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Fibrosis and loss of functional capillary surface area may contribute to renal tissue hypoxia in a range of kidney diseases. However, there is limited quantitative information on the impact of kidney disease on the barriers to oxygen diffusion from cortical peritubular capillaries (PTCs) to kidney epithelial tubules. Here, we used stereological methods to quantify changes in total cortical PTC length and surface area, PTC length and surface densities, and diffusion distances between PTCs and kidney tubules in adenine-induced kidney injury. After 7 days of oral gavage of adenine (100 mg), plasma creatinine was 3.5-fold greater than in vehicle-treated rats, while total kidney weight was 83% greater. The total length of PTCs was similar in adenine-treated (1.47 ± 0.23 km (mean ± standard deviation)) to vehicle-treated (1.24 ± 0.24 km) rats, as was the surface density of PTCs (0.025 ± 0.002 vs. 0.024 ± 0.004 μm 2 /μm 3 ). The total surface area of PTCs was 69% greater in adenine-treated than vehicle-treated rats. However, the length density of PTCs was 28% less in adenine-treated than vehicle-treated rats. Diffusion distances, from PTCs to the basal membrane of the nearest renal tubule (108%), and to the mid-point of the cytoplasmic height of the nearest tubular epithelial cell (57%), were markedly increased. These findings indicate that, in adenine-induced kidney injury, expansion of the renal cortical interstitium increases the distance required for diffusion of oxygen from PTCs to tubules, rendering the kidney cortex susceptible to hypoxia., (© 2024 The Author(s). The Anatomical Record published by Wiley Periodicals LLC on behalf of American Association for Anatomy.)

Alcohol during pregnancy can impair fetal development and result in offspring with neurodevelopmental deficits. Less is known about how low to moderate alcohol exposure can affect other organs, such as the kidney. Here, the effects of moderate ethanol exposure throughout pregnancy on kidney development were examined using a rat model. Rats were fed a liquid diet containing 6% ethanol (vol/vol) or control (0% ethanol) throughout pregnancy. Kidneys were collected at embryonic day (E) 20 or postnatal day (PN) 30 and total glomerular (nephron) number determined using unbiased stereology. Kidney function was examined in offspring at 8 and 19 months. At E20, fetuses exposed to ethanol had fewer nephrons with increased apoptosis. Alcohol exposure caused kidney dysregulation of pro- (Bax) and anti- (Bcl-2) apoptotic factors, and reduced expression of the cell proliferation marker, Ki67. Prenatal alcohol decreased expression of Gdnf and Tgfb1, important regulators of branching morphogenesis, in male fetuses. At PN30, kidney volume and nephron number were lower in offspring exposed to prenatal alcohol. Urine flow and osmolality were normal in offspring exposed to alcohol however sodium excretion tended to be lower in females prenatally exposed to alcohol. Findings suggest exposure to moderate levels of alcohol during pregnancy results in impaired kidney development and leads to a permanent nephron deficit. Although the impact on adult kidney function was relatively minor, these data highlight that even at moderate levels, alcohol consumption during pregnancy can have deleterious long-term outcomes and should be avoided., (© 2020 American Association for Anatomy.)

In 1998, I was appointed Chair of the Department of Anatomy at Monash University in Melbourne, Australia. On commencing as Chair, I had three main goals: (a) to maintain and extend the high quality of anatomy teaching in the medical program; (b) to introduce significantly more developmental biology, cell biology, and neuroscience into our existing Bachelor of Science major in human anatomy; and (c) to establish an active research program in the department. Over the next 18 years, I worked with staff and students at all levels of the university to turn this vision into a reality, with the Monash Department of Anatomy and Developmental Biology now arguably the top ranked anatomy department in Australia. During my tenure, countless challenges were faced and while some errors were made, and a good number of goals were never realized the general outcome was a vibrant scholarly environment where that rich nexus of research and teaching was realized. This personal account provides some insights into that 18-year journey, which I hope may prove useful for current and future Chairs of anatomy. For me personally, it was definitely a journey worth taking., (© 2020 American Association for Anatomy.)

Two major studies of structural changes associated with aging in human kidneys are reviewed and new information presented. The studies are the Monash University stereologically analyzed series of 319 autopsy kidneys from the United States in which 44% were white and the Mayo Clinic CT angiogram/biopsy analysis of 1,388 US kidney donors in which 97% were white. Hypertension rates in the Monash series were 48% and included moderate and severe hypertension. In the Mayo Clinic study, 12% had mild hypertension. The studies showed no relationship between glomerular number and hypertension except for a weak relationship with older white women in the Monash series. An inverse relationship was present between glomerular number and glomerular volume, a reciprocity that tended to enhance glomerular mass and by inference filtration capacity with lower nephron numbers. This relationship seemed to be present whether low nephron numbers were intrinsic or acquired. In the Mayo Clinic studies, pretransplant iothalamate clearances demonstrated that single nephron (SN) glomerular filtration rates (GFR) were similar throughout the range of glomerular number in subjects younger than 70 years, but that increased SNGFR correlated with nephron hypertrophy and increased nephrosclerosis particularly at 70 years of age and over. Hypertension at least through middle age cannot be related to a deficiency of glomeruli, but glomeruli are lost with later aging in association with adaptive nephron hypertrophy that can maintain GFR near normal. These studies help define an age-related nephropathy that overlaps with hypertension as a potential cause of end-stage renal disease when glomerulosclerosis is advanced., (© 2019 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.)

Fetal hypoxia is a common complication of pregnancy. We have previously reported that maternal hypoxia in late gestation in mice gives rise to male offspring with reduced nephron number, while females have normal nephron number. Male offspring later develop proteinuria and renal pathology, including glomerular pathology, whereas female offspring are unaffected. Given the central role of podocyte depletion in glomerular and renal pathology, we examined whether maternal hypoxia resulted in low podocyte endowment in offspring. Pregnant CD1 mice were allocated at embryonic day 14.5 to normoxic (21% oxygen) or hypoxic (12% oxygen) conditions. At postnatal day 21, kidneys from mice were immersion fixed, and one mid-hilar slice per kidney was immunostained with antibodies directed against p57 and synaptopodin for podocyte identification. Slices were cleared and imaged with a multiphoton microscope for podometric analysis. Male hypoxic offspring had significantly lower birth weight, nephron number, and podocyte endowment than normoxic male offspring (podocyte number; normoxic 62.86 ± 2.26 podocytes per glomerulus, hypoxic 53.38 ± 2.25; p < .01, mean ± SEM). In contrast, hypoxic female offspring had low birth weight but their nephron and podocyte endowment was the same as normoxic female offspring (podocyte number; normoxic 62.38 ± 1.86 podocytes per glomerulus, hypoxic 61.81 ± 1.80; p = .88). To the best of our knowledge, this is the first report of developmentally programmed low podocyte endowment. Given the well-known association between podocyte depletion in adulthood and glomerular pathology, we postulate that podocyte endowment may place offspring at risk of renal disease in adulthood, and explain the greater vulnerability of male offspring., (© 2020 American Association for Anatomy.)

A maternal low protein (LP) diet in rodents often results in low nephron endowment and renal pathophysiology in adult life, with outcomes often differing between male and female offspring. Precisely how a maternal LP diet results in low nephron endowment is unknown. We conducted morphological and molecular studies of branching morphogenesis and nephrogenesis to identify mechanisms and timepoints that might give rise to low nephron endowment. Sprague-Dawley rats were fed a normal protein (19.4% protein, NP) or LP (9% protein) diet for 3 weeks prior to mating and throughout gestation. Embryonic day 14.25 (E14.25) kidneys from males and females were either cultured for 2 days after which branching morphogenesis was quantified, or frozen for gene expression analysis. Real-time PCR was used to quantify expression of key nephrogenesis and branching morphogenesis genes at E14.25 and 17.25. At E17.25, nephron number was determined in fixed tissue. There was no effect of either maternal diet or sex on branching morphogenesis. Nephron number at E17.25 was 14% lower in male and female LP offspring than in NP controls. At E14.25 expression levels of genes involved in branching morphogenesis (Gfrα1, Bmp4, Gdnf) and nephrogenesis (Hnf4a, Pax2, Wnt4) were similar in the dietary groups, but significant differences between sexes were identified. At E17.25, expression of Gfrα1, Gdnf, Bmp4, Pax2 and Six2 was lower in LP offspring than NP offspring, in both male and female offspring. These findings provide new insights into how a LP diet leads to low nephron endowment and renal sexual dimorphism., (© 2020 American Association for Anatomy.)

Genes that regulate renal branching morphogenesis are likely to indirectly regulate nephron endowment, but few have been validated to do so in vivo. PTPN11, which encodes the nonreceptor protein tyrosine phosphatase Shp2, acts downstream of receptor tyrosine kinases to modulate the Ras-MAPK pathway and has been implicated in branching morphogenesis in vitro and in invertebrates, and is therefore a candidate in vivo regulator of nephron number. In this work, heterozygous null mutant Shp2(+/-) mice at postnatal days 30-35 were compared with their wild-type (WT) littermates using unbiased stereology to determine if, indeed, the former had decreased nephron number due to their 50% decrease in gene/protein dosage. Although there was a trend toward decreases in total glomerular (nephron) number and kidney volume in Shp2(+/-) mice compared with WT, neither difference was statistically significant (11310 vs. 12198 glomeruli, P = 0.22; 62.8 mm(3) vs. 66.0 mm(3) renal volume; P = 0.40). We conclude that loss of 50% gene/protein dosage of PTPN11/Shp2 is insufficient to affect glomerular (and thereby nephron) number in mouse kidneys in vivo., (Copyright © 2010 Wiley-Liss, Inc.)

We have shown that fetuses whose mothers underwent subtotal nephrectomy (STNx) before pregnancy had high urine flow rates and sodium excretions, but lower hematocrits, plasma chloride, and plasma renin levels compared with controls. To see if these functional differences in utero persist after birth and are the result of altered renal development, we studied 8 lambs born to STNx mothers (STNxL) and 10 controls (ConL) in the second week of life. These lambs were of similar body weights, nose-rump lengths and abdominal girths. Their kidney weights were not different (ConL 36.1 +/- 1.9 vs. STNxL 39.8 +/- 3.3 g), nor were kidney dimensions or glomerular number (ConL 423,520 +/- 22,194 vs. STNxL 429,530 +/- 27,471 glomeruli). However, STNxL had 30% larger glomerular volumes (both mean and total, P < 0.01) and there was a positive relationship between total glomerular volume and urinary protein excretion (P < 0.05) in STNxL. Despite this change in glomerular morphology, glomerular filtration rate, tubular function, urine flow, and sodium excretion rates were not different between STNxL and ConL, nor were plasma electrolytes, osmolality, and plasma renin levels. Thus while many of the functional differences seen in late gestation were not present at 1-2 weeks after birth, the alteration in glomerular size and its relationship to protein excretion suggests that exposure to this altered intrauterine environment may predispose offspring of mothers with renal dysfunction to renal disease in adult life.