Endothelial dysfunction as a potential contributor in diabetic nephropathy

Abstract

The mechanisms that drive the development of diabetic nephropathy remain undetermined. Only 30-40% of patients with diabetes mellitus develop overt nephropathy, which suggests that other contributing factors besides the diabetic state are required for the progression of diabetic nephropathy. Endothelial dysfunction is associated with human diabetic nephropathy and retinopathy, and advanced diabetic glomerulopathy often exhibits thrombotic microangiopathy, including glomerular capillary microaneurysms and mesangiolysis, which are typical manifestations of endothelial dysfunction in the glomerulus. Likewise, diabetic mice with severe endothelial dysfunction owing to deficiency of endothelial nitric oxide synthase develop progressive nephropathy and retinopathy similar to the advanced lesions observed in humans with diabetes mellitus. Additionally, inhibitors of the renin-angiotensin system fail to be renoprotective in some individuals with diabetic nephropathy (due in part to aldosterone breakthrough) and in some mouse models of the disease. In this Review, we discuss the clinical and experimental evidence that supports a role for endothelial nitric oxide deficiency and subsequent endothelial dysfunction in the progression of diabetic nephropathy and retinopathy. If endothelial dysfunction is the key factor required for diabetic nephropathy, then agents that improve endothelial function or raise intraglomerular nitric oxide level could be beneficial in the treatment of diabetic nephropathy.

Figure 1

Factors that contribute to the development of endothelial dysfunction in patients with diabetes. Factors including reactive oxygen species, eNOS inactivation and uric acid contribute to a reduction in the levels of nitric oxide in the endothelium, which in turn leads to endothelial dysfunction. Abbreviation: eNOS, endothelial nitric oxide synthase.

Figure 2

Development of acellular capillaries in the retina of diabetic eNOS-knockout mice. a | Representative images of retinal vessels from nondiabetic wild-type (WT nondiabetic) and diabetic wild-type (WT diabetic) mice 6 months after onset of diabetes treatment, and nondiabetic eNOS-knockout (eNOS^−/− nondiabetic) and diabetic eNOS-knockout (eNOS^−/− diabetic) mice 4 months after onset of diabetes. The arrows indicate the presence of acellular capillaries in diabetic eNOS-knockout mice. b | Quantitative measurements of acellular capillaries in the various mice. Abbreviations: eNOS, endothelial nitric oxide synthase; W T, wild-type C57BL/6 mice. Permission obtained from Investigative Ophthalmology & visual Science © Li, Q. et al. Invest. Ophthalmol. Vis. Sci. 51, 5240–5246 (2010).

Figure 3

Potential mechanisms by which endothelial nitric oxide deficiency causes advanced renal injury in diabetes. A number of mechanisms contribute to the development of diabetic nephropathy in patients with diabetes. Changes to the production of the mesangial matrix, loss of endothelial nitric oxide and upregulation of VEGF ultimately lead to advanced glomerular injury and tubulointerstitial damage. Abbreviations: VEGF, vascular endothelial growth factor; VWF, von Willebrand factor; WPB, Weibel–Palade bodies.

Figure 4

Proposed mechanism by which aldosterone causes renal injury and hypertension in diabetes independent of angiotensin II. According to data from studies in eNOS-knockout mouse, eNOS deficiency in combination with diabetes leads to angiotensin-II-independent increases in aldosterone levels, which in turn contributes to renal injury and hypertension. The aldosterone antagonist spironolactone is able to prevent renal injury and hypertension by blocking angiotensin-II-independent and angiotensin-II-dependent aldosterone action while enalapril (an ACE inhibitor) and telmisartan (an angiotensin-receptor blocker) are able to prevent angiotensin-II-dependent renal injury and hypertension. Abbreviations: ACE, angiotensin-converting enzyme; eNOS, endothelial nitric oxide synthase.