clinical complications and further leads to organ damage. Diabetic nephropathy (DN) leads to renal failure which leads to various severe complications named as retinopathy nephropathy and many more lethal complications. The starting of organ damage or kidney failure shows some symptomatic effect or morphological changes as in one or both the kidneys gets expanded or enlarged which differ from the original size of the kidneys and this enlargement process is known as nephromegaly. DN is detected by testing the urine sample if urine albumin is detected which is a sign of glomerular damage only then albumin can be seen in urine in a diabetic patient diabetic nephropathy is determined by proteinuria. This includes various changes in the kidney such as the thickening of basement membrane¹². DN is generally depicted by hyper-filtration, increased leakiness of blood vessels, changes in basement membrane of capillaries and mesangial proliferation¹³. Various growth factors like vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β), platelet-derived growth factor (PDGF) and enzyme (heparinase) are responsible for the pathology of diabetic nephropathy^4,14.

Progression of Diabetic Nephropathy:

Developed diseased condition includes thickening of basement membrane, mesangial matrix gets extended, arteriolar hyalinosis and sclerosis^9,15. DN led by hyperglycemia has been triggered by enhanced formation of reactive oxygen species (ROS) in multiple cell types incorporating cells of mesangium and podocytes¹⁶. ROS further leads to an increased activity of profibrotic molecules¹⁷. Connective tissue growth factor (CTGF) and TGF-β are responsible in the accumulation of extracellular matrix^18-20. Increased glucose level also enhances formation of advanced glycation end products (AGE) of extracellular matrix constituents in the cells of mesangium and in the basement membrane leads to the alteration of porosity of filtration barrier²¹.

Figure 1. Common elements involved in the progression of diabetic nephropathy.

The mechanism behind synthesis of abnormal blood vessels in diabetic nephropathy is not known yet^18,19. Most probable reason could be the disturbance in equilibrium between angiogenesis supporting elements as well as inhibiting elements which leads to disturbed vascular permeability and ontogenesis and therefore, progression of diabetes^5,20. In reference to this, enhanced visibility of supporting factors in angiogenesis and low visibility of anti-angiogenic factors present on surface of glomerulus in diabetic patients^21,22. The most important angiogenic and non-angiogenic factors included in the pathogenesis of diabetic kidney disease are shown in Figure 1²³.

Angiogenesis:

The blood vessels start forming same type of new blood vessels, this condition is known as angiogenesis [24]. Major factor responsible for both physiological and pathological conditions involves diabetes, menstruation, tumor growth, embryonic development and wound healing²⁵. Angiogenesis occurs or take shape in 4 different steps in diabetic patients which is executed with the help of endothelial cells and these steps occurs independently as depicted below²⁶.

· Separation from the basement membranes,

· Migration of cells and then further

· Proliferation or growth occurs and then

· Maturation of cells takes place.

But these events take place with the help of some factors named as proangiogenic and anti-angiogenic factors²⁷. Angiogenic factors basically increases the vascularity or the space between the plasma membranes and in between blood vessels as well because of which the blood vessels named as leaky²⁸. Cytokines growth element is the major one.

Pro-angiogenic factors:

There are some soluble growth factors which are VEGF, and angiopoietins (Angiopoietin 1 and Angiopoietin 2) which are the best growth factors responsible for angiogenesis²⁹. The cytokine growth element consists of four family members VEGFA, VEGFB, VEGFC, VEGF-C, and VEGFD. VEGF-A is the most dominant growth factor in the early stages containing at least 8 isoforms³⁰. Cytokine growth element recognized as a vascular permeability constituent due to the capability of inducing distortion in vessels making them leaky³¹. The mechanism of action involves binding with 3 receptors exclusively visible on the surface of membrane i.e. VEGF receptor 1 (VEGFR1, Flt-1), VEGF receptor 2 (VEGFR2, Flk-1), and VEGF receptor 3 (VEGFR3)^30-33. VEGF is the most important angiogenic factor and its increased regulation is often observed in diseased conditions like cancer, diabetes, rheumatoid arthritis. The up-regulated VEGF formation together with increased endothelial cell motility, proliferation and synthesis of underdeveloped vessels recognized by leakiness and low vascular resistance^33,34.

Role of VEGF in ontogenesis:

Most potent cytokine vascular endothelial growth factor is VEGF-A but it shows haploid insufficiency due to which inactivation of genes occurs further resulting in embryonic fatality^34,35. There is an important function of VEGF-A in vasculogenesis and ontogenesis. This potent factor has various functions but it solely promotes angiogenesis by triggering, differentiation and movement of endothelial cells³⁶. It also has chemotactic activity as well as vascular permeability activity. There are different isoforms of VEGF-A for example, VEGF-A₁₂₁, VEGF-A1₁₆₅, VEGF-A₁₈₉, VEGF-A₂₀₆, and VEGF-A_165b. VEGF-A attaches to and stimulates the tyrosine kinase receptors VEGFR1 (Flt-1), VEGFR2 (Flk-1). In comparison to VEGFR2, VEGF-A can bind to VEGFR1 very easily due to its excellent affinity towards VEGFR1 ³⁷. On the other hand, VEGFR2 is more susceptible tyrosine kinase and shows high activity. Angiogenic impulse is mainly produced from VEGF-A bound to VEGFR2. VEGF-A has various functions and one of the most important function it is not only maintains the glomerular structure but also helps in healing endothelial wounds³⁸. In developed kidneys there should be a balanced VEGF-A, both too much or too little can lead to various renal complications³⁸ (Figure 2).

Figure 2. Observed changes of glomerulus linked with excessive or insufficient VEGF-A

Angiopoietins

They belong to a family of at least 4 members, named as Angiopoietin 1 and angiopoietin 2³⁹. They are very dominant factors can be named as the angiogenesis supporting element in the early stages⁴⁰. Angiopoietin 1 and Angiopoietin 2 show its mechanism by getting attached to the attaching site having the most binding affinity to the same receptor Tie-2^41,42. This receptor is exclusively shown at the membrane of endothelial cells. In spite of getting attached to the same receptor, both the angiopoietins exert totally opposite effects on function of endothelial cells⁴³.

· Angiopoietin 1: Its mechanism of action occurs by stimulating Tie-2 which further enhances vessel maturation quiescence and decreased leakage. It promotes endothelial cell binding and its dispersion. Hence leads to the formation of various focal contacts^41,44.

· Angiopoietin 2: It stops the function of Angiopoietin 1 (Tie-2 stimulation) which leads to an increase in angiogenesis, leakage and vessel instability. It increases endothelial cell movement and tubulogenesis^44-46.

Both Angiopoietin 1 and Angiopoietin 2 are different from vascular endothelial growth factor and they are actually not recognized as true angiogenic factors due to the reason that they are not capable of stimulating angiogenic actions by themselves, instead they enhances or decreases the VEGF cell function⁴⁵. The VEGF formation along with an increased Angiopoietin 2 with no change in Angiopoietin 1 levels leads to angiogenesis in diabetes⁴⁷.

Anti-angiogenic factors:

For the sustenance and maintenance between the over or less production of blood vessels there are various prohibition pathways as well as inhibition factors of angiogenesis called as antiangiogenic factors^48,49. They are further classified into two main categories:

· Proteolytic fragments: The derived fragments from the extra cellular matrix and the plasaminogen basically inhibit the production of new vasculature or angiogenesis by inhibiting the cell movement, proliferation and tubulogenesis⁵⁰.

· Gene product: In contrary to this gene products inhibits do not play a specific function in management of ontogenesis⁵¹. Like in thromospondin-1 and pigment epithelium derived factor (PEDF) are the major factors which inhibit angiogenesis in normal and diseased condition but enhance the endothelial cell death⁵². PEDF is mainly responsible for maturation and differentiation of neuronal cell, safeguarding neurons from the toxicity caused by neurotoxic agents and majorly inhibition of angiogenesis⁵³.

Role of proangiogenic elements in diabetic nephropathy:

In the entire pro-ontogenic component, vascular endothelial growth element very important, potent permeability element gets increased in this diabetic condition⁵⁴. It is formed or synthesized from the podocytes present in the glomerulus in the early stages⁵⁵. Due to diabetic conditions the level of glucose increases which leads to increase VEGF synthesis in podocytes as well as tubular cells⁵⁶. In recent diagnosis, many of the patients expressed increased levels of VEGF along with increased VEGF receptors activated in mildly injured glomeruli⁵⁷. It was along with the increase in endothelial cell proliferation, which concludes that the angiogenic cytokine growth element causes activation in diseased humans which do not severe diabetic conditions or mildly affected with diabetes the renal functions may be changed and enhancement of glomerular angiogenesis is seen⁵⁸. The genetic makeup of vascular endothelial growth factor in association with glomerular angiogenesis in human diabetic nephropathy and patients with appearance of type-2 diabetic condition expresses the elevation in the level of VEGF121 isoform⁵⁹. On the other hand, the true mechanism of VEGF contribution towards blood vessel damage in glomerulus is unknown. For maintaining glomerular capillary cells, it is needed to initiate, conduct the required actions⁶⁰. In contrary to this, the podocyte specific VEGF164 isoform moves towards the destruction of glomerulus. Reason of elevated VEGF synthesis in diabetes is still suspicious⁶¹. The known pathways due to which the glucose level increases are protein kinase C, ROS and AGEs. They expressed an increase in VEGF synthesis in both portions glomerular and non-glomerular constituents⁶². As stated earlier, Angiopoietin 1 and Angiopoietin 2 together belongs to proangiogenic and antiangiogenic molecules and hence shows their all cell functions by getting attached to a receptor named Tie-2⁶³. In the early stage of kidney development both Angiopoietin 1 and Angiopoietin 2 and Tie-2 are very much recognized and they have crucial character in the development, differentiation, maturation of glomeruli and renal vasculature^54,64. Angiopoietin 2 supports formation of new vasculature from the existing ones as well as the formation of damaged vessels having leakage and Angiopoietin 1 promotes the stability of cell and a marked decrease in leaky vessels. Both these factors, also known as angiogenesis associated factors in the development of diabetic kidney disease^50,55,60.

Role of inhibiting elements in diabetic nephropathy

The factor involved PEDF is observed in both retinal and renal vasculature problems⁶⁵. In contrary to this, there is an opposite relationship between pigment endothelial derived factor and vascular endothelial derived factor together shows pathological, physiological responses in formation of new blood vessels⁶⁶. Because of diabetic condition hence leads to advanced glycation end products lowers pigment endothelial derived factor formation in mesangial cells as well as in the cells present in endothelium⁶⁷. Function of PEDF is to protect high glucose level which further leads to uncontrolled expression of profibrotic factor TGF-β. Both these statements conclude that low levels of PEDF in diabetic patients leads to overproduction or increased development growth of new blood vessels and continuous progression of (DN)^67,68.

Remedy of Angiogenesis in Diabetic Nephropathy:

Pathology of diabetic nephropathy involves microvascular as well as macrovascular complications so new methods of prevention to these complications should be discovered⁷⁰. It is mentioned previously, excessive appearance of elements involved in promoting angiogenesis, low appearance of inhibiting elements of angiogenesis, high blood pressure, hyperglycemia mediated advanced glycation end products synthesis depicts main components of diabetes initiates destruction of vasculature^69,71. Hence, change in the activity of these mediators can be one of the beneficial and strong solutions for treatment and protection of glomerular vascular problems present in diabetes type-1 and type-2 ⁷².

Renin-angiotensin-aldosterone system (RAAS) in diabetic nephropathy:

This system has a crucial function during the growth of diabetic kidney disease by inhibiting the mechanism, the most efficient preventive strategy applied for stopping the progression of this process⁷³. There are proofs present by various multiple large trials which depicts interrupting the RAAS lowers the development of DN and overall proteinuria^74,75. It is suggested for initiating firstly changing the hemodynamics of glomerulus which leads to lowering of intraglomerular pressure^74,76. There is new proof proposing that the RAAS might lead to diabetes initiated vascular damage by altering cell functions of glomerular endothelial^77-79. In reference to this, angiotensin II provides development to the vasculature in glomerulus and supporting leaky vessels by promoting formation of potent cytokine VEGF by podocytes^56,80. Other fascinating process presently observed in tumor angiogenesis is that angiotensin II could enhance the movement of endothelial cells and tubulogenesis. Thus directly supporting the pathology of angiogenesis^78,81.

Obstructing traditional pro-angiogenic factors:

Diabetic patients have been most commonly examined with an encouraged expression of factors supporting angiogenesis and their binding sites⁸². The reason being some of these factors mainly contribute or involved in glomerular vascular damage by enhancing the proliferation of basement membrane of endothelial cells. A large amount of data was collected after the studies were done to hinder these processes in various animal models of diabetes⁸³. The type-1 diabetic rats were administered with ani-VEGF antibodies. The results expressed decline in hyperfiltration, albuminuria and increased cell number in glomerulus⁸⁴. Cytokine growth element obstruction protected with increment in enzyme of endothelium nitric oxide synthase appearance in the cells of glomerular capillary which proposed that the therapy which could be efficient is anti-vascular endothelial growth element therapy in prevention in early stages starting vascular damage in diabetic nephropathy^85-87. Likewise, anti-VEGF treatment stopped the increased weight of kidney and glomerular volume of diabetic mouse. This anti-VEGF therapy has a great potential and potent effect on animals with diabetes but it is not of clinical use in humans yet therefore it becomes difficult to actually know the potency⁸⁸. However, when this treatment was applied for colorectal cancer there were various side effects, involving high blood pressure, blood loss at various intervals, clotting events and proteinuria were noted concluding that this therapy or these antibodies will be hard to take by the patients having DN^78,85.

Promoting the synthesis of elements inhibiting angiogenesis:

Reduced visibility of anti-angiogenic factors comprising pigment endothelial derived factor, non-ECM and ECM breakage products has been noted in DN proposing that incorporation of these anti-angiogenic factors could be efficient in the treating DN⁸⁹. There were studies done some rats were induced with streptozotocin in kidneys and showed decreased levels of anti-angiogenic PEDF^80,84. PEDF lowers the synthesis of sugar stimulates transforming growth factor beta produced by cells present in the mesangium. The rats having diabetes were administered with a different virus named adenovirus which expresses pigment endothelial derived growth factor to check its after actions on DN. Due to increased appearance of renal PEDF specifically promote microalbuminuria in the initial phase of kidney disease and decreases the action of profibrotic agents TGF-β and CTGF. These observations concluded that the appearance of plasma endothelial derived growth factor is beneficial in a rat model of DN^87,88

Obstructing AGEs and their receptors:

Advanced glycation end products could be proteins or lipids that are non-enzymatically glycated coming in touch with polsaccharides^80,84. Encouraged glycation end products are widespread in diseased vasculature and lead to micro and macro vascular complications because of formation of cross-linking between the molecules in the extracellular matrix^75,80. In support to this, they changed the cell functioning by interaction with receptor for advanced glycation end products (RAGE) receptors. In the endothelium, promotes glycation end products are responsible for the production of ROS and also responsible for regulating the appearance of both growth elements^89,85. Instead identification and subtracting effects on the pharmacological treatment of diabetes present for type-1 and type-2 diabetic patients are not diagnosed directly with an excess deposition of advanced glycation end products^56,78. Various studies were performed on animal models having diseased condition proposed that protecting AGE production or hindering their actions of cell would be an efficient treatment in the regression of DN. Both progression and mortality of DN were specifically decreased with these single treatments^89-91. If given in combination, these therapies would definitely be effective in treating diabetic nephropathy.

CONCLUSION:

Diabetic nephropathy is specifically related to a medical problem and its increased incidence shows the fatality, mortality and morbidity which is noted. The most important pathogenic mechanism for diabetic kidney disease is abnormal blood vessel synthesis. This review focuses on the main factors which supports or inhibits angiogenesis possibly alter vasculature of glomerulus thus leading to its damage in the presence of type-1 and type-2 diabetes. The role of angiogenesis in diabetes can be understood properly by understanding the progression of successful inhibitors to this process because prohibition in RAAS is the only treatment present to deaccelerate successive increase of this non curable disease. By emphasizing the pathogenesis of abnormal angiogenesis of diabetic nephropathy could be seen as a valid tool for the reduction, stoppage of fatality, mortality linked with this disease.

ACKNOWLEDGEMENT:

The authors are thankful to Chitkara College of Pharmacy, Chitkara University, Punjab, India for providing support for compilation of this review.

CONFLICTS OF INTEREST:

The authors declare no conflict of interest.

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Received on 09.01.2020           Modified on 27.11.2020

Accepted on 19.05.2021         © RJPT All right reserved

Research J. Pharm. and Tech. 2021; 14(7):3947-3954.

DOI: 10.52711/0974-360X.2021.00685