Roles of Insulin Receptor Substrates (IRS) in renal function and renal hemodynamics.

Abstract

We have reported previously that renal hemodynamic abnormalities exist in the prediabetic stage of type II diabetic rats. At this stage these rats have insulin resistance. It is well known that insulin resistance is frequently associated with renal abnormalities, but the mechanism underlying this association has remained speculative. Although insulin is known to modify renal hemodynamics, little is known about the roles of insulin receptor substrates (IRS1, IRS2) in the renal actions of insulin. To address this issue, we investigated in wild type (WT), IRS1‐deficient (IRS1‐/‐), and IRS2‐deficient (IRS2‐/‐) mice. IRS2‐/‐ mice had elevated blood pressure and glucose level as expected. 24‐h urine collections revealed that creatinine clearance did not significantly differ between these groups. Fractional excretion of sodium was significantly lower in IRS1‐/‐ and IRS2‐/‐ compared to WT mice. Albuminuria was found in IRS1‐/‐ and IRS2‐/‐ groups. We assessed autoregulatory responses of total renal blood flow (RBF), and of superficial (SBF) and deep renal cortical blood flow (DBF) to stepwise reductions of renal perfusion pressure (RPP) induced by a manual clamp on the abdominal aorta. RBF, SBF and DBF fell significantly more in IRS1‐/‐ and IRS2‐/‐ than in WT mice. These results indicate that IRS plays a major role in the stimulation of renal functions and renal hemodynamics in type II diabetes.

Reduced insulin signaling and high glucagon in early insulin resistance impaired fast‐fed regulation of renal gluconeogenesis via insulin receptor substrate

“…To further determine the associated link, we studied the IRS1 and IRS2, the key insulin signaling targets. IRSs are required for hormonal control of glucose metabolism, and their deregulations have been linked to insulin resistance and diabetes 14,15,35,36 . Whether reduced insulin receptor signaling would affect the expression of these IRS genes in the hPT was not explored.…”

“…Efforts have been made to clarify the role of insulin receptor expression and its primary downstream targets, insulin receptor substrates (IRS) (type 1 and type 2), in gluconeogenesis in physiological and pathological conditions. Deletion of IRS proteins has been shown to negatively impact renal function and hemodynamics 14–16 . Systemic or tissue‐specific Knockdown of IRS1 and IRS2 suggested their physiological importance in different tissues, including the kidney.…”

“…Systemic or tissue‐specific Knockdown of IRS1 and IRS2 suggested their physiological importance in different tissues, including the kidney. Renal‐specific deletion of IRS2 was found to elevate glucose levels in mice, while PT‐specific IRS1/2 double knockout mice resulted in impaired insulin signaling and upregulated gluconeogenic enzyme expression 14,17,18 . Moreover, Nakamura 2020, reported that Insulin promotes sodium transport but suppresses gluconeogenesis via IRS1 mediated signaling in human and rat renal PT 19 .…”

Pioglitazone in diabetic kidney disease: forgotten but not gone

“…Its activity to modify Ang II induced renal haemodynamic responses was associated with downregulation of the number and expression of renal AT 1 R receptors [81]. Moreover, studies in insulin receptor substrate (IRS)-1 and IRS-2 knockout mice suggested suppressed kidney autoregulatory function at lowered perfusion pressure levels; they proposed the possible involvement of IRSs in renal haemodynamic abnormalities found in diabetes [82,83]. This phenomenon was more con-spicuous in the deep renal layer compared to the superficial layer.…”