Sex‐dependent Impairment of Renal Microvascular Function in the Pkhd1pck Rat Model of ARPKD
Authors: Inscho Edward W. , Mrug Michal , Cook Anthony K. , Kesterson Robert A. , Pollock David M , Yoder Bradley K. 
Published: November 2023

Renal dysfunction in polycystic kidney disease (PKD) has received considerable attention from the stand point of cystogenesis and reduced renal function. Little attention has been directed toward renal microvascular function in PKD. We performed experiments on three groups of animals to define renal microvascular autoregulatory capability of male and female 8–10 week old Pkhd1pck rats, a model of autosomal recessive PKD (ARPKD) compared to aged‐matched male Sprague Dawley (SD) rats which are the genetic controls for the Pkhd1pck rat. Experiments were performed in vitro using the blood perfused juxtamedullary nephron technique and rats were fed a normal salt diet (0.4% NaCl). The blood perfusate was collected from the kidney donor rat and an identically prepared blood donor rat that was either an age‐matched Pkhd1pck rat or normal SD control rat as appropriate. Baseline arteriole diameters at 100 mmHg were similar across the three groups and averaged 15.2±1.2, 15.6±0.6 and 16.2±0.3 μm. Normal SD control rats (n=6) exhibited highly efficient autoregulatory behavior as arteriole diameter increased to 112±2% of control when perfusion pressure was reduced from 100 mmHg to 65 mmHg. Diameter then decreased to 69±6% of control when perfusion pressure was increased to 170 mmHg. Responses in male (n=7) or female (n=7) Pkhd1pck rats were significantly blunted compared to SD controls (P<0.05). Reducing perfusion pressure from 100 to 65 mmHg resulted in no detectable increase in diameter. When perfusion pressure was increased to 170 mmHg, diameter only decreased to 87±2 and 88±2 % of control in male and female Pkhd1pck rats, respectively. We also examined the impact of ARPKD on afferent arteriolar reactivity to UTP. UTP was selected because P2Y2 receptor expression is markedly increased in cystic rat kidneys compared to normal SD rats. Afferent arteriole reactivity to P2Y2 receptor activation with UTP was determined in normal SD control and Pkhd1pck rats. In the SD controls (n=5), increasing concentrations of UTP from 10−8M to 10−4M evoked a pronounced afferent arteriole vasoconstriction, decreasing diameter to 42±2% of control. When repeated in male (n=7) and female (n=7) Pkhd1pck rats, we observed marked sex‐dependent differences. Female Pkhd1pck rats exhibited responses that were similar to normal male SD controls (41±1% of control) whereas arterioles in kidneys from age‐matched male Pkhd1pck rats exhibited a significantly (P<0.05 vs SD) blunted UTP‐mediated vasoconstriction with afferent arteriole diameter decreasing to just 77±6% of control compared to control and female Pkhd1pck rats. Taken together, these data demonstrate that afferent arteriolar autoregulatory behavior is impaired in Pkhd1pck kidneys along with sex‐dependent reactivity to P2Y2 signaling. These findings suggest important functional deficiencies renal microvascular control and may reveal potential P2 receptor signaling defects in ARPKD that may contribute to hypertension, glomerular damage and renal injury.

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DK44628, HL098135, HL095499, DK056957, DK097423, BX00298, DK065655, DK074038