**5. Effects of inhibition of nitric oxide on fetal renal developmental in animal models**

The fetal kidney appears to be extremely vulnerable to the effects of growth retardation. Studies on human infants with growth retardation indicate that the kidneys are disproportionately affected relative to other organs [49].

One study noted that maternal hypertension during pregnancy results in reduced birth weight and a decreased area and number of glomeruli [50]. Certainly, there is a link between maternal environmental factors, particularly nitric oxide inhibition, and the development of hypertension in adulthood.

Some models of arterial hypertension have been studied in animals in order to detect imbalances in fetal development, including protein restriction, excessive sodium intake, impaired uterine or placental circulation, blockade of the reninangiotensin system (RAS), and increased exposure to maternal glucocorticoids, all of them leading to hypertension in offspring [51–54].

Experimental studies indicate that fetal exposure to an adverse maternal environment may reduce glomerular filtration rate by decreasing the surface area of the glomerular capillaries. In addition, fetal responses to environmental insults, such as maternal hypertension, may contribute to the development of hypertension early in life, including increased expression of apical or basolateral tubular Na<sup>+</sup> carriers and increased production of renal superoxide leading to reabsorption which increased Na<sup>+</sup> [55].

Reductions in NO synthesis decrease renal sodium excretory function, not only through direct action on the renal vasculature but also through modulation of other vasoconstrictor processes and through direct and indirect alterations in tubular sodium transport [56].

Moreover, environmental factors of intrauterine life may worsen the prognosis of offspring hypertension, at least in part, by determining the number of nephrons. The reduced number and size of nephrons may also predispose the individual to the development of progressive renal disease [54, 57].

### *Complications of Pregnancy*

Kidneys with lower numbers of nephrons maintain their hemodynamic and excretory functions by increasing local vascular resistance and glomerular pressure. The increase in glomerular pressure within the nephrons can trigger a cascade leading to progressive deterioration and loss of nephrons [56].

 Nitric oxide is produced within the kidney and plays an important role in the control of many intrarenal processes. NO contributes to the regulation of sodium excretion and thus maintenance of vascular volume and arterial pressure in the adult [50]. Studies have shown that certain animal models of genetic hypertension and forms of human hypertension are associated with a decrease in NO synthesis [58].

The deficient production of NO in the intrauterine period is associated with a reduction in the mass and number of nephrons in the initial period of life. NO is involved in maturation and renal function in the postnatal period [50].

Inhibition of NO synthesis during gestation in rats treated with L-NAME promoted structural changes of the renal microvessels (thickening of the media) in newborns. The remodeling of the microvasculature of the kidneys of the newborns can be involved with adaptive responses to maternal arterial hypertension, activation of local/systemic of RAS in newborns, and enhanced synthesis of peptide growth factors, such as platelet-derived growth factor, which promote smooth muscle cell hyperplasia of the microvasculature [59–61].

Spontaneously hypertensive rats (SHR) at 2 days of age also showed an increase in the area and in the media/lumen ratio of the renal microvasculature due to hypertrophy or hyperplasia of the media layer. Hypertrophy and polyploidy are preferentially found in conduit arterioles, whereas hyperplasia and remodeling are found mainly in small arteries and arterioles [62].

Pups of spontaneously hypertensive rats (SHR) had significantly higher concentrations of renin than Wistar-Kyoto pups from birth until the beginning of the third postnatal week [63] as well as increased expression of angiotensinogen mRNA [64].

The elevated renin concentration of the SHR is linked to increased renal vascular resistance and thus to a reduced renal blood flow and glomerular filtration rate [65]. Also, it appears that sustained activity of the renin-angiotensin system may be required for exaggerated vascular growth responses in SHR [66].

Intrauterine growth restriction by nitric oxide inhibition during pregnancy is associated with a decrease in the number and size glomeruli and microvascular remodeling. Therefore, the nitric oxide inhibition during pregnancy may be linked to structural changes in the kidney which potentially lead to hypertension in later life [54].

Therefore, individuals born after intrauterine growth restriction, such as the L-NAME-induced hypertension model in rats, are at increased risk for kidney and heart morbidities. Endothelial dysfunction, with inhibition of NO synthesis, increases oxidative stress, dysfunction of endothelial progenitor cells, and accelerated vascular aging. L-arginine supplementation and treatment with NO modulators represent promising strategies to improve endothelial function and mitigate long-term outcomes and possibly vascular problems in newborns that have undergone growth restriction during maternal hypertension [67].

### **6. Conclusions**

The inhibition of nitric oxide synthesis during pregnancy promotes changes in the renal and cardiac microvasculature and, in addition, reduction in the number of fetal nephrons, leading to hypertension in the adult life of rat pups and, potentially, in humans. In this sense, the effects of preeclampsia for the mother and the fetus should be considered.

*Maternal and Fetal Complications Due to Decreased Nitric Oxide Synthesis during Gestation DOI: http://dx.doi.org/10.5772/intechopen.85383* 
